Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases and epidemiology Module № Infectious diseases and epidemiology Topic Acute respiratory viral . Clinical characteristics and prevention of influenza. Course 4 Faculty Stomatological Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. Infectious diseases today remain extremely relevant. In the past decades, previously unknown infections — HIV infection, Lyme disease, campylobacteriosis, SARS, and others — have spread, and the achieved reduction in the incidence of diphtheria and has not been maintained. There is an increase in the incidence of viral hepatitis, acute intestinal infectious diseases, tuberculosis among the population of Ukraine and other countries. The clinical manifestations of infectious diseases can be different, often atypical, can lead to hospitalization of the patient in a medical institution of any profile. The ability to recognize infectious , correctly conduct differential diagnosis, prescribe appropriate treatment, ensure that the necessary preventive measures are taken that are necessary for a doctor of any specialty. In our country, the classification of infectious diseases, academician L.V. Gromashevsky, has become most widespread. The classification is based on the principle of the predominant localization of the pathogen in the body, which is due to a certain transmission mechanism. One of the most important components in the treatment of patients for infectious diseases is inpatient treatment. Infectious Diseases Hospital is a special medical institution, which has a number of structural and functional units in order to ensure effective treatment, examination and isolation of patients. The features of the infectious diseases hospital, which are related to the possibility of transmission of the infection from person to person, determine not only the special structure of the infection departments, but also the particularities of maintaining medical documentation - emergency messages to the epidemiological service institutions and related records, sanitary treatment of patients things, etc. . Currently, influenza is the most common infection in the world and is registered on all continents. A feature of this infection is the incredible spread rate - a large place is covered by the disease in 1.5-2 weeks, a large country in 3-4 weeks. During epidemic outbreaks, up to 30-50 people in the affected region are affected, which leads to large epidemic losses. In the calmest years, nearly 30 million people are affected by the flu. Currently, the flu remains an uncontrolled and little controlled infection. The mortality rate of uncomplicated influenza is low and amounts to 0.01-0.2, but it increases sharply in the case of influenza in the elderly and weakened people, especially in those who have chronic heart disease, lungs, and young children. During an influenza epidemic, mortality from cardiovascular, pulmonary diseases always increases. It is estimated that uncomplicated influenza and other respiratory infections take a person’s life for at least 1 year. Annually (according to the WHO), 40 million people are infected with infectious diseases in the world, 90% of them account for ARVI. Each adult on average 2 times a year has the flu, or SARS, a schoolboy - 3 times, a preschooler - 6. In practical medicine, acute respiratory viral infections occupy a special place among other human diseases for another reason. As with other common diseases, an acute respiratory viral infection is often diagnosed without good reason. The error rate for the diagnosis of acute respiratory viral infections is 50%. At the same time, the diagnosis of acute respiratory viral infections can only take place if, during the examination of the patient, the doctor determines the signs of airway impression. However, it must be remembered that not only can cause respiratory syndrome, but also bacteria, mycoplasmas, chlamydia, and rickettsia. 2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of influenza and SARS, pathogenicity factors of the pathogen; epidemiology of influenza; pathogenesis, clinical manifestations of influenza, SARS; the period of occurrence and clinical manifestations of complications of influenza, SARS; diagnosis of influenza, SARS; principles of treatment and prevention; categories of people to whom vaccination is shown first; treatment of influenza, indications for the appointment of antibacterial drugs; indications for hospitalization of patients with influenza. Analyze the rules for staying in an infectious diseases hospital and, in particular, near the patient’s bed; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization of the patient for an infectious disease; draw up and submit the appropriate documentation to the SES; adhere to the rules for discharge of the patient with infection department. Explain the basic rules of work near the bed of a patient with influenza, SARS; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and flu syndromes, substantiate the clinical diagnosis, determine the need for hospitalization in a hospital; conduct differential diagnosis of influenza, SARS; on the basis of a clinical examination, in a timely manner to identify possible complications of influenza, urgent conditions, draw up medical documentation on the fact of the establishment of a previous diagnosis of influenza (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti-epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence. 3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the influenza , methods for the specific diagnosis of influenza Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. The etiology of SARS and influenza. 2. Epidemiology of SARS and influenza. 3. Pathogenesis of SARS and influenza 4. Clinic for acute respiratory viral infections and influenza. 5. Diagnosis of SARS and influenza. 6. Treatment of SARS and influenza. 7. Prevention of SARS and influenza. 1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture:

Influenza Aetiology. The disease is caused by the virus belonging to the family Orthomyxoviridae. Three serotypes of the influenza virus are distinguished: A, B, and C. Virus A is of greatest epidemiologic danger. Its antigen structure is constantly changing. Four subtypes of virus A have been established: AO, Al, A2 and A3. Virus B has a more stable antigen structure. Virus C is the most stable influenza virus. Two various antigens are contained in the outer envelope of the influenza virus: haemagglutinin (H) and neuraminidase (N). Haemagglutinin (H) has four independent subtypes: HO, HI, H2 and H3, which relate to viruses AO, Al, A2 and A3, respectively. The other antigen of the influenza virus of the envelope, neuraminidase (N), has two subtypes: Nl (common for viruses AO and Al) and N2 (common for viruses A2 and A3). Depending on the presence of particular surface antigens, influenza A virus is designated A(HONl), A(H1N1), A(H2N3), A(H3N2), etc. Influenza viruses are intracellular parasites. The virus is unstable in the environment, is rapidly destroyed on heating, drying, and by various disinfectants; it withstands frosting. Influenza viruses are cultivated and isolated on chick embryo. Among laboratory animals, hamsters, mice and pole cats are most susceptible to the influenza virus. Epidemiology. Diseased humans, especially during the first days of the disease, are the main source of infection. The virus is released from the patient during sneezing, coughing and talking till the 4-7th day of the disease. If influenza is complicated by pneumonia, the virus is liberated for 10-12 days. Patients with abortive and asymptomatic diseases are dangerous for the surrounding, because the quantity of such patients is much greater than of patients with clinical symptoms, and they continue actively infecting people. Infection is transmitted by air-borne route in enclosures where an influenza patient is present. Infection spread is facilitated by inadequate living conditions, overcrowding that promotes close contacts with the patient, nadequate labour conditions, intensive migration of population. Since the influenza virus is unstable in the external environment, fomites (dishes, toys, towels, etc.) are not substantially important. Influenza occurs as sporadic infections and epidemic outbreaks, pandemics. Influenza A epidemic is characterized by a rapid spread, which is due to generation of new antigenic variants of the virus. During an epidemic outbreak, the number of influenza cases and acute respiratory diseases increases 10-20 times. Within a short lapse of time (1- 11/2 months) residents of many cities and countries become involved (the sick rate from 30 to 40 per cent). People of almost all age groups are equally involved. The duration of circulation of all new virus A serotypes is 10-11 years. During this period, each serotype gives 3-4 antigenic variants, which, in turn, become the cause of new epidemic outbreaks of influenza every 2 or 3 years. During the past seventy years, virus A changed its antigenic structure five times. One virus type superseded the other: A0-A1-A2-A3. Late in 1977, when cases with influenza A3 were still reported, a new influenza appeared due to serotype A(H1N1). Since the last pandemic caused by this serotype was in 1956, people aged under 25 years were mostly afflicted. Stable immunity to serotype A(H1N1) in persons who sustained this infection in the past was thus discovered. Epidemics due to virus B develop slowly and involve to 10-25 per cent of population; they occur every 2 or 3 years. Virus C causes sporadic infections mostly among children. The spread of influenza is thus promoted by the instability of the antigenic structure of virus A under the influence of immunity in those who sustained the disease in the past. The spread is also promoted by high natural susceptibility of population, by a considerable proportion of asymptomatic (abortive) forms of the disease, by the short-lasting incubation period, and by the easiness of infection transmission through the droplet mechanism. The influenza incidence increases during the autumn and winter, and also in the spring. Pathogenesis. The portal of infection is mucosa of the upper airways. Columnar epithelium of the trachea is afflicted selectively. As the virus multiplies in the epithelium it causes its degeneration and necrosis. The underlying tissues are affected by oedema, the vessels become permeable to cause epistaxis, blood in the sputum, etc. Toxaemia evokes the lesion of the nervous and cardiovascular system. Suppressed immunity facilitates development of secondary complications due to exogenic and endogenic microorganisms; chronic diseases are exacerbated. Miltiplication of the virus is inhibited by interferon that is formed from the very first hours of the disease in the infected cells. By the end of the first week, the titre of the specific antibodies increases. The type-specific immunity after the sustained disease persists for 20 years. Clinical course. The incubation period lasts 1-2 days with variations from a few hours to 3 days. Influenza can be mild, moderate and severe. The disease can have a typical or atypical clinical manifestations. A typical influenza begins acutely with elevation of body temperature and chilliness. In 4-5 hours the body temperature can be as high as 38.7-40 °C. If the disease is mild, the body temperature can be subfebrile. The condition of the patient worsens. He complains of headache, mostly frontal and retro-ocular, which is accentuated by the movement of the eyes, pain in the muscles and bones, insomnia, cough, nasal obstruction, dry throat, sneezing, sweating, and weakness. Examination reveals hyperaemic face and neck, and injected scleral vessels. There are also tachypnoea and arterial hypotension; the heart sounds are dull; the pulse is slow (disagrees with body temperature). Nosebleed is possible. Among the respiratory symptoms are catarrh of the upper airways: stuffy nose, sneezing, hoarse voice, dry cough. The fauces are hyperaemic, the tongue is coated. Cough can persist in the young for 10-12 days, and in the elderly for longer time. The influenza virus and its toxins affect the peripheral nervous system and bone marrow, which is manifested by neuralgia, neuritis and symptoms of encephalitis. If influenza is not aggravated by complications, persists for 2-4 days, less frequently 5 days, or it may be as short as 1 day. A severe (toxic) form of influenza is characterized by marked symptoms of toxaemia: severe headache, hyperpyrexia (to 40 °C), dyspnoea, cyanosis, hypotension, weak and fast pulse, insomnia or somnolence, sometimes delirium, , , loss of consciousness, muscular cramping, symptoms of meningitis; haemorrhages in the skin can develop. Severe forms of influenza usually occur during the first two weeks of an epidemic. Influenza is characterized by specific leucopenia with relative lymphocytosis and a neutrophilic shift to the left, and aneosinophilia. Complications. The chief complications are pneumonias due to the virus or secondary bacterial infection (pneumococci, staphylococci, haemolytic streptococci, etc.). Acute cardiovascular failure, laryngitis, tracheobronchitis, bronchitis, bronchiolitis, frontal sinusitis, maxillary sinusitis, otitis and various haemorrhages, from epistaxis to haemorrhagic oedema of the lungs, are also complications of influenza. Diagnosis. It is not difficult to establish the diagnosis of influenza during an epidemic outbreak. During the interepidemic period, when the course of influenza is mild, it should be differentiated from other acute respiratory viral infections. Influenza is characterized by an acute onset, marked toxaemia, mild catarrhal phenomena, and leucopenia. A final and accurate diagnosis of influenza and other acute viral respiratory infections can be established in the laboratory by serologic, virologic and immunofluorescent methods. The first specimen of serum is taken not later than on the third day of the disease, the second not earlier than in three weeks. A four-fold increase in the titre is considered as a decisive diagnostic evidence. Serologic reactions are used to confirm the clinical diagnosis. The influenza virus can be isolated from the pharyngeal washings obtained during the first days of the disease or when the disease is in its full swing. The filtrate of the washings is mixed in the laboratory with a 2 per cent suspension of hen or guinea pig erythrocytes. The mixture is kept on ice for 20-30 minutes and the erythrocytes are precipitated by centrifuging. An isotonic sodium chloride solution and antibiotics are added to the precipitated erythrocytes with the virus adsorbed on them. The obtained material is used to inoculate chick embryos, cell cultures, and experimental animals. The isolated pure virus culture is used for serologic identification of the virus type. The result is ready only in 72-96 hours. The immunofluorescent method can confirm the diagnosis of influenza or differentiate it from other acute viral respiratory diseases. To that end, a smear is taken from the mucosa of the inferior concha (after preliminary cleaning of the nose from mucus and crusts). The cotton tampon with a smear is placed in a test tube containing 2-3 ml of physiological saline solution and delivered immediately to the laboratory. Fluorescent antibodies help detect the virus in 3-4 hours in the cells of columnar epithelium of the patient's nose. The disadvantage of this method is that it is impossible to identify the serotype of the circulating virus. Treatment. Regardless of severity of the disease, the patient must keep bed until his body temperature normalizes and symptoms of toxaemia subside. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who:  is hospitalized;  has severe, complicated, or progressive illness; or  is at higher risk for influenza complications. Decisions about starting antiviral treatment should not wait for laboratory confirmation of influenza. Figure: Guide for considering influenza testing and treatment when influenza viruses are circulating in the community (regardless of influenza vaccination history)

The recommended treatment course for uncomplicated influenza is oral oseltamivir 75 mg twice daily or two 5-mg inhalations twice daily of inhaled zanamivir for 5 days, or one 600 mg dose of intravenous peramivir or oral baloxavir (40 to <80 kg: one 40 mg dose; >80 kg: one 80 mg dose) for 1 day. Amantadine and rimantadine are antiviral drugs in a class of medications known as adamantanes, which target the M2 ion channel protein of influenza A viruses. Therefore, these medications are active against influenza A viruses, but not influenza B viruses. As in recent past seasons, there continues to be high levels of resistance (>99%) to adamantanes among circulating influenza A(H3N2) and influenza A(H1N1)pdm09 (“2009 H1N1”) viruses. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses. Drinking of great amount of hot liquid (tea with lemon, jam or honey; warm milk) is recommended. Polyvitamins should be taken 3 times a day. If the nose is stuffy, a 2 per cent ephedrine (naphthyzine, or sanorine) solution should be instilled into the nose. Codeine, libexin preparations and steam inhalations are useful for cough. Analgin, amidopyrin, ascophen should be given to lessen headache and myalgia. Anti-influenza donor immunoglobulin is an effective specific preparation. It is given in severe forms of influenza, preferably during the first days of the disease. Immunoglobulin should be given to children intramuscularly, 0.15-0.2 ml/kg body weight. Adults should be given 6 ml. Influenza due to virus. Severe forms of influenza should be treated by repeated administrations of anti-influenza immunoglobulin, detoxicating fluids (isotonic sodium chloride solution, haemodez, polyglucin, rheopolyglucin), 800-1000 ml a day, with an obligatory administration of lasix, brinaldix (saluretics), or urea and mannitol. Development of complications is an indication for antibiotic therapy. Prevention and control. CDC recommends a yearly flu vaccine as the first and most important step in protecting against influenza and its potentially serious complications. Inactivated influenza vaccine [IIV], recombinant influenza vaccine [RIV], or live attenuated influenza vaccine (LAIV) are used for specific prophylaxis of influenza. Everyone 6 months and older should get an influenza (flu) vaccine every season with rare exception. Vaccination to prevent flu is particularly important for people who are at high risk of developing serious flu complications. The seasonal flu vaccine protects against the influenza viruses that research indicates will be most common during the upcoming season. Trivalent vaccines are made to protect against three flu viruses; an influenza A (H1N1) virus, an influenza A (H3N2) virus, and an influenza B virus. Quadrivalent vaccines protect against four viruses; the same viruses as the trivalent vaccine as well as an additional B virus. Prophylactic vaccination should be completed 1-2 months before the expected rise of the morbidity. Chemoprophylaxis: Recommended duration is 7 days (after last known exposure). For control of outbreaks in institutional settings (e.g. long-term care facilities for elderly people and children) and hospitals, CDC recommends antiviral chemoprophylaxis with oral oseltamivir or inhaled zanamivir for a minimum of 2 weeks and continuing up to 1 week after the last known case was identified. Antiviral chemoprophylaxis is recommended for all residents, including those who have received influenza vaccination. General hygiene is important for control of influenza spread. Adequate airing and intensive insolation of enclosures, using ultraviolet radiation (especially in children's and medical institutions), adequate washing of dishes in hot water, proper individual hygiene (washing hands, using separate dishes, towels, linen, etc.) are important prophylactic measures. Patients with non-complicated influenza in the focus of infection should be isolated in home conditions. Patients with severe forms of the disease and complications, and also first patients with acute respiratory infections at closed children's institutions (sanatoria, children's homes, etc.) and in big families, should be hospitalized. The patients should be isolated until complete recovery. Rooms where influenza patients are kept should be regularly aired and cleaned. Patients are given their individual towels and dishes. Persons who take care of influenza patients must wear masks (respirators). Contacts of patients with the rest of the family must be restricted. Asthenic infants (aged under 1 year) should be given anti-influenza immunoglobulin intramuscularly in a dose of 0.2 ml/kg body weight. Passive immunity lasts for 18- 20 days. After recovery of the patient, the room should be aired thoroughly and cleaned with soap- soda solution. Especially strict sanitary and hygienic regimen must be ensured during epidemic in children's institutions, policlinics, hospitals, maternity houses, etc. Personnel of lying-in hospitals, children's medical and prophylactic institutions should wear respirators in order to prevent infection and its spread. Rooms for isolation of influenza patients must be provided at hostels and other places where people live in close communities. Children attending schools or preschool institutions should be isolated at home. If the disease is severe or home conditions are suboptimal, the patient should be hospitalized. After isolation of the patient from the rest of the group, the room should be aired properly and cleaned with a 0.5 per cent chloramine solution. The personnel must wear respirators. All healthy children must be examined every day in order to reveal timely new patients. The rooms must be treated with ultraviolet radiation when the children are out-of-doors.

Acute respiratory tract infection - is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, or larynx. This commonly includes nasal obstruction, sore throat, tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. Most infections are viral in nature, and in other instances, the cause is bacterial. URTIs can also be fungal or helminthic in origin, but these are less common. In 2015, 17.2 billion cases of URTIs are estimated to have occurred.[1] As of 2014, they caused about 3,000 deaths, down from 4,000 in 1990. Table 1. Differential diagnosis between URI and Influenza Symptoms URI Influenza Itchy, watery Rare (conjunctivitis may occur Soreness behind eyes, sometimes eyes with adenovirus) conjunctivitis Nasal Common Common discharge Nasal Common Sometimes congestion Sneezing Very common Sometimes Sore throat Very common Sometimes Cough Common (mild to moderate, Common (dry cough, can be severe) hacking) Headache Rare Common Fever Rare in adults, possible in Very common children 100–102 °F (or higher in young children), lasting 3–4 days; may have chills Malaise Sometimes Very common Fatigue, Sometimes Very common (can last for weeks, extreme weakness exhaustion early in course)

Muscle pain Slight Very common (often severe)

Parainfluenza Aetiology. The disease is caused by the virus belonging to the family of Paramyxoviridae. The parainfluenza virus contains RNA. Four serotypes are known that afflict humans. In laboratory conditions they are cultivated in cells of human embryo kidney. The viruses are unstable in the environment. Epidemiology. The source of infection is a diseased human. Infection is transmitted by air-borne route. Infants are mostly affected, although adults can also develop the disease. A sufficiently stable immunity to a specific virus is produced in those who sustained the disease. Parainfluenza occurs during the whole year as sporadic infection, but seasonal rise in the morbidity (during the spring and the cold season) is also observed. Pathogenesis. This is the same as in influenza. Clinical course. The incubation period lasts from 3 to 4 days with variations from 2 to 7 days. As a rule, the disease develops gradually and runs a sluggish course of 3-5 days. Catarrhal phenomena are not pronounced: cough, mild rhinorrhoea, less frequently subfebrile temperature. The patient complains of chilliness, headache, and slight fatigue. Hoarseness and chest pain are due to laryngitis (the most common symptom of parainfluenza) and laryngotracheitis. Nasal breathing is impeded. Serous nasal discharge gradually thickens and becomes mucous or mucopurulent due to secondary infection. Children, and especially infants, develop severe laryngitis, which is often attended by the clinical symptoms of laryngeal stenosis and croup. The entire respiratory tract can be involved in parainfluenza. Bronchitis runs a severer course and is attended by lesion of small ronchi (bronchiolitis) and lung parenchyma (pneumonia). Complications. Croup, pneumonia, acute tonsillitis, sinusitis, otitis and some other diseases develop; these usually occur in infants with rickets, anaemia and other disease due to secondary infection. Diagnosis. As distinct from influenza, toxaemia is not manifest in parainfluenzal infection. Cardiovascular and nervous lesions are absent; involvement of the larynx and the lower airways is more pronounced. The diagnosis is verified in the laboratory by virologic tests (isolation of the parainfluenza virus from nasopharyngeal washings), serologic (blood serum tests) and immunofluorescence. Treatment. Treatment is symptomatic. Anti-influenza immunoglobulin can be administered intramuscularly for therapeutic and prophylactic purposes. Antibiotics, sulpha drugs and inhalations should be given for complications. Prophylaxis is the same as in influenza.

Adenoviral Infections Aetiology. The causative agent belongs to the family of Adenoviridae. Among the 32 types of adenovirus isolated from man, types 3, 4, 7, 14, and 21 cause severe diseases. Type 8 causes keratoconjunctivitis in susceptible persons. Adenoviruses contain DNA. They are more stable in the environment than the influenza virus. Epidemiology. The source of infection is a diseased person, who liberates adenoviruses with nasal, nasopharyngeal mucus, sputum, and conjunctival discharge during the first 5-6 days of the disease. Virus carriers are another source of infection. At later terms of the disease adenoviruses are shed with faeces. The infection is mainly transmitted by the air-borne route. Since the virus is stable in the environment, infection can spread by contact, food or water (bathing in swimming pools, ponds, lakes, etc.). Infants aged from 6 months to 3 years are usually afflicted. Type-specific immunity is produced in convalescents. Adenovirus infections occur as sporadic cases and epidemic outbreaks in children's institutions. The morbidity rises in the autumn and winter. Since the incubation period lasts from 3 to 12 days, outbreaks of adenoviral infection last longer than those of influenza. Pathogenesis. Adenoviruses mostly affect respiratory mucosa, and less frequently conjunctiva. They can multiply in the intestinal mucosa as well. The lymphoid tissue of the regional lymph nodes is damaged, the vegetative nervous and endocrine systems are also upset with subsequent vascular disorders (pallor, tachycardia). Clinical course. The incubation period lasts from 3 to 12 days, most frequently from 5 to 6 days. Acute adenoviral infection is characterized by the following clinical symptoms: rhinopharyngitis, rhinopharyngotonsillitis, rhinopharyngobronchitis, pharyngoconjunctival fever, membranous or follicular conjunctivitis, and pneumonia. Rhinopharyngotonsillitis and rhinopharyngoconjunctivitis are more common. The incubation period lasts 5-6 days. The disease onset is usually gradual (2-3 days). The general symptoms are marked: malaise, chilliness, fever, headache. Local symptoms develop early: stuffy nose, hyperaemia of the fauces and the posterior wall of the pharynx, difficult swallowing, cough (dry or with expectoration of sputum) and chest pain. Some patients complain of , intestinal disorders, sometimes hepatic enlargement. Fever lasts from 2 to 7 days. Malaise and other general symptoms abate with normalization of body temperature, but catarrh can persist for 1-2 days more. Acute rhinopharyngoconjunctivitis is characterized by a moderate impairment of the general condition, inflammation of the respiratory mucosa, the fauces, and the eyes (rhinitis, tonsillitis, pharyngitis, nasopharyngitis, laryngitis, tracheitis, bronchitis, conjunctivitis). The internal organs can be involved separately or in various combinations. Respiratory mucosa and the mucosa of the eyes can be involved simultaneously, but sometimes only pharyngitis or only conjunctivitis can develop. Conjunctivitis lasts from several days to 2 weeks and longer. The eyelid mucosa and the eyeballs are injected, the conjunctiva can be affected with oedema and gentle granularity (catarrhal or follicular conjunctivitis). Membranous conjunctivitis is also possible. The eye secretion is meagre and serous in character. The cornea and the iris remain usually uninvolved. Among rare symptoms are nosebleed, nausea, vomiting and diarrhoea. In addition to the mentioned symptoms, small round foci of corneal opacity develop in several days (to 2 weeks) after the onset of keratoconjunctivitis. The foci sometimes fuse together. The disease lasts 2-4 weeks and usually ends in complete recovery. Pneumonia is the most severe form of adenoviral infection. It usually afflicts infants under 1 year of age. Pneumonia can occur with other forms of adenoviral infection. Pneumonia is usually focal (bronchopneumonia). The body temperature can remain high for 1-2 weeks and longer. Dyspnoea, cyanosis, and symptoms of toxaemia develop. Complications. The condition can be complicated by otitis, sinusitis, pneumonia, pleuritis, arthritis, which are due to secondary infections. Adenoviral infection can be the cause of exacerbation of chronic diseases. Diagnosis. Adenoviral infection is characterized by pronounced exudation; toxaemia is absent; conjunctivitis, especially membranous, is typical of the infection. An accurate diagnosis can be established only in the laboratory: virologically (isolation of the adenovirus in tissue culture), serologically, and by the immunofluorescent method. Treatment. Symptomatic treatment is used: analgesics, cardiacs, antitussives. Severe cases should be treated with immunoglobulin, interferon, desoxyribonuclease. To prevent complications, the patient must remain in bed. Food must be adequate and rich in vitamins. Prevention and control. Cases with severe course of the disease should only be hospitalized. The other patients should be isolated in home conditions till complete recovery. Chlorination of water in swimming pools is used to prevent outbreaks of the infection. For other preventive measures see "Influenza". 8. Materials for activating students during a lecture: 1. Which group of infectious diseases by source of infection does the influenza and ARVI belong to? 2. To characterize the causative agent of influenza, aggression factors, different serotypes of the virus and antigenic variants, to define antigenic drift and shift. 3. The mechanism of transmission of influenza and SARS. 4. The pathogenesis of influenza and acute respiratory viral infections and the main clinical symptoms. 5. Classification of influenza and SARS. 6. Describe the main clinical symptoms and name the criteria for the severity of influenza and SARS. 7. Name the possible complications of influenza and SARS and their diagnostic criteria. 8. The effects of influenza and SARS. 9. The plan for the examination of the patient with influenza and SARS. 10. Methods of specific diagnosis of influenza and SARS. 11. Etiotropic therapy of influenza and SARS and the principles of basic therapy. 12. Duration and indications for the appointment of antibiotic therapy for influenza and SARS. 13. Nonspecific and specific prophylaxis of influenza and SARS. 14. Categories of persons to whom vaccination is shown first.

Task 1 The patient turned to FD on the 3rd day of illness. The disease developed acutely. It began with the fever to 39 ° C, chills, severe headache with localization in the forehead, eyebrows, aches in the body. On the 2nd day there was a dry painful cough, dryness and sore throat, nasal congestion. On examination: temperature 38.5, sluggish answers, hyperemia of the face and upper body skin, vascular injection of the sclera, hyperemia, granularity and dryness of the mucous membrane of the oropharynx, blood pressure 100/60, pulse 90 / min., BH 20 in 1 min. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Task 2 Patient P., 28 years old, fell ill suddenly. The disease began with chills, muscle pain, intense headache in the frontal region, eyeballs. The temperature rose to 39 ° C. On the second day of the disease, a dry, annoying cough, nasal congestion appeared. On examination, the temperature is 39.2 ° C, the face is hyperemic, edematous. Injection of vascular sclera. Bright hyperemia of the tongue, soft palate, granularity of the posterior pharyngeal wall. Auscultatory: vesicular breathing. Heart sounds are deaf, pulse 100 / min. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Test control. 1. When antibacterial drugs for flu patient should be prescribed? A. in the presence of a chronic focus of infection; B. from the first day of illness C. in the presence of signs of bacterial complications, regardless of the duration of the disease; D. in cases of prolonged fever (more than 5 days) with severe intoxication; E. regardless of the duration of the disease in the presence of high fever and signs of tracheitis.

2. What are the complications of influenza caused by the action of the virus: A. pneumonia B. hemorrhagic pulmonary edema C. glomerulonephritis D. arachnoiditis E. sinusitis

3. Clinical signs of the toxic effect of the virus on the vascular and nervous system: A. headache, dizziness, meningism; B. nosebleeds, gum bleeding, toxic hemorrhagic pulmonary edema С. blood pressure lability, a tendency to collapse, tachycardia and bradycardia, sweating, hyperemia of the face and mucous membranes; D. cough

4. Basic symptom of influenza: A. high body temperature; B. hepato-lienal syndrome C. spotted rash on the face D. dry painful cough E. liquid bowel movements

5. Flu fever without complications in a typical course: A. Generally high or moderate B. constant C. wave D. grows during the first 3 days E. observed for 3 to 5 days

6. Characteristic of Guillain-Barre syndrome: A. peripheral paralysis with preservation of superficial sensitivity; B. ascending nature of paralysis; C. the descending nature of paralysis; D. protein-cell dissociation in the cerebrospinal fluid; E. cell-protein dissociation in the cerebrospinal fluid.

7. Etiotropic drugs for the treatment of patients with influenza: A. lamivudin B. oseltamivir C. zanamivir D. acyclovir E. influenza immunoglobulin

8. The main means of pathogenetic therapy in patients with influenza: A. heavy drinking; B. glucocorticoids; C. antibiotics D. crystalloid solutions intravenously under the control of CVP E. decongestants, expectorant, antihistamines.

9. The fly patient should be discharged from the hospital: A. according to the clinical signs of recovery; B. regardless of the results of specific diagnosis B. 5 days after normalization of body temperature; G. after receiving negative results of specific diagnostic methods D. after control radiography of the lungs

10. Vaccination against influenza indicated primarily for: A. All persons over 50 B. persons with chronic diseases of the cardiovascular, respiratory systems, kidneys, diabetes mellitus, immunodeficiency of various origins C. Newborns D. persons with 2 or 4 blood groups E. family members of an influenza patient

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. Characterization of the causative agent of diphtheria. 2. Source, mechanism, transmission pathways for diphtheria. 3. The nature of immunity in diphtheria. 4. What organs are affected by diphtheria? 5. Classification of diphtheria. 6. What is combined diphtheria, give an example. 7. Classification of diphtheria croup. 8. Features of the films with diphtheria of the larynx. 9. In what infectious diseases, besides diphtheria and tonsillitis, is the impression of tonsils. 10. Name the main factors of aggression of diphtheria bacillus. 11. The main links in the pathogenesis of diphtheria. 12. Clinic of general intoxication syndrome with diphtheria. 13. Clinic of localized membranous diphtheria of tonsils. Changes in the oropharynx with islet diphtheria of the tonsils. 14. Characteristic changes in the oropharynx in patients with localized diphtheria of the tonsils and lacunar tonsillitis. Indicate changes. 15. Features of the course of diphtheria of the larynx. 16. Specific laboratory diagnosis of diphtheria. Nonspecific laboratory tests for diphtheria. 17. List the complications that can occur with diphtheria. Specific complications of diphtheria. 18. Causes of death with diphtheria. 19. The principles of treatment of diphtheria. Etiotropic therapy of diphtheria. Rules for the introduction of antidiphtheria serum. 20. Prevention of diphtheria. What anti-epidemic measures are carried out in the focus of diphtheria? 21. To which group of infectious diseases do herpes virus infections belong? 22. Routes of transmission of herpes virus infections. 23. Stages of the pathogenesis of various manifestations of herpes virus infections. 24. Clinical classification of herpes virus infections. 25. The main symptoms of various nosological forms of herpes virus infections. 26. Features of the course of various manifestations of herpes virus infections in AIDS patients. 27. Complications of various manifestations of herpes virus infections. 28. The main causes of death in various nosological forms of herpes virus infections. 29. Plan for examination of a patient with various forms of herpes virus infections. 30. Changes in cerebrospinal fluid with lesions of the nervous system caused by herpes viruses. 31. Methods of specific diagnosis of herpes virus infections. 32. Interpretation of results depending on the duration of the disease and the study material. 33. Etiotropic therapy of herpes virus infections: doses, routes of administration, duration of treatment. 34. Principles of the pathogenetic treatment of herpes virus infections 35. Rules for extracting convalescents from the hospital. 36. The etiological structure of infectious mononucleosis. 37. Classification of infectious mononucleosis. 38. Clinical variants of the course of infectious mononucleosis. 39. Complications and consequences of infectious mononucleosis. 40. Features of the defeat of the oropharynx with infectious mononucleosis. 41. Features of damage in infectious mononucleosis. 42. The main clinical manifestations of infectious mononucleosis. 43. The nature of the changes in the hemogram with infectious mononucleosis. 44. Criteria for the severity of infectious mononucleosis. 45. Ultrasound diagnosis for infectious mononucleosis. 46. The main stages of pathogenesis in infectious mononucleosis. 47. The principles of treatment of infectious mononucleosis. 48. Rules for discharge of patients with infectious mononucleosis.

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Introduction to infectology. Infectious diseases with foodborne transmission. Topic The concept of infectious process and infectious diseases. Diarrheal syndrome in infectology. Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. Acute is defined as the abrupt onset of 3 or more loose stools per day. The augmented water content in the stools (above the normal value of approximately 10 mL/kg/d in the infant and young child, or 200 g/d in the teenager and adult) is due to an imbalance in the physiology of the small and large intestinal processes involved in the absorption of ions, organic substrates, and thus water. A common disorder in its acute form, diarrhea has many causes and may be mild to severe. Acute diarrhea is usually caused by infection of the small and/or large intestine; however, numerous disorders may result in diarrhea, including a malabsorption syndrome and various enteropathies. Acute-onset diarrhea is usually self-limited; however, an acute infection can have a protracted course. By far, the most common complication of acute diarrhea is dehydration. Although the term "acute gastroenteritis" is commonly used synonymously with "acute diarrhea," the former term is a misnomer. The term gastroenteritis implies inflammation of both the stomach and the small intestine, whereas, in reality, gastric involvement is rarely if ever seen in acute diarrhea (including diarrhea with an infectious origin); in addition, enteritis is also not consistently present. Examples of infectious acute diarrhea syndromes that do not cause enteritis include Vibrio cholerae– induced diarrhea and Shigella -induced diarrhea. Thus, the term acute diarrhea is preferable to acute gastroenteritis. Diarrheal episodes are classically distinguished into acute and chronic (or persistent) based on their duration. Acute diarrhea is thus defined as an episode that has an acute onset and lasts no longer than 14 days; chronic or persistent diarrhea is defined as an episode that lasts longer than 14 days. The distinction, supported by the World Health Organization (WHO), has implications not only for classification and epidemiological studies but also from a practical standpoint because protracted diarrhea often has a different set of causes, poses different problems of management, and has a different prognosis. 2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases , pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence. 3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the influenza virus, methods for the specific diagnosis of influenza Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan:

The concept of infectious process and infectious diseases. The etiology of infectious diarrhea. Pathophysiology of infectious diarrhea. Clinical presentation of acute diarrhea. Management of acute diarrhea.

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture:

THE CONCEPT OF INFECTIOUS PROCESS AND INFECTIOUS DISEASES. An infectious process is the interaction of a pathogenic microorganism with a macroorganism under certain environmental and social conditions. The concept 'infectious disease' means the condition manifested by a disease state of a patient and the so-called carrier state. The specific properties of infective agents, various pathogenicity and virulence of these agents, as well as the quantity of microorganisms that enter the macroorganism, resistance of the macroorganism and duration of specific immunity account for the multitude of clinical manifestations of infection. Infection can be clinically pronounced or it may be asymptomatic, which is known as the carrier state (parasite, bacterium, virus carrier state). A clinically manifest infection can run a typical or atypical course. Patients with a typical form of infection demonstrate all symptoms specific for a given disease. One or several symptoms of a given disease are absent from the clinical picture of an atypical form, or the symptoms can be modified. A disease can be acute or run a protracted or even a chronic course. A clinically manifest disease is usually classed as mild, moderate, and severe; according to the duration, the disease can be acute or chronic. An acute infection (smallpox, measles, plague) is characterized by a short stay of the causative agent in the body and development of specific immunity in the patient toward the given infection. A chronic infection (brucellosis, tuberculosis) can last for years. Asymptomatic infections can be subclinical and latent. A person with a subclinical infection (acute and chronic) looks in full health, and the disease can only be diagnosed by detecting the causative agents, specific antibodies, and functional and morphological changes in the organs and tissues that are specific for a given disease. Such patients (or carriers) are a special danger for the surrounding people since they are the source of infection. At the same time, a repeated subclinical infection in poliomyelitis, diphtheria, influenza, and some other acute infections promotes formation of an immune group of people (herd immunity). Acute and chronic subclinical forms (carrier state) are more common in typhoid fever, paratyphoid B, salmonellosis, viral hepatitis B, etc. Latent or persistent forms of human and animal infections are a prolonged asymptomatic interaction of macroorganisms with the pathogenic agents which are present in modified ('defective') forms. These are defective interfering particles in latent viral infections, and L forms, spheroplasts, etc. in bacterial infections. Being inside the host cell, these forms survive for long periods of time and are not released into the environment. Under the action of various provoking factors (such as thermal effects, injuries, psychic trauma, transplantation, blood transfusion, various disease states), persistent infection can be activated and become clinically manifest. The microbe regains its pathogenic properties. Persistence of virus has been studied best of all, but at the present time, persistence of other pathogenic factors has been intensively studied as well, e.g. of the L forms of streptococci, staphylococci, meningococci, cholera vibrio, typhoid fever bacilli, microbes causing diphtheria, tetanus, etc. Protozoa and rickettsia can also persist. For example, latent epidemic recrudescent typhus infection is manifested by relapses of epidemic recrudescent typhus (Brill's disease).

In the 19th century, infectious diseases were classed as contagious (transmissible from person to person), miasmatic (transmitted through air), and contagious-miasmatic. Late in the 19th century, in view of advances made in bacteriology, the diseases were classified according to their aetiology. These classifications could not satisfy clinicians or epidemiologists since diseases with different pathogenesis, clinical course and epidemiologic characteristics were united in one group. Classifications based on clinical and epidemiologic signs proved ineffective too. The classification proposed by Gromashevsky seems to be more reasonable than many others. It is based on the location of infection in the macroorganism. In accordance with the main sign, that determines the transmission mechanism, all infectious diseases are divided by the author into Jour groups: 1. intestinal infections; 2. respiratory infections; 3. blood infections; 4. skin infections. According to Gromashevsky, each group is subdivided into anthroponoses and zoonoses; their epidemiology and prevention differ substantially. Intestinal infections. Intestinal infections are characterized by location of the causative agents in the intestine and their distribution in the environment with excrements. If the causative agent circulates in the blood (typhoid fever, paratyphoid A and B, leptospirosis, viral hepatitis, brucellosis, etc.), it can also be withdrawn through various organs of the body, e. g. the kidneys, lungs, the mammary glands. As a microbe is released into the environment with faeces, urine, vomitus (cholera), it can cause disease in a healthy person only after ingestion with food or water. In other words, intestinal infections are characterized by the faecal-oral mechanism of transmission. Maximum incidence of intestinal infections occurs usually during the warm seasons. The anthroponoses include typhoid fever, paratyphoid, bacterial and amoebic dysentery, cholera, viral hepatitis A, poliomyelitis, helminthiasis (without the second host). The zoonoses include brucellosis, leptospirosis, salmonellosis, botulism, etc. The main means of control of intestinal infection are sanitary measures that prevent possible transmission of the pathogenic microorganisms with food, water, insects, soiled hands, etc. Timely detection of the diseased and carriers, their removal from food catering and the like establishments is also very important. Specific immunization is only of secondary importance in intestinal infections. Respiratory infections. This group includes diseases whose causative agents parasitize on the respiratory mucosa and are liberated into the environment with droplets of sputum during sneezing, cough, loud talks, or noisy respiration. People get infected when the microbes contained in sputum get on the mucosa of the upper airways. If the causative agent is unstable in the environment, a person can only be infected by close contact with the sick or carrier (pertussis). Pathogenic microorganisms causing some diseases can persist for a period of time in an enclosure where the sick is present. Infected particles of sputum or mucus can dry and be suspended in the air. Some diseases of this group can spread through contaminated linen, underwear, utensils, toys, etc. Since susceptibility of people, and especially of children to respiratory infection is very high, and since the infection is easily transmitted from the diseased (or carriers) to healthy people, almost entire population of a given area usually gets infected, and some people can be infected several times. Some diseases of this group form a special subgroup of children's infections (diphtheria, scarlet fever, measles, pertussis, epidemic parotitis, chickenpox, rubella). A durable immunity is usually induced in children who sustained these diseases. The main measure to control respiratory infections is to increase non-susceptibility of population, especially of children, by specific immunization. It is important to timely reveal the sick and carriers, and also to break the mechanism of infection transmission: control of overcrowding, proper ventilation and isolation of enclosures, using UV-lamps, wearing masks, respirators, disinfection, and the like. Blood infections. The diseases of this group are transmitted by blood-sucking insects, such as fleas, mosquitoes, ticks, etc., which bite people and introduce the pathogenic agent into the blood. Tick-borne encephalitis, Japanese B encephalitis and some other infections are characterized by natural nidality which is due to specific geographic, climatic, soil and other conditions of infection transmission. The morbidity is the highest during the warm season which coincides with the maximum activity of the transmitters - ticks, mosquitoes, etc. Control of blood infections includes altering natural conditions, improvement of soils, draining swamps, destroying sites where the insects multiply, disinsection measures against mosquitoes, ticks, etc., detoxication of sources of infection by their isolation and treatment, carrying out preventive measures. If the source of infection are rodents, measures to control them are taken. Active immunization is also effective. Skin infections. The diseases of this group occur as a result of contamination of the skin or mucosa with the pathogenic microorganisms. They can remain at the portal of infection (tetanus, dermatomycoses), or affect the skin, enter the body and be carried to various organs and tissues with the circulating blood (erysipelas, anthrax). The transmitting factors can include bed linen, clothes, plates and dishes and other utensils, that can be contaminated with mucus, pus or scales. Pathogenic microorganisms causing venereal diseases, , AIDS, and some other diseases are transmitted without the agency of the environmental objects. Wound infections are characterized by damage to the skin as a result of injury (tetanus, erysipelas). The main measures to control skin infections include isolation and treatment of the source of infection, killing diseased animals, homeless dogs and cats, improving sanitation and living conditions of population, personal hygiene, control of traumatism, and specific prophylaxis. A nosocomial infection is an infection that develops in a patient inside a hospital in a lapse of time that exceeds the duration of the incubation period of a given infection, or an infection that develops in a patient after his discharge from the hospital in a period of time that is shorter than the incubation period for a given infection. Extrahospital infection implies cases of infection before hospitalization (the patient is admitted to the hospital during the incubation period of a given infection). Among nosocomial infections, most common are air-borne infections, such as influenza and acute respiratory diseases, chickenpox, rubella, epidemic parotitis, scarlet fever, or measles. Nosocomial infections result from admittance to the hospital of patients with unrevealed diseases. Anti-epidemic measures should be taken in cases of development of nosocomial infections. These measures are aimed at prevention of infection spread. Quarantine should be established whenever necessary. During this period, only those patients can be admitted to the hospital who have already sustained this particular disease. The first patient with a nosocomial infection should be isolated from the others or placed in a mixed-infection ward, while the room and objects that were used by this patient must be disinfected. Other patients and personnel who had contacts with the nosocomial infection patient should be observed during the incubation period. Depending on the disease, they should be given immunoglobulin (prophylactic therapy) and tested for the carrier state.

DIARRHEAL SYNDROME IN INFECTOLOGY. «Diarrhea» is an alteration in a normal bowel movement characterized by an increase in the water content, volume, or frequency of stools. A decrease in consistency (i.e., soft or liquid) and an increase in frequency of bowel movements to>3stools per day have often been used as a definition for epidemiological investigations. “Infectious diarrhea” is diarrhea due to an infectious etiology, often accompanied by symptoms of nausea, vomiting, or abdominal cramps. “Acute diarrhea” is an episode of diarrhea of<14 days in duration. “Persistent diarrhea” is diarrhea of >14 days in duration. Although we will not categorize persistent diarrhea further here, some experts refer to diarrhea that lasts>30 days as chronic.

Etiology. Viral, bacterial, and parasitic infections are the most common cause of diarrhea, and they are typically spread through the fecal-oral route. This occurs when an individual comes into contact with a contaminated surface (doorkob, button, counter top, or handshake) or by ingesting contaminated food or beverages. There are also non-infectious reasons that a patient might develop diarrhea, and these are often related to medical conditions affecting the digestive, immune, or endocrine (hormone) systems. These conditions include irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), celiac disease, hyperthyroidism, and lactose intolerance.2 The term gastroenteritis typically refers to bacterial of viral infections the affect both the stomach and small/large intestines. These patients present with nausea, vomiting, and abdominal pain, as well as diarrhea. "Dysentery" refers to patients with infectious or inflammatory diarrheal diseases that result in the frequent passage of smaller stools containing varying amounts of mucus and/or blood. Viral Causes Viruses are the most common cause of diarrhea and are related predominately to four specific types:  Norovirus, also known as the "cruise ship virus," is the most common cause of food-borne gastroenteritis in the U.S.  Rotavirus is the most common cause of diarrhea in American children and a leading cause of death of children in the developing world.  Adenoviruses include a family of more than 50 subtypes. Types 40 and 41 are primarily responsible for causing diarrhea in humans. (Other adenoviral subtypes include cold viruses).  Astroviruses are common causes of diarrhea in the elderly, children, and people with compromised immune systems. Bacterial Causes Bacterial diarrhea is a major contributor to illness and death worldwide. Although less common than viral diarrhea, bacterial diarrhea disorders more often lead to dysenteric disease due to the development of ulcers and inflammation in the intestines. Among the most common causes:  Salmonella enteritidis can cause diarrhea, fever, and abdominal cramps within 12 to 72 hours of consuming contaminated food or beverage.  Escherichia coli (especially E. coli 0157) is spread through contaminated food and dairy products and can lead to a condition known as hemorrhagic colitis.  Shigella is common both in the U.S. and around the world and can often cause bloody diarrhea, particularly in children of preschool age.  Campylobacter is among the most common bacterial food-borne infections and can cause bloody diarrhea due to acute intestinal inflammation  Vibrio infection is often associated with eating raw seafood or sushi.  Staphylococcus aureus can cause explosive diarrhea due to toxins released by the bacteria.  Clostridium difficile is unique in that the rise of the infection is frequently linked to prior or concurrent antibiotic use. It is today the most common cause of hospital-acquired diarrhea.  Yersinia is a species of bacteria that can cause a number of different diseases in humans. Yersinia enterocollitica is a common cause of infectious diarrhea. In contrast, Yersinia pestis has been isololated as a primary cause of the bubonic plague. Humans typically encounter Yersinia species in dairy products. Parasitic Causes Protozoa are the primary cause of parasitic diarrhea around the world. These single-celled organisms come in many forms and are often transmitted through infected drinking water. Among the three most common causes of parasitic diarrhea:4  Giardia lamblia is passed through contaminated food or by person-to-person contact and can result in explosive diarrhea within two days of infection.  Entamoeba histolytica is related to fecal-oral transmission and can cause bloody diarrhea as these invasive parasites bore their way into the intestinal wall.  Cryptosporidium is known to cause both respiratory and gastrointestinal illness and is characterized by the development of watery stools. Pathophysiology Diarrhea is the reversal of the normal net absorptive status of water and electrolyte absorption to secretion. Such a derangement can be the result of either an osmotic force that acts in the lumen to drive water into the gut or the result of an active secretory state induced in the enterocytes. In the former case, diarrhea is osmolar in nature, as is observed after the ingestion of nonabsorbable sugars such as lactulose or lactose in lactose malabsorbers. Instead, in the typical active secretory state, enhanced anion secretion (mostly by the crypt cell compartment) is best exemplified by enterotoxin-- induced diarrhea. In osmotic diarrhea, stool output is proportional to the intake of the unabsorbable substrate and is usually not massive; diarrheal stools promptly regress with discontinuation of the offending nutrient, and the stool ion gap is high, exceeding 100 mOsm/kg. In fact, the fecal osmolality in this circumstance is accounted for not only by the electrolytes but also by the unabsorbed nutrient(s) and their degradation products. The ion gap is obtained by subtracting the concentration of the electrolytes from total osmolality (assumed to be 290 mOsm/kg), according to the formula: ion gap = 290 – [(Na + K) × 2]. In secretory diarrhea, the epithelial cells’ ion transport processes are turned into a state of active secretion. The most common cause of acute-onset secretory diarrhea is a bacterial infection of the gut. Several mechanisms may be at work. After colonization, enteric pathogens may adhere to or invade the epithelium; they may produce enterotoxins (exotoxins that elicit secretion by increasing an intracellular second messenger) or cytotoxins. They may also trigger release of cytokines attracting inflammatory cells, which, in turn, contribute to the activated secretion by inducing the release of agents such as prostaglandins or platelet-activating factor. Features of secretory diarrhea include a high purging rate, a lack of response to fasting, and a normal stool ion gap (ie, 100 mOsm/kg or less), indicating that nutrient absorption is intact.

Clinical presentation Acute diarrhea is defined as the abrupt onset of 3 or more loose stools per day and lasts no longer than 14 days; chronic or persistent diarrhea is defined as an episode that lasts longer than 14 days. The distinction has implications not only for classification and epidemiologic studies but also from a practical standpoint, because protracted diarrhea often has different etiologies, poses different management problems, and has a different prognosis.

The clinical presentation and course of diarrhea therefore depend on its cause and on the host. Consider the following to determine the source/cause of the patient’s diarrhea:

 Stool characteristics (eg, consistency, color, volume, frequency)  Presence of associated enteric symptoms (eg, nausea/vomiting, fever, abdominal pain)  Food ingestion history (eg, raw/contaminated foods, food poisoning)  Water exposure (eg, swimming pools, marine environment)  Camping history (possible exposure to contaminated water sources)  Travel history (common pathogens affect specific regions; also consider rotavirus and Shigella, Salmonella, and Campylobacter spp regardless of specific travel history, as these organisms are prevalent worldwide)  Animal exposure (eg, young dogs/cats: Campylobacter spp; turtles: Salmonella spp)  Predisposing conditions (eg, hospitalization, antibiotic use, immunocompromised state)

Signs and symptoms of diarrhea may include the following:

 Dehydration: Lethargy, depressed consciousness, sunken anterior fontanel, dry mucous membranes, sunken eyes, lack of tears, poor skin turgor, delayed capillary refill  Failure to thrive and malnutrition: Reduced muscle/fat mass or peripheral edema  Abdominal pain/cramping  Borborygmi  Perianal erythema

Knowledge of the characteristics of consistency, color, volume, and frequency can be helpful in determining whether the source is from the small or large bowel. Table 1 outlines these characteristics and demonstrates that an index of suspicion can be easily generated for a specific set of organisms. Table 1. Stool Characteristics and Determining Their Source Stool Small Bowel Large Bowel Characteristics Appearance Watery Mucoid and/or bloody Volume Large Small Frequency Increased Highly increased Blood Possibly positive but never Commonly grossly bloody gross blood pH Possibly < 5.5 >5.5 Reducing Possibly positive Negative substances WBCs < 5/high power field Commonly >10/high power field Serum WBCs Normal Possible leukocytosis, bandemia Organisms Viral Invasive bacteria  Rotavirus  Escherichia Coli (enteroinvasive,  Adenovirus enterohemorrhagic)  Calicivirus  Shigella species  Astrovirus  Salmonella species  Norovirus  Campylobacter species  Yersinia species  Aeromonas species  Plesiomonas species Enterotoxigenic bacteria Toxic bacteria  E coli  Clostridium difficile  Klebsiella  Clostridium perfringens  Cholera species  Vibrio species Parasites Parasites  Giardia species  Entamoeba organisms  Cryptosporidium species

Management. Fecal laboratory studies include the following:

 Examination for ova and parasites  Leukocyte count  pH level: A pH level of 5.5 or less or the presence of reducing substances indicates carbohydrate intolerance, which is usually secondary to viral illness  Examination of exudates for presence/absence of leukocytes  Cultures: Always culture for Salmonella, Shigella, and Campylobacter spp and Y enterocolitica in the presence of clinical signs of colitis or if fecal leukocytes are present; look for Clostridium difficile in those with diarrhea characterized by colitis and/or bloody stools; assess for Escherichia coli, particularly O157:H7, with bloody diarrhea and a history of eating ground beef; screen for Vibrio and Plesiomonas spp with a history of eating raw seafood or foreign travel  Enzyme immunoassay for rotavirus or adenovirus antigens  Latex agglutination assay for rotavirus

Figure 1.Recommendations for the diagnosis and management of diarrheal illnesses.

Acute-onset diarrhea is usually self-limited; however, an acute infection can have a protracted course. Management is generally supportive: In most cases, the best option for treatment of acute- onset diarrhea is the early use of oral rehydration therapy (ORT). Although many patients with mild diarrhea can prevent dehydration by ingesting extra fluids (such as clear juices and soups), more severe diarrhea, postural light-headedness, and reduced urination signify the need for more rehydration fluids. Oral rehydration solutions approaching the WHO-recommended electrolyte concentrations (e.g., Ceralyte, Pedialyte, or generic solutions) can be purchased at local pharmacies or obtained from pediatricians. WHO-recommended oral rehydration solutions can also be prepared by a pharmacy by mixing 3.5 g of NaCl, 2.5 g of NaHCO3 (or 2.9 g of Na citrate), 1.5 g of KCl, and 20 g of glucose or glucose polymer (e.g., 40 g of sucrose or 4 tablespoons of sugar or 50–60 g of cooked cereal flour such as rice, maize, sorghum, millet, wheat, or potato) per liter (1.05 qt) of clean water. This makes a solution of approximately Na 90 mM, K 20 mM, Cl 80 mM, HCO3 30 mM, and glucose 111 mM. Therapeutic considerations. Because of increasing threats from antimicrobial-resistant infections, side effects of treatment with antimicrobial agents, suprainfections when normal flora are eradicated by antimicrobial agents, and the possibility of induction of disease-producing phage by antibiotics (such as Shiga-toxin phage induced by quinolone antibiotics, any consideration of antimicrobial therapy must be carefully weighed against unintended and potentially harmful consequences. One situation in which empirical antibiotics are commonly recommended without obtaining a fecal specimen is in cases of traveler's diarrhea, in which enterotoxigenic E. coli or other bacterial pathogens are likely causes, and prompt treatment with fluoroquinolone or, in children, trimethoprim- sulfamethoxazole (TMP-SMZ) can reduce the duration of an illness from 3–5 days to <1–2 days (A- I). Some also consider empirical treatment of diarrhea that lasts longer than 10–14 days for suspected giardiasis, if other evaluations are negative and, especially, if the patient's history of travel or water exposure is suggestive. Otherwise, for patients with febrile diarrheal illnesses, especially those believed to have moderate to severe invasive disease, empirical treatment should be considered (after a fecal specimen is obtained for the performance of the studies noted above). This empirical treatment can be with an agent such as a quinolone antibiotic or, for children, TMP-SMZ, which can reduce the duration and shedding of organisms in infections with susceptible Shigella species and possibly in infections with susceptible Campylobacter species.

Table 9.Recommendations for therapy against specific pathogens Pathogen Recommendations Shigella species TMP-SMZ, 160 and 800 mg, respectively (pediatric dose, 5and 25 mg/kg, respectively) b.i.d.33 d (if susceptible) or fluoroquinolone (e.g., 300 mg ofloxacin, 400 mg norfloxacin, or 500 mg ciprofloxacin); nalidixic acid, 55 mg/kg/d (pediatric) or 1 g/d(adults)35 d or ceftriaxone; azithromycin Non-typhi species of Not recommended routinely, but if severe or patient is <6mo or Salmonella >50 y old or has prostheses, valvular heart disease, severe atherosclerosis, malignancy, or uremia, TMP-SMZ (if susceptible) or fluoroquinolone as above, b.i.d.35–7 d; ceftriaxone, 100mg/kg/d in 1 or 2 divided doses Campylobacter species Erythromycin, 500 mg b.i.d.35d Escherichia coli species TMP-SMZ, 160 and 800 mg, respectively, b.i.d.,33 d (if susceptible), or fluoroquinolone (e.g., 300 mg ofloxacin,400 mg norfloxacin, or 500 mg ciprofloxacin b.i.d.33d Vibrio cholerae Doxycycline, 300-mg single dose; or tetracycline, 500 mgq.i.d.33 d; or TMP-SMZ, 160 and 800 mg, respectively,b.i.d.33 d; or single-dose fluoroquinolone Toxigenic Clostridium Offending antibiotic should be withdrawn if possible; difficile metronidazole, 250 mg q.i.d. to 500 mgt.i.d.310 d

Complications Common complications include the following:  Campylobacter species -Bacteremia, meningitis, , urinary tract infection, pancreatitis, Reiter syndrome (RS)  C difficile - Chronic diarrhea  C perfringens serotype C - Enteritis necroticans  Enterohemorrhagic E coli - Hemorrhagic colitis  Enterohemorrhagic E coli O157:H7 - HUS  Salmonella species - Seizures, HUS, perforation, RS  Vibrio species - Rapid dehydration  Rotavirus - Isotonic dehydration, carbohydrate intolerance  Giardia species - Chronic fat malabsorption  Cryptosporidium species - Chronic diarrhea Enteric fever is caused by S typhi. This syndrome has an insidious onset of malaise, fever, abdominal pain, and bradycardia. Diarrhea and rash (rose spots) appear after 1 week of symptoms. Bacteria may have disseminated at that time, and treatment is required to prevent systemic complications such as hepatitis, myocarditis, cholecystitis, or GI bleeding. HUS is caused by damage to vascular endothelial cells by verotoxin (released by enterohemorrhagic E coli and by Shigella organisms). Thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure characterize HUS. Symptoms usually develop one week after onset of diarrhea, when the organism may be absent. RS can complicate acute infections and is characterized by arthritis, urethritis, conjunctivitis, and mucocutaneous lesions. Individuals with RS usually do not demonstrate all features. Carrier states are observed after some bacterial infections.  After diarrhea caused by Salmonella organisms, 1-4% of individuals with nontyphoid and enteric fever infections become carriers. The carrier stage for Salmonella organisms is more likely for females, infants, and individuals with biliary tract disease.  Asymptomatic C difficile carriage may be observed in as many as 20% of hospitalized patients receiving antibiotics and in 50% of infants.  Rotavirus is excreted asymptomatically in feces of children who were previously infected, typically for as long as 1-2 weeks.

8. Materials for activating students during a lecture: 1. Define the concepts: infection, infectious process, infectious disease. 2. Define the concept: exacerbation, remission, relapse of an infectious disease. 3. Define the concept: co-infection, superinfection, reinfection, autoinfection. 4. Give a definition of the concept: nosocomial, ubiquitous, natural focal infection. 5. Features of infectious diseases. 6. What does the term «diarrhea» means? 7. What is the difference between acute, persistent and chronic diarrhea? 8. Which causes of infectious diarrhea do you know? 9. Which are the pathophysiological types of diarrhea? 10. What are the typical symptoms of diarrhea? 11. What is the difference between small and large bowel diarrhea? 12. What is the role of lab testing in the diagnosis of diarrhea? 13. Which drugs have been approved for the treatment of diarrhea? 14. What is the role of antimicrobial treatment of diarrhea?

Task 1 The patient, 32 years old, was admitted to the infectious department with complaints of fever, abdominal pain, diarrhea, nausea, vomiting. The illness began in the morning with chills, diffuse abdominal pain, nausea and vomiting, followed by short-term relief. An hour later, diarrhea joined. Diarrhea and vomiting were repeated at least 8 times, there was a pronounced weakness, cramps in the calf muscles. He ate meat salad, scrambled eggs, and homemade sausage for dinner. Objectively: moderate condition, body T - 38.9oC. The skin is pale, dry, its turgor is reduced, acrocyanosis, isolated cramps of the calf muscles. Blood pressure - 100/50 mm, pulse 102 beats / min, weak. Heart tones are muffled. The tongue is dry, covered with white plaque. The is soft, moderately painful around the navel, in the epigastric and iliac regions. There are no symptoms of peritoneal irritation. Stools - abundant, liquid, smelly, greenish, without mucus and blood. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Task 2 Patient K., 27 years old, a cook, was admitted to an infectious disease hospital on the second day of illness with complaints of headache, frequent (up to 15 times a day) loose stools, nausea, vomiting, lower abdominal pain, false calls to the bottom. The disease began acutely with chills, fever up to 39˚C, repeated vomiting. After 5-7 hours, there was severe cramping pain in the abdomen, which worsened before defecation, loose stools with mucus and streaks of blood. Volume: 38.2˚C, sluggish. The skin is pale, turgor is preserved. Heart tones are weakened. Blood pressure 100/60 mm Hg. Pulse 104 beats / min. The tongue is dry, covered with a gray plaque. The abdomen is soft, hurts on palpation, there is a "growl" along the colon and sigmoid spasm. Liver at the edge of the costal arch. Stools fecal, semi-liquid, with mucus, up to 10 times a day. Urination is not disturbed. 1. Preliminary diagnosis. 2. Survey plan. 3. Treatment.

Task 3 A 29 year-old man was admitted to the hospital because of fatigue, anorexia, malaise, occipital headache, fever and difficulty concentrating. On physical examination he appeared tired and thin. His temperature was 40 oC. The liver edge was tender and palpated 3 cm below the right costal margin, with diffuse abdominal tenderness. An abdominal computed tomographyc scan showed thickening of the terminal ileum wall and clumped-enlarged mesenteric lymph nodes in the right lower quadrant. Laboratory test: white cells count, 4,600/mm3; aspartate-aminotransferase, 790 U/L; lactate-dehydrogenase, 1,562 U/L. He also had roseola spots distributed on the trunk. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment. Test control. 1. The main sources of salmonellosis are: A. Ducks B. Fish C. Dogs D. Cows E. Pigs 2. Signs of subclinical form of salmonellosis are following: A. Disposable diarrhea B. Increase in titers of anti-salmonella antibodies in paired serum samples C. The presence of ulcers of the intestinal mucosa during rectoromanoscopy D. Isolation of salmonella from feces E. Isolation of salmonella from food samples 3. Complications of the localized form of salmonellosis A. Dehydration shock B. Formation of liver abscesses C. Infectious and toxic shock D. Sepsis E. Chronic bacterial excretion 4. Which clinical variant of salmonellosis is generalized? A. Typhoid B. Gastric C. Colitis D. Gastroenteritic E. Gastroenterocolytic 5. Specific therapy of shigellosis includes: A. Nifuroxazide B. Doxycycline C. Ampicillin D. Intetrix E. Ciprofloxacin 6. Which type of Shigellas produces an exotoxin? A. Sonne B. Flexner C. Grigorieva-Shiga D. Large-Sachs E. All pathogens of shigellosis 7. The main transmission factors of cholera are following: A. milk and dairy products B. eggs of waterfowl C. water D. confectionery E. seafood 8. Dehydration of the III degree (according to Pokrovsky VI) corresponds to what percentage of loss of liquid from body weight: A. 1-2% of body weight B. 2-4% of body weight C. 5-7% of body weight D. 7-9% of body weight E. 10% or more by body weight 9. Which of the transmission pathways is leading in Sonne's shigellosis infection: A. Contact and household B. Dusty C. Water D. Sexual E. Food 10. Features of vomiting typical for cholera patients are following: A. occurs suddenly, without nausea B. accompanied by nausea, abdominal pain C. vomiting brings relief D. occurs before diarrhea E. occurs after diarrhea

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What is the role of antigenic drift and shift in the pathogenesis of influenza? 2. How are influenza viruses transmitted? 3. What is the incubation period of influenza? 4. How is influenza diagnosed? 5. What are the of influenza? 6. Which physical findings suggest influenza? 7. How is primary influenza pneumonia characterized? 8. What are the possible complications of influenza pneumonia? 9. What are the differential diagnoses for Influenza? 10. What is the role of lab testing in the diagnosis of influenza? 11. What is the criterion standard for confirming influenza? 12. Which drugs have been approved for the treatment of influenza? 13. How is influenza prevented? 14. What are recommendations for influenza vaccination?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Infectious diseases with airborne transmission Topic General characteristics of the group of infectious diseases with airborne transmission. Influenza. Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. Infectious diseases today remain extremely relevant. In the past decades, previously unknown infections — HIV infection, Lyme disease, campylobacteriosis, SARS, and others — have spread, and the achieved reduction in the incidence of diphtheria and measles has not been maintained. There is an increase in the incidence of viral hepatitis, acute intestinal infectious diseases, tuberculosis among the population of Ukraine and other countries. The clinical manifestations of infectious diseases can be different, often atypical, can lead to hospitalization of the patient in a medical institution of any profile. The ability to recognize infectious pathology, correctly conduct differential diagnosis, prescribe appropriate treatment, ensure that the necessary preventive measures are taken that are necessary for a doctor of any specialty. In our country, the classification of infectious diseases, academician L.V. Gromashevsky, has become most widespread. The classification is based on the principle of the predominant localization of the pathogen in the body, which is due to a certain transmission mechanism. One of the most important components in the treatment of patients for infectious diseases is inpatient treatment. Infectious Diseases Hospital is a special medical institution, which has a number of structural and functional units in order to ensure effective treatment, examination and isolation of patients. The features of the infectious diseases hospital, which are related to the possibility of transmission of the infection from person to person, determine not only the special structure of the infection departments, but also the particularities of maintaining medical documentation - emergency messages to the epidemiological service institutions and related records, sanitary treatment of patients things, etc. . Currently, influenza is the most common infection in the world and is registered on all continents. A feature of this infection is the incredible spread rate - a large place is covered by the disease in 1.5-2 weeks, a large country in 3-4 weeks. During epidemic outbreaks, up to 30-50 people in the affected region are affected, which leads to large epidemic losses. In the calmest years, nearly 30 million people are affected by the flu. Currently, the flu remains an uncontrolled and little controlled infection. The mortality rate of uncomplicated influenza is low and amounts to 0.01-0.2, but it increases sharply in the case of influenza in the elderly and weakened people, especially in those who have chronic heart disease, lungs, and young children. During an influenza epidemic, mortality from cardiovascular, pulmonary diseases always increases. It is estimated that uncomplicated influenza and other respiratory infections take a person’s life for at least 1 year. Annually (according to the WHO), 40 million people are infected with infectious diseases in the world, 90% of them account for ARVI. Each adult on average 2 times a year has the flu, or SARS, a schoolboy - 3 times, a preschooler - 6. In practical medicine, acute respiratory viral infections occupy a special place among other human diseases for another reason. As with other common diseases, an acute respiratory viral infection is often diagnosed without good reason. The error rate for the diagnosis of acute respiratory viral infections is 50%. At the same time, the diagnosis of acute respiratory viral infections can only take place if, during the examination of the patient, the doctor determines the signs of airway impression. However, it must be remembered that not only viruses can cause respiratory syndrome, but also bacteria, mycoplasmas, chlamydia, and rickettsia. 2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of influenza and SARS, pathogenicity factors of the pathogen; epidemiology of influenza; pathogenesis, clinical manifestations of influenza, SARS; the period of occurrence and clinical manifestations of complications of influenza, SARS; diagnosis of influenza, SARS; principles of treatment and prevention; categories of people to whom vaccination is shown first; treatment of influenza, indications for the appointment of antibacterial drugs; indications for hospitalization of patients with influenza. Analyze the rules for staying in an infectious diseases hospital and, in particular, near the patient’s bed; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization of the patient for an infectious disease; draw up and submit the appropriate documentation to the SES; adhere to the rules for discharge of the patient with infection department. Explain the basic rules of work near the bed of a patient with influenza, SARS; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and flu syndromes, substantiate the clinical diagnosis, determine the need for hospitalization in a hospital; conduct differential diagnosis of influenza, SARS; on the basis of a clinical examination, in a timely manner to identify possible complications of influenza, urgent conditions, draw up medical documentation on the fact of the establishment of a previous diagnosis of influenza (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti-epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence. 3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the influenza virus, methods for the specific diagnosis of influenza Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. The etiology of SARS and influenza. 2. Epidemiology of SARS and influenza. 3. Pathogenesis of SARS and influenza 4. Clinic for acute respiratory viral infections and influenza. 5. Diagnosis of SARS and influenza. 6. Treatment of SARS and influenza. 7. Prevention of SARS and influenza. 1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture:

The group of respiratory infections includes diseases whose causative agents parasitize on the respiratory mucosa and are liberated into the environment with droplets of sputum during sneezing, cough, loud talks, or noisy respiration. People get infected when the microbes contained in sputum get on the mucosa of the upper airways. If the causative agent is unstable in the environment, a person can only be infected by close contact with the sick or carrier (pertussis). Pathogenic microorganisms causing some diseases can persist for a period of time in an enclosure where the sick is present. Infected particles of sputum or mucus can dry and be suspended in the air. Some diseases of this group can spread through contaminated linen, underwear, utensils, toys, etc. Since susceptibility of people, and especially of children to respiratory infection is very high, and since the infection is easily transmitted from the diseased (or carriers) to healthy people, almost entire population of a given area usually gets infected, and some people can be infected several times. Some diseases of this group form a special subgroup of children's infections (diphtheria, scarlet fever, measles, pertussis, epidemic parotitis, chickenpox, rubella). A durable immunity is usually induced in children who sustained these diseases. The main measure to control respiratory infections is to increase non-susceptibility of population, especially of children, by specific immunization. It is important to timely reveal the sick and carriers, and also to break the mechanism of infection transmission: control of overcrowding, proper ventilation and isolation of enclosures, using UV-lamps, wearing masks, respirators, disinfection, and the like. Influenza Etiology. The disease is caused by the virus belonging to the family Orthomyxoviridae. Three serotypes of the influenza virus are distinguished: A, B, and C. Virus A is of greatest epidemiologic danger. Its antigen structure is constantly changing. Four subtypes of virus A have been established: AO, Al, A2 and A3. Virus B has a more stable antigen structure. Virus C is the most stable influenza virus. Two various antigens are contained in the outer envelope of the influenza virus: haemagglutinin (H) and neuraminidase (N). Haemagglutinin (H) has four independent subtypes: HO, HI, H2 and H3, which relate to viruses AO, Al, A2 and A3, respectively. The other antigen of the influenza virus of the envelope, neuraminidase (N), has two subtypes: Nl (common for viruses AO and Al) and N2 (common for viruses A2 and A3). Depending on the presence of particular surface antigens, influenza A virus is designated A(HONl), A(H1N1), A(H2N3), A(H3N2), etc. Influenza viruses are intracellular parasites. The virus is unstable in the environment, is rapidly destroyed on heating, drying, and by various disinfectants; it withstands frosting. Influenza viruses are cultivated and isolated on chick embryo. Among laboratory animals, hamsters, mice and pole cats are most susceptible to the influenza virus.

Epidemiology. Diseased humans, especially during the first days of the disease, are the main source of infection. The virus is released from the patient during sneezing, coughing and talking till the 4-7th day of the disease. If influenza is complicated by pneumonia, the virus is liberated for 10-12 days. Patients with abortive and asymptomatic diseases are dangerous for the surrounding, because the quantity of such patients is much greater than of patients with clinical symptoms, and they continue actively infecting people. Infection is transmitted by air-borne route in enclosures where an influenza patient is present. Infection spread is facilitated by inadequate living conditions, overcrowding that promotes close contacts with the patient, nadequate labour conditions, intensive migration of population. Since the influenza virus is unstable in the external environment, fomites (dishes, toys, towels, etc.) are not substantially important. Influenza occurs as sporadic infections and epidemic outbreaks, pandemics. Influenza A epidemic is characterized by a rapid spread, which is due to generation of new antigenic variants of the virus. During an epidemic outbreak, the number of influenza cases and acute respiratory diseases increases 10-20 times. Within a short lapse of time (1- 11/2 months) residents of many cities and countries become involved (the sick rate from 30 to 40 per cent). People of almost all age groups are equally involved. The duration of circulation of all new virus A serotypes is 10-11 years. During this period, each serotype gives 3-4 antigenic variants, which, in turn, become the cause of new epidemic outbreaks of influenza every 2 or 3 years. During the past seventy years, virus A changed its antigenic structure five times. One virus type superseded the other: A0-A1-A2-A3. Late in 1977, when cases with influenza A3 were still reported, a new influenza appeared due to serotype A(H1N1). Since the last pandemic caused by this serotype was in 1956, people aged under 25 years were mostly afflicted. Stable immunity to serotype A(H1N1) in persons who sustained this infection in the past was thus discovered. Epidemics due to virus B develop slowly and involve to 10-25 per cent of population; they occur every 2 or 3 years. Virus C causes sporadic infections mostly among children. The spread of influenza is thus promoted by the instability of the antigenic structure of virus A under the influence of immunity in those who sustained the disease in the past. For instance, In the United States, as of early January 2020, influenza B/Victoria was the predominant strain during the 2019-2020 flu season, followed by A(H1N1)pdm09. Influenza A(H3N2) and B/Yamagata viruses were reported to be circulating at very low levels. The spread is also promoted by high natural susceptibility of population, by a considerable proportion of asymptomatic (abortive) forms of the disease, by the short-lasting incubation period, and by the easiness of infection transmission through the droplet mechanism. The influenza incidence increases during the autumn and winter, and also in the spring. Pathogenesis. The portal of infection is mucosa of the upper airways. Columnar epithelium of the trachea is afflicted selectively. As the virus multiplies in the epithelium it causes its degeneration and necrosis. The underlying tissues are affected by oedema, the vessels become permeable to cause epistaxis, blood in the sputum, etc. Toxaemia evokes the lesion of the nervous and cardiovascular system. Suppressed immunity facilitates development of secondary complications due to exogenic and endogenic microorganisms; chronic diseases are exacerbated. Miltiplication of the virus is inhibited by interferon that is formed from the very first hours of the disease in the infected cells. By the end of the first week, the titre of the specific antibodies increases. The type-specific immunity after the sustained disease persists for 20 years. Clinical course. The incubation period lasts 1-2 days with variations from a few hours to 3 days. Influenza can be mild, moderate and severe. The disease can have a typical or atypical clinical manifestations. A typical influenza begins acutely with elevation of body temperature and chilliness. In 4-5 hours the body temperature can be as high as 38.7-40 °C. If the disease is mild, the body temperature can be subfebrile. The condition of the patient worsens. He complains of headache, mostly frontal and retro-ocular, which is accentuated by the movement of the eyes, pain in the muscles and bones, insomnia, cough, nasal obstruction, dry throat, sneezing, sweating, and weakness. Examination reveals hyperaemic face and neck, and injected scleral vessels. There are also tachypnoea and arterial hypotension; the heart sounds are dull; the pulse is slow (disagrees with body temperature). Nosebleed is possible. Among the respiratory symptoms are catarrh of the upper airways: stuffy nose, sneezing, hoarse voice, dry cough. The fauces are hyperaemic, the tongue is coated. Cough can persist in the young for 10-12 days, and in the elderly for longer time. The influenza virus and its toxins affect the peripheral nervous system and bone marrow, which is manifested by neuralgia, neuritis and symptoms of encephalitis. If influenza is not aggravated by complications, fever persists for 2-4 days, less frequently 5 days, or it may be as short as 1 day. A severe (toxic) form of influenza is characterized by marked symptoms of toxaemia: severe headache, hyperpyrexia (to 40 °C), dyspnoea, cyanosis, hypotension, weak and fast pulse, insomnia or somnolence, sometimes delirium, nausea, vomiting, loss of consciousness, muscular cramping, symptoms of meningitis; haemorrhages in the skin can develop. Severe forms of influenza usually occur during the first two weeks of an epidemic. Influenza is characterized by specific leucopenia with relative lymphocytosis and a neutrophilic shift to the left, and aneosinophilia. 2009-2010 H1N1 influenza pandemic In the 2009-2010 H1N1 influenza pandemic, initial symptoms included the following:  High fever  Myalgias  Rhinorrhea  Sore throat  Nausea and vomiting  Diarrhea Complications. The chief complications are pneumonias due to the virus or secondary bacterial infection (pneumococci, staphylococci, haemolytic streptococci, etc.). Acute cardiovascular failure, laryngitis, tracheobronchitis, bronchitis, bronchiolitis, frontal sinusitis, maxillary sinusitis, otitis and various haemorrhages, from epistaxis to haemorrhagic oedema of the lungs, are also complications of influenza. Diagnosis. It is not difficult to establish the diagnosis of influenza during an epidemic outbreak. During the interepidemic period, when the course of influenza is mild, it should be differentiated from other acute respiratory viral infections. Influenza is characterized by an acute onset, marked toxaemia, mild catarrhal phenomena, and leucopenia. A final and accurate diagnosis of influenza and other acute viral respiratory infections can be established in the laboratory by serologic, virologic and immunofluorescent methods. The first specimen of serum is taken not later than on the third day of the disease, the second not earlier than in three weeks. A four-fold increase in the titre is considered as a decisive diagnostic evidence. Serologic reactions are used to confirm the clinical diagnosis. The influenza virus can be isolated from the pharyngeal washings obtained during the first days of the disease or when the disease is in its full swing. The filtrate of the washings is mixed in the laboratory with a 2 per cent suspension of hen or guinea pig erythrocytes. The mixture is kept on ice for 20-30 minutes and the erythrocytes are precipitated by centrifuging. An isotonic sodium chloride solution and antibiotics are added to the precipitated erythrocytes with the virus adsorbed on them. The obtained material is used to inoculate chick embryos, cell cultures, and experimental animals. The isolated pure virus culture is used for serologic identification of the virus type. The result is ready only in 72-96 hours. The immunofluorescent method can confirm the diagnosis of influenza or differentiate it from other acute viral respiratory diseases. To that end, a smear is taken from the mucosa of the inferior concha (after preliminary cleaning of the nose from mucus and crusts). The cotton tampon with a smear is placed in a test tube containing 2-3 ml of physiological saline solution and delivered immediately to the laboratory. Fluorescent antibodies help detect the virus in 3-4 hours in the cells of columnar epithelium of the patient's nose. The disadvantage of this method is that it is impossible to identify the serotype of the circulating virus. Treatment. Regardless of severity of the disease, the patient must keep bed until his body temperature normalizes and symptoms of toxaemia subside. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who:  is hospitalized;  has severe, complicated, or progressive illness; or  is at higher risk for influenza complications. Decisions about starting antiviral treatment should not wait for laboratory confirmation of influenza. Figure: Guide for considering influenza testing and treatment when influenza viruses are circulating in the community (regardless of influenza vaccination history)

The following antiviral drugs are recommended for chemoprophylaxis and/or treatment of influenza:  Baloxavir marboxil  Oseltamivir  Peramivir  Zanamivir Treatment regimens Treatment regimens for patients with influenza A and influenza B are outlined below. The regimens are based on patient age and weight. Baloxavir marboxil (Xofluza) Adolescents and adults aged 12 years or older Dose based on body weight, as follows:  40 to < 80 kg: 40 mg PO as a single dose

 ≥ 80 kg: 80 mg PO as a single dose Oseltamivir (Tamiflu, generic) Adolescents and adults  Aged ≥13 years: 75 mg PO q12h for 5 days Children aged 1-12 years Oseltamivir treatment varies by weight, as follows:  ≤15 kg: Oseltamivir 30 mg PO q12h for 5 days

 >15 to 23 kg: Oseltamivir 45 mg PO q12h for 5 days

 >23 to 40 kg: Oseltamivir 60 mg PO q12h for 5 days

 >40 kg: Oseltamivir 75 mg PO q12h for 5 days Children aged 2 weeks to younger than 1 year  3 mg/kg/dose PO q12h for 5 days Zanamivir (Relenza DIskhaler) Adults and children aged ≥7 years  10 mg (2 inhalations) inhaled q12h for 5 days Peramivir (Rapivab) Infuse diluted IV over 15-30 minutes Adolescents and adults  Aged >13 years: 600 mg IV as a single dose

 CrCl 30-49 mL/min: 200 mg IV

 CrCl 10-29 mL/min: 100 mg IV Children aged 2-12 years  12 mg/kg IV as a single dose; not to exceed 600 mg/dose

 CrCl 30-49 mL/min: 4 mg/kg IV

 CrCl 10-29 mL/min: 2 mg/kg IV

The neuraminidase inhibitors (oseltamivir, peramivir, and zanamivir) and cap-dependent endonuclease inhibitors (baloxavir marboxil) have activity against influenza A and B viruses (including H1N1), whereas the adamantanes (amantadine and rimantadine) have activity against influenza A viruses only. Therefore, these medications are active against influenza A viruses, but not influenza B viruses. As in recent past seasons, there continues to be high levels of resistance (>99%) to adamantanes among circulating influenza A(H3N2) and influenza A(H1N1)pdm09 (“2009 H1N1”) viruses. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses. To be effective as treatment, these agents must be administered within 48 hours of symptom onset. These agents are most effective if started within the first 24 hours of symptoms and less effective if begun 24-48 hours after symptoms appear. Drinking of great amount of hot liquid (tea with lemon, jam or honey; warm milk) is recommended. Polyvitamins should be taken 3 times a day. If the nose is stuffy, a 2 per cent ephedrine (naphthyzine, or sanorine) solution should be instilled into the nose. Codeine, libexin preparations and steam inhalations are useful for cough. Analgin, amidopyrin, ascophen should be given to lessen headache and myalgia. Anti-influenza donor immunoglobulin is an effective specific preparation. It is given in severe forms of influenza, preferably during the first days of the disease. Immunoglobulin should be given to children intramuscularly, 0.15-0.2 ml/kg body weight. Adults should be given 6 ml. Influenza due to virus. Severe forms of influenza should be treated by repeated administrations of anti-influenza immunoglobulin, detoxicating fluids (isotonic sodium chloride solution, haemodez, polyglucin, rheopolyglucin), 800-1000 ml a day, with an obligatory administration of lasix, brinaldix (saluretics), or urea and mannitol. Development of complications is an indication for antibiotic therapy. Prevention and control. CDC recommends a yearly flu vaccine as the first and most important step in protecting against influenza and its potentially serious complications. Inactivated influenza vaccine [IIV], recombinant influenza vaccine [RIV], or live attenuated influenza vaccine (LAIV) are used for specific prophylaxis of influenza. Everyone 6 months and older should get an influenza (flu) vaccine every season with rare exception. Vaccination to prevent flu is particularly important for people who are at high risk of developing serious flu complications. The seasonal flu vaccine protects against the influenza viruses that research indicates will be most common during the upcoming season. Trivalent vaccines are made to protect against three flu viruses; an influenza A (H1N1) virus, an influenza A (H3N2) virus, and an influenza B virus. Quadrivalent vaccines protect against four viruses; the same viruses as the trivalent vaccine as well as an additional B virus. For instance vaccine viruses included in the 2019-2020 trivalent influenza vaccines contain the following components:

 A/Brisbane/02/2018 (H1N1)pdm09-like virus (new for 2019-2020)  A/Kansas/14/2017 (H3N2)-like virus (new for 2019-2020)  B/Colorado/06/2017-like virus (B/Victoria/2/87 lineage) (no change from preceding season) Prophylactic vaccination should be completed 1-2 months before the expected rise of the morbidity. Chemoprophylaxis: Recommended duration is 7 days (after last known exposure). For control of outbreaks in institutional settings (e.g. long-term care facilities for elderly people and children) and hospitals, CDC recommends antiviral chemoprophylaxis with oral oseltamivir or inhaled zanamivir for a minimum of 2 weeks and continuing up to 1 week after the last known case was identified. Antiviral chemoprophylaxis is recommended for all residents, including those who have received influenza vaccination.

General hygiene is important for control of influenza spread. Adequate airing and intensive insolation of enclosures, using ultraviolet radiation (especially in children's and medical institutions), adequate washing of dishes in hot water, proper individual hygiene (washing hands, using separate dishes, towels, linen, etc.) are important prophylactic measures. Patients with non-complicated influenza in the focus of infection should be isolated in home conditions. Patients with severe forms of the disease and complications, and also first patients with acute respiratory infections at closed children's institutions (sanatoria, children's homes, etc.) and in big families, should be hospitalized. The patients should be isolated until complete recovery. Rooms where influenza patients are kept should be regularly aired and cleaned. Patients are given their individual towels and dishes. Persons who take care of influenza patients must wear masks (respirators). Contacts of patients with the rest of the family must be restricted. Asthenic infants (aged under 1 year) should be given anti-influenza immunoglobulin intramuscularly in a dose of 0.2 ml/kg body weight. Passive immunity lasts for 18- 20 days. After recovery of the patient, the room should be aired thoroughly and cleaned with soap- soda solution. Especially strict sanitary and hygienic regimen must be ensured during epidemic in children's institutions, policlinics, hospitals, maternity houses, etc. Personnel of lying-in hospitals, children's medical and prophylactic institutions should wear respirators in order to prevent infection and its spread. Rooms for isolation of influenza patients must be provided at hostels and other places where people live in close communities. Children attending schools or preschool institutions should be isolated at home. If the disease is severe or home conditions are suboptimal, the patient should be hospitalized. After isolation of the patient from the rest of the group, the room should be aired properly and cleaned with a 0.5 per cent chloramine solution. The personnel must wear respirators. All healthy children must be examined every day in order to reveal timely new patients. The rooms must be treated with ultraviolet radiation when the children are out-of-doors. ACUTE RESPIRATORY VIRAL INFECTIONS Upper respiratory tract infection (URI) represents the most common acute illness evaluated in the outpatient setting. URIs range from the common cold—typically a mild, self-limited, catarrhal syndrome of the nasopharynx—to life-threatening illnesses such as epiglottitis. Viral nasopharyngitis Patients with the common cold may have a paucity of clinical findings despite notable subjective discomfort. Findings may include the following:  Nasal mucosal erythema and edema are common  Nasal discharge: Profuse discharge is more characteristic of viral infections than bacterial infections; initially clear secretions typically become cloudy white, yellow, or green over several days, even in viral infections  Foul breath  Fever: Less common in adults but may be present in children with rhinoviral infections. Epiglottitis This condition is more often found in children aged 1-5 years, who present with a sudden onset of the following symptoms:  Sore throat  Drooling, difficulty or pain during swallowing, globus sensation of a lump in the throat  Muffled dysphonia or loss of voice  Dry cough or no cough, dyspnea  Fever, fatigue or malaise (may be seen with any URI)  Tripod or sniffing posture Laryngotracheitis and laryngotracheobronchitis  Nasopharyngitis often precedes laryngitis and tracheitis by several days  Swallowing may be difficult or painful  Patients may experience a globus sensation of a lump in the throat  Hoarseness or loss of voice is a key manifestation of laryngeal involvement Parainfluenza Etiology. The disease is caused by the virus belonging to the family of Paramyxoviridae. The parainfluenza virus contains RNA. Four serotypes are known that afflict humans. In laboratory conditions they are cultivated in cells of human embryo kidney. The viruses are unstable in the environment. Epidemiology. The source of infection is a diseased human. Infection is transmitted by air-borne route. Infants are mostly affected, although adults can also develop the disease. A sufficiently stable immunity to a specific virus is produced in those who sustained the disease. Parainfluenza occurs during the whole year as sporadic infection, but seasonal rise in the morbidity (during the spring and the cold season) is also observed. Pathogenesis. This is the same as in influenza. Clinical course. The incubation period lasts from 3 to 4 days with variations from 2 to 7 days. As a rule, the disease develops gradually and runs a sluggish course of 3-5 days. Catarrhal phenomena are not pronounced: cough, mild rhinorrhoea, less frequently subfebrile temperature. The patient complains of chilliness, headache, and slight fatigue. Hoarseness and chest pain are due to laryngitis (the most common symptom of parainfluenza) and laryngotracheitis. Nasal breathing is impeded. Serous nasal discharge gradually thickens and becomes mucous or mucopurulent due to secondary infection. Children, and especially infants, develop severe laryngitis, which is often attended by the clinical symptoms of laryngeal stenosis and croup. The entire respiratory tract can be involved in parainfluenza. Bronchitis runs a severer course and is attended by lesion of small ronchi (bronchiolitis) and lung parenchyma (pneumonia). Complications. Croup, pneumonia, acute tonsillitis, sinusitis, otitis and some other diseases develop; these usually occur in infants with rickets, anaemia and other disease due to secondary infection. Diagnosis. As distinct from influenza, toxaemia is not manifest in parainfluenzal infection. Cardiovascular and nervous lesions are absent; involvement of the larynx and the lower airways is more pronounced. The diagnosis is verified in the laboratory by virologic tests (isolation of the parainfluenza virus from nasopharyngeal washings), serologic (blood serum tests) and immunofluorescence. Treatment. Treatment is symptomatic. Anti-influenza immunoglobulin can be administered intramuscularly for therapeutic and prophylactic purposes. Antibiotics, sulpha drugs and inhalations should be given for complications. Prophylaxis is the same as in influenza.

Adenoviral Infections Etiology. The causative agent belongs to the family of Adenoviridae. Among the 32 types of adenovirus isolated from man, types 3, 4, 7, 14, and 21 cause severe diseases. Type 8 causes keratoconjunctivitis in susceptible persons. Adenoviruses contain DNA. They are more stable in the environment than the influenza virus. Epidemiology. The source of infection is a diseased person, who liberates adenoviruses with nasal, nasopharyngeal mucus, sputum, and conjunctival discharge during the first 5-6 days of the disease. Virus carriers are another source of infection. At later terms of the disease adenoviruses are shed with faeces. The infection is mainly transmitted by the air-borne route. Since the virus is stable in the environment, infection can spread by contact, food or water (bathing in swimming pools, ponds, lakes, etc.). Infants aged from 6 months to 3 years are usually afflicted. Type-specific immunity is produced in convalescents. Adenovirus infections occur as sporadic cases and epidemic outbreaks in children's institutions. The morbidity rises in the autumn and winter. Since the incubation period lasts from 3 to 12 days, outbreaks of adenoviral infection last longer than those of influenza. Pathogenesis. Adenoviruses mostly affect respiratory mucosa, and less frequently conjunctiva. They can multiply in the intestinal mucosa as well. The lymphoid tissue of the regional lymph nodes is damaged, the vegetative nervous and endocrine systems are also upset with subsequent vascular disorders (pallor, tachycardia). Clinical course. The incubation period lasts from 3 to 12 days, most frequently from 5 to 6 days. Acute adenoviral infection is characterized by the following clinical symptoms: rhinopharyngitis, rhinopharyngotonsillitis, rhinopharyngobronchitis, pharyngoconjunctival fever, membranous or follicular conjunctivitis, and pneumonia. Rhinopharyngotonsillitis and rhinopharyngoconjunctivitis are more common. The incubation period lasts 5-6 days. The disease onset is usually gradual (2-3 days). The general symptoms are marked: malaise, chilliness, fever, headache. Local symptoms develop early: stuffy nose, hyperaemia of the fauces and the posterior wall of the pharynx, difficult swallowing, cough (dry or with expectoration of sputum) and chest pain. Some patients complain of abdominal pain, intestinal disorders, sometimes hepatic enlargement. Fever lasts from 2 to 7 days. Malaise and other general symptoms abate with normalization of body temperature, but catarrh can persist for 1-2 days more. Acute rhinopharyngoconjunctivitis is characterized by a moderate impairment of the general condition, inflammation of the respiratory mucosa, the fauces, and the eyes (rhinitis, tonsillitis, pharyngitis, nasopharyngitis, laryngitis, tracheitis, bronchitis, conjunctivitis). The internal organs can be involved separately or in various combinations. Respiratory mucosa and the mucosa of the eyes can be involved simultaneously, but sometimes only pharyngitis or only conjunctivitis can develop. Conjunctivitis lasts from several days to 2 weeks and longer. The eyelid mucosa and the eyeballs are injected, the conjunctiva can be affected with oedema and gentle granularity (catarrhal or follicular conjunctivitis). Membranous conjunctivitis is also possible. The eye secretion is meagre and serous in character. The cornea and the iris remain usually uninvolved. Among rare symptoms are nosebleed, nausea, vomiting and diarrhoea. In addition to the mentioned symptoms, small round foci of corneal opacity develop in several days (to 2 weeks) after the onset of keratoconjunctivitis. The foci sometimes fuse together. The disease lasts 2-4 weeks and usually ends in complete recovery. Pneumonia is the most severe form of adenoviral infection. It usually afflicts infants under 1 year of age. Pneumonia can occur with other forms of adenoviral infection. Pneumonia is usually focal (bronchopneumonia). The body temperature can remain high for 1-2 weeks and longer. Dyspnoea, cyanosis, and symptoms of toxaemia develop. Complications. The condition can be complicated by otitis, sinusitis, pneumonia, pleuritis, arthritis, which are due to secondary infections. Adenoviral infection can be the cause of exacerbation of chronic diseases. Diagnosis. Adenoviral infection is characterized by pronounced exudation; toxaemia is absent; conjunctivitis, especially membranous, is typical of the infection. An accurate diagnosis can be established only in the laboratory: virologically (isolation of the adenovirus in tissue culture), serologically, and by the immunofluorescent method. Treatment. Symptomatic treatment is used: analgesics, cardiacs, antitussives. Severe cases should be treated with immunoglobulin, interferon, desoxyribonuclease. To prevent complications, the patient must remain in bed. Food must be adequate and rich in vitamins. Prevention and control. Cases with severe course of the disease should only be hospitalized. The other patients should be isolated in home conditions till complete recovery. Chlorination of water in swimming pools is used to prevent outbreaks of the infection.

Table 1. Differential diagnosis between ARI and Influenza Symptoms ARI Influenza Itchy, watery Rare (conjunctivitis may occur Soreness behind eyes, sometimes eyes with adenovirus) conjunctivitis Nasal Common Common discharge Nasal Common Sometimes congestion Sneezing Very common Sometimes Sore throat Very common Sometimes Cough Common (mild to moderate, Common (dry cough, can be severe) hacking) Headache Rare Common Fever Rare in adults, possible in Very common children 100–102 °F (or higher in young children), lasting 3–4 days; may have chills Malaise Sometimes Very common Fatigue, Sometimes Very common (can last for weeks, extreme weakness exhaustion early in course)

Muscle pain Slight Very common (often severe)

8. Materials for activating students during a lecture: 1. Which group of infectious diseases by source of infection does the influenza and ARI belong to? 2. What is influenza? 3. What is the global incidence of influenza? 4. What is the etiology of influenza? 5. What are the mutation rates of influenza A? 6. What is the role of antigenic drift and shift in the pathogenesis of influenza? 7. How are influenza viruses transmitted? 8. What is the incubation period of influenza? 9. How is influenza diagnosed? 10. What are the signs and symptoms of influenza? 11. Which physical findings suggest influenza? 12. How is primary influenza pneumonia characterized? 13. What are the possible complications of influenza pneumonia? 14. What are the differential diagnoses for Influenza? 15. What is the role of lab testing in the diagnosis of influenza? 16. What is the criterion standard for confirming influenza? 17. Which drugs have been approved for the treatment of influenza? 18. How is influenza prevented? 19. What are recommendations for influenza vaccination?

Task 1 The patient turned to FD on the 3rd day of illness. The disease developed acutely. It began with the fever to 39 ° C, chills, severe headache with localization in the forehead, eyebrows, aches in the body. On the 2nd day there was a dry painful cough, dryness and sore throat, nasal congestion. On examination: temperature 38.5, sluggish answers, hyperemia of the face and upper body skin, vascular injection of the sclera, hyperemia, granularity and dryness of the mucous membrane of the oropharynx, blood pressure 100/60, pulse 90 / min., BH 20 in 1 min. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Task 2 Patient P., 28 years old, fell ill suddenly. The disease began with chills, muscle pain, intense headache in the frontal region, eyeballs. The temperature rose to 39 ° C. On the second day of the disease, a dry, annoying cough, nasal congestion appeared. On examination, the temperature is 39.2 ° C, the face is hyperemic, edematous. Injection of vascular sclera. Bright hyperemia of the tongue, soft palate, granularity of the posterior pharyngeal wall. Auscultatory: vesicular breathing. Heart sounds are deaf, pulse 100 / min. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Test control. 1. When antibacterial drugs for flu patient should be prescribed? A. in the presence of a chronic focus of infection; B. from the first day of illness C. in the presence of signs of bacterial complications, regardless of the duration of the disease; D. in cases of prolonged fever (more than 5 days) with severe intoxication; E. regardless of the duration of the disease in the presence of high fever and signs of tracheitis.

2. What are the complications of influenza caused by the action of the virus: A. pneumonia B. hemorrhagic pulmonary edema C. glomerulonephritis D. arachnoiditis E. sinusitis

3. Clinical signs of the toxic effect of the virus on the vascular and nervous system: A. headache, dizziness, meningism; B. nosebleeds, gum bleeding, toxic hemorrhagic pulmonary edema С. blood pressure lability, a tendency to collapse, tachycardia and bradycardia, sweating, hyperemia of the face and mucous membranes; D. cough

4. Basic symptom of influenza: A. high body temperature; B. hepato-lienal syndrome C. spotted rash on the face D. dry painful cough E. liquid bowel movements

5. Flu fever without complications in a typical course: A. Generally high or moderate B. constant C. wave D. grows during the first 3 days E. observed for 3 to 5 days

6. Characteristic of Guillain-Barre syndrome: A. peripheral paralysis with preservation of superficial sensitivity; B. ascending nature of paralysis; C. the descending nature of paralysis; D. protein-cell dissociation in the cerebrospinal fluid; E. cell-protein dissociation in the cerebrospinal fluid.

7. Etiotropic drugs for the treatment of patients with influenza: A. lamivudin B. oseltamivir C. zanamivir D. acyclovir E. influenza immunoglobulin

8. The main means of pathogenetic therapy in patients with influenza: A. heavy drinking; B. glucocorticoids; C. antibiotics D. crystalloid solutions intravenously under the control of CVP E. decongestants, expectorant, antihistamines.

9. The fly patient should be discharged from the hospital: A. according to the clinical signs of recovery; B. regardless of the results of specific diagnosis B. 5 days after normalization of body temperature; G. after receiving negative results of specific diagnostic methods D. after control radiography of the lungs

10. Vaccination against influenza indicated primarily for: A. All persons over 50 B. persons with chronic diseases of the cardiovascular, respiratory systems, kidneys, diabetes mellitus, immunodeficiency of various origins C. Newborns D. persons with 2 or 4 blood groups E. family members of an influenza patient

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture

1. 1 What is diphtheria? 2. What are common presenting complaints in patients with diphtheria? 3. What is the clinical course of respiratory diphtheria? 4. What are the general clinical findings in diphtheria? 5. Which lab studies definitively diagnose diphtheria? 6. When should treatment of diphtheria be initiated? 7. Why is it important to secure an airway in patients with diphtheria? 8. How effective is diphtheria vaccination, and how often are booster vaccines recommended? 9. What is meningococcal infection? What is meningococcal meningitis? What is meningococcemia? 10. What are serogroups of meningococci that cause meningococcal infection? 11. What are the clinical types of meningococcal infection 12. What are the signs and symptoms of meningococcal nasopharyngitis? 13. What are the signs and symptoms of meningococcal meningitis? 14. What are the signs and symptoms of meningococcemia? 15. How is a diagnosis of meningococcal infection confirmed? 16. What are the differential diagnoses for Meningococcal Meningitis? 17. How is meningococcal meningitis prevented? 18. What is the role of CT/MRI scanning in the workup of meningococcal meningitis? 19. What is the role of empiric therapy in the treatment of meningococcal meningitis? 20. What is the prognosis of meningococcal infection?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 «» from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases and epidemiology Module № Infectious diseases and epidemiology Topic Lesions of oral mucosa in infectious diseases (tonsillitis, diphtheria, herpes infections). Course 4 Faculty Stomatological

Number of teaching hours: 2

Poltava 2019 1. Scientific and methodological substantiation of the topic. High contagiousness of tonsillitis, general susceptibility, lack of specific prophylaxis, significant economic losses that occur with temporary disability require knowledge of the diagnosis, treatment and prevention of this disease. Diphtheria is an acute anthroponous infectious disease with a drip transmission mechanism, which is caused by diphtheria corynebacteria and is characterized by local fibrinous inflammation (more often than the mucous membranes of the oropharynx) and general intoxication phenomena with a predominant damage to the cardiovascular and nervous systems. Immunization of children against diphtheria in the USSR, which has been carried out since the 30s of the 20th century, made it possible to practically eliminate diphtheria by the mid-70s. She was registered in the form of lonely cases, but periodically reminded of herself in different countries. And from the late 80s - early 90s, an epidemic of diphtheria began, which covered mainly the republics of the former SS, the maximum incidence fell on Russia and Ukraine. The diphtheria problem is still relevant today. Against the background of a decrease in morbidity, the proportion of severe and complicated forms and mortality rates remain high. Knowledge of this pathology is necessary for a doctor of any specialty, since the effectiveness and timeliness of providing medical care and anti-epidemic measures depends on the quality and speed of diagnosis. Meningococcal nasopharyngitis is often asymptomatic in carriers, which is very dangerous in the epidemic plan. The relevance of this topic is also due to the high prevalence of herpes viruses among the population, ease of infection, often latent course and lifelong persistence. Herpes virus infections occupy the 3rd place in frequency after cardiovascular and oncological , are characterized by different localization of the process and a diverse clinic. According to the WHO, diseases caused by herpes simplex viruses of the 1st and 2nd types occupy the 2nd place (15.8%) after the flu (35.8%) as the cause of death from viral infections.Recently, more and more attention has been paid to herpes viruses and as representatives of the group of TORCH infections, their role in the development of hematological, neurological and oncological diseases has been proved; a certain role is given in the occurrence of Alzheimer's disease, sarcoidosis, chronic fatigue syndrome and other pathologies. Infectious mononucleosis (IM) is a disease accompanied by a variety of clinical and laboratory manifestations, the most logical of which is the reaction of the lymph nodes and hematological changes. Until recently, its development was associated exclusively with the Epstein- Barr virus (EBV). As the possibilities of virology and immunology increased, it became clear that similar pathological changes, in addition to EBV, can also be caused by some other pathogens, mainly representatives of the herpes virus family. And if earlier, in order not to be confused with EBV infection, a similar pathology caused by other lymphotropic viruses was described as a mononucleosis-like or mononucleosis syndrome, then in recent times there are more and more recommendations in the literature to combine them under the common name “IM”, adding an etiological decoding. However, in most cases, the etiological structure of the disease remains undecrypted, and the course, outcome and consequences largely depend on the etiology of the causative agent.The causative agents of IM are opportunistic infections with AIDS. 2. The educational goals of the lecture. To analyze the anatomical and physiological characteristics of the respiratory system; know the rules for hospitalization of patients with diphtheria; modern views on the etiology, epidemiology of diphtheria; main pathogenesis chains in diphtheria; pathological and anatomical changes in the oropharynx and other organs with diphtheria; the role of allergic and autoimmune processes in diphtheria; clinical classification of diphtheria; features of clinical symptoms, the nature of the course of the main clinical options, the frequency of complications, the prognosis for various clinical variants of diphtheria, leading syndromes during the course of the disease; the nature of the course of diphtheria in severity and severity of the process; clinical characteristics of symptoms in early and late complications of diphtheria; principles of specific and non-specific laboratory diagnosis of diphtheria and its complications (examination protocol); features of instrumental research methods in various clinical forms; differential diagnosis of diphtheria; treatment principles for various clinical variants of diphtheria, taking into account the severity of the course; etiotropic therapy of diphtheria; treatment of emergency conditions with diphtheria; anti-epidemic measures in the center of diphtheria; diphtheria prophylaxis; rules for extracting convalescents of diphtheria; principles of medical examination. To interpret the etiology and epidemiology of herpes infection, chickenpox, herpes zoster, pathogenicity factors of pathogens; clinical manifestations of herpes infection, chickenpox, herpes zoster; pathogenesis, MI, the timing and clinical manifestations of complications of herpes infection, chickenpox, herpes zoster, MI; laboratory diagnosis of herpes infection, chickenpox, herpes zoster, MI; principles of treatment of herpes infection, chickenpox, herpes zoster; principles of prevention of herpes infection, chickenpox, herpes zoster, MI; indication for hospitalization for herpes infection, chickenpox, herpes zoster, MI; management tactics in case of emergency; prognosis of the disease, depending on the severity and form of herpes infection, chickenpox, herpes zoster, MI; rules for discharge from the hospital and rules for medical examination of convalescents; the concept of manifest and latent forms, carriage, persistence, relapse and exacerbation; classification of infectious diseases according to the duration of the course; features of the defeat of herpes viruses of the central nervous system; the role of herpes viruses in the pathology of pregnant women and the fetus; Features of the course of herpes virus infections in AIDS patients. Explain the basic rules of work at the bed of an infectious patient; to collect a medical history with an assessment of epidemiological data characteristic of airborne infections; apply the rules for hospitalization of patients with diphtheria in compliance with the rules of anti-epidemic and personal safety; physically examine the patient with suspected diphtheria in compliance with the rules of anti- epidemic safety; identify the main symptoms and the timing of their occurrence, localization of the pathological process; draw up medical documentation on the fact of establishing a preliminary diagnosis of diphtheria (emergency notification to the sanitary-epidemiological station (SES); evaluate macroscopic changes during examination and collect material for bacteriological research; draw up a laboratory plan and additional examination of the patient; interpret the results of a laboratory examination, including specific diagnostic methods; draw up a preliminary diagnosis according to the existing classification, justify it according to the epidemiological history, medical history, objective examination; appoint the necessary laboratory and instrumental examination in compliance with the rules of anti-epidemic safety, give interpretation of the results to substantiate the final clinical diagnosis according to the clinical classification; conduct differential diagnosis with other similar inf diseases and non-infectious diseases; draw up a treatment plan depending on age, clinical form, course and complications that have arisen premorbid background; provide assistance in case of emergency conditions inherent in diphtheria; outline a preventive plan in the center of diphtheria; give recommendations for follow-up observation, regimen , diets, treatment in the period of convalescence. 3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc. 4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork

Autonomy and No. Competence Awareness Skill Communication responsibility 7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. protect the environment Autonomy and No. Competence Awareness Skill Communication responsibility 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions Autonomy and No. Competence Awareness Skill Communication responsibility examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care systems, the medical algorithm for treatment providing measures Autonomy and No. Competence Awareness Skill Communication responsibility emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the Corynebacterium diphtheria, Neisseria meningitis, EBV, methods for the specific diagnosis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture № The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. The etiology of tonsillitis, diphtheria, herpesvirus infections 2. Epidemiology of tonsillitis, diphtheria, herpes virus infections 3. Pathogenesis of tonsillitis, diphtheria, herpes virus infections 4. Clinic of tonsillitis, diphtheria, herpes virus infections 5. Diagnosis of tonsillitis, diphtheria, herpesvirus infections 6. Treatment of tonsillitis, diphtheria, herpes virus infections 7. Prevention of tonsillitis, diphtheria, herpesvirus infections. 1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture:

Meningococcal infection Meningococcal infection is an acute infectious disease of the human, caused by meningococcous Neisseria Meningitigis. The mechanism of the transmission of the infection is air-drop. The disease is characterized by damage of mucous membrane of nasopharynx (nasopharingitis), generalization of the process in form of specific septicemia (meningococcemia) and inflammation of the soft cerebral membranes (meningitis). Etiology. The causative agent is Neisseria meningitidis. It is small gramm-negative diplococcus, aerobic, catalise and oxidase-positive, not-motile and possess a polysaccharide capsule, which is the main antigen and determines the serotype of the species. Meningococcus may be seen inside and outside of neutrophills (Fig.14). The main serogroups of pathogenic organisms are A, B, C, D, and W135, X, Y, Z and L. The bacterial membrane is a lipopolysaccaride. The pathogenic properties of meningococcus are known insufficiently, because meningococcal infection is anthroponosis. The factors of pathogenic action of meningococcus are biological properties, promoting its attachment on the mucous membrane of nasopharynx, depression symbiotic microflora, penetration through mucous barriers, toxic properties and other. One of such properties is specific attachment or adhesion of meningococcous to the cells of epithelium of respiratory tract. Adhesion is phenomenon, promoting to colonization of meningococcus on the mucus. Physical factors (adsorption of microbes on the surface of the cell) and fermentative processes have the meaning in the appearance of adhesion. Epidemiology. Meningococcal infection is typical anthroponosis. The sourses of infection are healthy carriers of meningococcus, the patients with meningococcal nasopharingitis and the patients with generalized forms of the disease. The patients with generalized form of the disease are the source of infection for 1-3 % of infected persons, the patients with meningococcal nasopharingitis – for 10-30 %, carriers are the sources of infection for 70-80 % from general number of infected. The level of healthy carriers promotes the level of morbility in certain region. So, carriers may compose 3-12 %. It is temperate sporadic morbility. Carriers may achieve 20 %. This situation is marked as unsatisfactory. The outbreaks are observed. Carriers may achieve 30-40 %. In this case epidemic of meningococcal infection arises. The mechanism of transmission of the infection is air-drop. The infection is realized during cough, sneezing. In this the narrow contact and sufficient exposition are necessary. The estimate of the age morbidity of meningococcal infection testifies about that 70-80 % of the cases of the diseases have occasion to children. Children of the age 1-5 years compose 50 %. Meningococcal infection is marked rarely at the first three month of the life. Pathogenesis. In meningococcal infection entrance gates are mucous membrane of nasopharynx. It is place of primary localization of the agent. Further meningococci may persist in epithelium of nasopharynx in majority of the cases. It is manifested by asymptomatic healthy carriers. In some cases meningococci may cause inflammation of mucous membrane of upper respiratory tract. It leads to development of nasopharingitis. The localization of meningococcus on mucous membrane of nasopharynx leads to development of inflammation in 10-15 % of the cases. The stages of inculcation on the mucous membrane of nasopharynx and penetration of meningococcus into the blood precede to entrance of endotoxin into the blood and cerebrospinal fluid. These stages are realized with help of factors of permeability. It promotes of the resistance of the meningococcus to phagocytosis and action antibodies. Meningococci penetrate into the blood after break of protective barriers of mucous membrane of upper respiratory tract. There is hematogenous dissemination (meningococcemia). It is accompanied by massive destruction of the agents with liberation of endotoxin. Meningococcemia and toxinemia lead to damage of endothelium of the vessels. Hemorrhages are observed in mucous membrane, skin and parenchymatous organs. It may be septic course of meningococcemia with formation of the secondary metastatic focuses in the endocardium, joints, internal mediums of the eyes. In most of the cases penetration of meningococci in the cerebrospinal fluid and the soft cerebral covering is fought about by hematogenous ways through the hematoencephalic barrier. Sometimes meningococci may penetrate into the skull through perineural, perilymphatic and the perivascular way of the olfactory tract, through the enthoid bone. Morbid anatomy. In meningococcal infection pathologoanatomical changes depend on form and duration of the disease. Nasopharingitis is characterized by hyperemia of the pharyngeal walls, edema of the epithelial cells, regional infiltration, hyperplasion and hyperthophy of lymphoid follicles. Signs of catarrhic inflammation are found in trachea and bronchi. Cases of fulminate meningococcal infection is characterized by blood vessels disorders and severe impairments of blood circulation. The main target are the microcirculation vessels. The vascular lumen turns narrow, thrombs are found. Thrombs are usually found in small veins. Hemorrhages into skin, subcutaneous tissue, lungs, myocardium, subendocardial hemorrhages, hemorrhages into renal parenchyma, adrenals, brain (Fig.2) and subarachnoidal space are typical. Classification of the clinical forms of meningococcal infection: I. Primarily localized forms: a) meningococcal carrier state b) acute nasopharyngitis; c) pneumonia. II. Gematogenously generalized forms: a) meningococcemia: typical acute meningococcal sepsis; chronic; b) meningitis; meningoencephalitis; c) mixed forms (meningococcemia + meningitis, meningoencephalitis). d) rare forms (endocarditis, arthritis, iridocyclitis). In meningococcal carriers the clinical manifestations are absent. Clinical current of meningococcal nasopharingitis. The most common complains of the a patients are headache, mainly in the frontal-parietal region, sore throat, dry cough, blocked nose, fatigue, weakness, loss of appetite, violation of the sleep. In most of the patients body temperature rises upto subfebrile and lasts for not more than 3-7 days, sometimes 5-7 days. The skin is pale, conjunctival vessels and sclera are injected. There are hyperemia and edema of the mucous membrane of the nose. In many patients the posterior wall of the pharynx seem to be covered by mucous or mucous – purulent exudation. Inflammatory changes in the nasopharynx can be noticed after 5-7 days, hyperplasion of lymphoid follicles lasts longer (till 14-16 days). In the peripheral blood temperate leukocytosis with neutrophylosis and a shift of leukocytaric formula to the left, increase in ERS may be revealed. Nasopharyngitis precedes to development of generalized forms of the disease. Diagnostics. The diagnosis of all forms of meningococcal infection is based on the complex of epidemiological and clinical data. The final diagnosis is established with help of the laboratory examination. Separate methods have different diagnostical significance in various clinical forms of meningococcal infections. The diagnosis of meningococcal carrier is possible only by use of bacteriological method. The material for analysis is the mucus from proximal portions of upper respiratory tract. In diagnostics of meningococcal nasopharyngitis epidemiological and bacteriological methods occupy the main place. Clinical differention of meningococcal nasopharyngitis from nasopharyngitis of the other genesis is no possible or very difficult. In recognition of generalized forms, anamnestical and clinical methods of diagnostics have real diagnostic significance, mainly in combination of meningococcemia and meningitis. The examination of cerebrospinal fluid (CSF) has great meaning in diagnostics of meningitis. In lumbar punction cerebrospinal fluid flows out under high pressure and by frequent drops. The cerebrospinal fluid may flow out by rare drops only due to increased viscosity of purulent exudation or partial blockade of liquor’s ways. Cerebrospinal fluid is opalescent in initial stages of the disease. Then it is turbid, purulent, sometimes with greenish shade. Pleocytosis achieves till 10-30 103 in 1 mcl. Neuthrophils leukocytes predominate in cytogram. Neuthrophilous compose 60-100% of all cells. In microscopy neuthrophils cover intirely all fields of vision, inrarely. Quantity of protein of cerebrospinal fluid increases (till 0,66-3,0 g/l). There is positive Nonne-Appelt’s reaction. The reaction of Pandy composed (+++). Concentration of glucose and chlorides are usually decreased. In generalized forms the final diagnosis is confirmed by bacteriological method. In diagnostics immunological methods are used too. Reactions of hemagglutination, latex agglutination are more sensitive. Therapy. The therapeutic tactics depends from the clinical forms, severity of the course of the disease, presence of complications, premordal state. In serious and middle serious course of nasopharyngitis antibacterial remedies are used. Peroral antibiotics oxacillin, ampyox, chloramphenicol, erythromycin are used. The duration of the therapy is 3-5 days and more. Sulfonamides of prolonged action are used in usual dosages. In light duration of nasopharyngitis the prescription of antibiotics and sulfonamides is no obligatory. In therapy of generalized forms of meningococcal infection the central place is occuped by antibiotics, in which salt benzil penicillin stands at the first place. Benzyl penicillin is used in dosage of 200,000-300,000 IU/kg/day. In serious form of meningococcal infection daily dosage may be increased to 500,000 IU/kg/day. Such doses are recommended particularly in meningococcal meningoencephalitis. In presence of ependimatitis or in signs of consolidation of the puss the dose of penicillin increases to 800 000 IU/kg/day. In similar circumstances it is necessary to inject sodium salt of penicillin by intravenously in dose 2 000 000-12 000 000 units in day. Potassium salt of penicillin is no injected by intravenously, because it is possible the development of hyperkalemia. Intramuscular dose of penicillin is preserved. Endolumbar injection of penicillin is no used practically last years. Daily dose is injected to the patient every 3 hours. In some cases interval between injections may be increased up to 4 hours. The duration of the therapy by penicillin is decided individually depending on clinical and laboratory data. The duration of penicicllin therapy usually 5-8 days. There are satisfactory results of the treatment of meningococcal infection by remedies from the group of tetracycline. Tetracycline is injected in dose 25 mg/kg intramuscularly and intravenously in the cases of resistant agents to the other antibiotics. Pathogenetic therapy has exceptional significance in therapeutic measures. It is performed simultaneously with etiotropic therapy. The basis of pathogenetic therapy is the struggle with toxicosis. Salt solutions, macromolecular colloid solutions, plasma, albumin are used. Generally 50-40 ml of fluid is injected on 1 kg of body’s mass per day in adults under the control of diuresis. Prophylaxis of hyperhydratation of the brain is performed simultaneously. Diuretics (lasix, uregit) are injected. In serious cases glucocorticosteroids are prescribed. Full doses is determined individually. It depends on dynamics of the main symptoms and presence of complications. Generally hydrocortisone is used in dose of 3-7 mg/kg/day, prednisolone – 1-2 mg/kg/day. Oxygen therapy has great significance in the treatment of the patients. Diphtheria Etiology. This disease is produced by Corynebacterium diphtheriae, non-motile, gram-positive rod with a characteristic swelling at one end. Neisser-stained bacilli viewed microscopically by the fluorescent method demonstrate the presence of volutin grains (Babes-Erns granules) in their ends. The genus Corynebacterium diphtheriae includes toxicogenic (causative agent of diphtheria) and non- toxicogenic corynebacteriae which do not cause diseases with clinical symptoms of diphtheria. By their cultural biochemical and other properties Corynebacteria diphtheriae are classed into mitis, gravis, and intermedins groups. There is no correlation between the type of the causative agent and severity of the clinical symptoms of the disease. As the bacteria multiply they produce exotoxin which evokes the main clinical manifestations of the disease. Corynebacteria diphtheriae are stable in the environment. In the dry state they can survive on various objects, such as toys, dishes, linen, for many days; in milk and other foods they remain viable for 10-15 days. The bacteria are stable to low temperatures but are sensitive to high temperature. All disinfectants in common concentrations (3-5 per cent) kill the bacteria in 20-30 minutes. Epidemiology. The source of infection is a diphtheria patient with clinically manifest symptoms or with an asymptomatic course of the disease, convalescents, and carriers of toxicogenic strains of the bacteria. The infected person can be the source of infection during the last days of the incubation period and remain contagious for the entire duration of the disease. From the epidemiologic standpoint, the greatest danger are patients with mild and obliterated forms of the disease that now prevail and can be mistaken for lacunar or catarrhal tonsillitis, rhinitis, and the like. Eradication of the agent from convalescents usually ends in 15-20 days, less frequently in 1-2 months. Healthy carriers of toxicogenic strains of the bacteria are dangerous because their number is much greater than of diphtheria patients and convalescents. The number of toxicogenic carriers depends on the morbidity; their number is much greater in the foci of diphtheria. Overcrowding and duration of contacts are important for the rate of carrier state. In closed collective bodies the number of carriers is 2-3 times greater than in other communities. The main transmission mechanism is air-borne, because patients and carriers dissipate the bacteria with droplets of mucus during coughing, sneezing, crying, or talking. The infection can be transmitted through the fomites (dishes, toys), food (milk, cold dishes) that may be infected from a patient or a carrier. Not all infected develop the disease; some become healthy carriers. The percentage of carriers in the focus of infection can be as high as 10. The presence of antitoxic immunity in vaccinated children does not exclude toxigenic carrier state, while disease does not develop. Diphtheria occurs as sporadic infections with rises during the cold season. Stable immunity is induced in those who sustained the disease. Pathogenesis. The portal of entry is the mucosa of the upper airways. Less frequently the bacteria enter through the mucosa of the yes, external genitalia or injured skin. The bacteria multiply at the site of their entry and produce toxin. Local changes and general manifestations of the disease are associated with toxaemia of the patient. Local changes in diphtheria are manifested by necrosis of the mucosa and formation of a fibrinous membrane that tightly adheres to the underlying tissue. Grey or yellow membrane consisting of fibrin, leucocytes, desquamated epithelium of the mucosa and bacteria can be seen on the surface of inflamed mucosa. As the disease progresses, not only the multilayered epithelium of the faucial or pharyngeal mucosa is necrotized, but also the basement membrane. The thick fibrous membrane is detached from the underlying tissue with difficulty (diphtheritis inflammation). After the membrane is removed with a cotton tampon or a spatula, the tonsillar surface bleeds. When the tracheal and bronchial mucosa (which is lined with a single layer of columnar epithelium) is involved, only the epithelial layer is usually necrotized and the formed membrane is therefore loosely adherent to the underlying tissue and is easily detachable (croupous inflammation). Regional lymph nodes are also involved. The toxic form of diphtheria is attended by oedema of the facial and pharyngeal mucosa and by oedema of the neck connective tissue. The diphtheria toxin affects first of all the nervous and cardiovascular system, the adrenal glands and the kidneys. Clinical picture. The incubation period is from 2 to 10 days (usually 3-5 days). According to location of the primary lesion, the following clinical forms are distinguished: faucial diphtheria, laryngeal diphtheria, nasal diphtheria, and diphtheria of rare location (in the eye, ear, genitalia, skin, wound). Each of these forms is divided according to severity into mild and toxic forms. The toxic form is, in turn, subdivided into subtoxic, toxic (degrees I, II, III), hypertoxic and haemorrhagic. Faucial diphtheria. The region of the tonsils is only involved (local form). If the membrane extends from the tonsils onto the mucosa of the palatine arches, uvula, fauces, the disease is diffuse. In the toxic form of the disease, in addition to the vast process in the fauces (Plate IV), involved also are the regional lymph nodes with toxic oedema of the neck cellular tissue; the condition is characterized by toxaemia. The localized form of diphtheria is most common. The catarrhal (without membrane) and insular (separate islands of membrane can be seen on the tonsils) subtypes are distinguished. The onset of the disease is gradual, with moderate elevation of temperature to 38 °C, malaise, poor appetite, headache and slight pain during swallowing. The fauces become hyperaemic by the end of the first or second day. Greyish-white membrane of moderate thickness appears on one or, most frequently, both tonsils. When removed by a cotton tampon or a spatula, bleeding surface is exposed. Submandibular and anterior neck lymph nodes are slightly enlarged. Signs of toxaemia are absent. Timely treatment eliminates the membrane in 2-5 days; the temperature normalizes. The diffuse form of the disease usually begins acutely, the body temperature rises to 38.5-39 °C, the patient complains of chill, weakness, headache, and deranged sleep. The tonsils are oedematous and enlarged, with a thick grey membrane on both sides of the tonsils. It extends to the palatine arches, the soft palate and the nasopharynx. The regional lymph nodes are tender and enlarged to a slightly greater extent than in the localized form. The diffuse form of diphtheria is often the result of untreated local form. Timely specific treatment leads to recovery of the patient in 7-10 days. Toxic form of faucial diphtheria. The onset of the toxic faucial diphtheria is usually fulminant: the body temperature rises to 39-40 °C, weakness is severe, the face is pallid and slightly oedematous. The heart sounds are dull; tachycardia is seen (140-160 beats per minute). The membrane is thick, greyish-white or brownish-grey; it covers the tonsils and extends to the soft and even hard palate. The nasopharynx and the nasal cavity can also be involved. Nasal discharge is serosanguineous. The breath is foul and sweetish. Oedema of the faucial mucosa and the membrane can mechanically impede respiration which becomes noisy and hoarse. Changes in the upper neck lymph nodes and oedema of the neck are a specific symptom of toxic diphtheria. The extent of oedema of the subcutaneous fat corresponds to the degree of toxaemia; the following three degrees of toxic diphtheria are distinguished in this connection: degree I-oedema extends to the middle of the neck, degree II - oedema extends to the clavicle, and degree III - below the clavicle. After specific treatment with antidiphtheria serum, the oedema and membrane disappear only in 5-10 days. Local symptoms of the disease subside. Hypertoxic form is characterized by severe fulminant local process in the fauces, toxaemia attended by quickly developing cardiovascular failure. The patients often die in the first 4- 5 days. Laryngeal diphtheria (diphtheritic or true croup). The disease can be independent, or it can be superimposed upon faucial or nasal diphtheria (secondary croup). Three stages are distinguished in the course of laryngeal diphtheria. The dysphonic stage of the disease begins with elevation of body temperature, malaise, and hoarseness. The patient complains of barking cough, which becomes' voiceless with progression of dysphonia to aphonia. In 1-3 days, the disease transforms into the stenotic phase. Its early symptom is noisy respiration that resembles the sound of a saw cutting a wet wood. Another symptom of stenosis of the upper airways is retraction of the yielding parts of the chest during inspiration (due to rarefaction in the chest). Accessory muscles are involved in the respiration act. Duration of the stenotic stage varies from several hours to 2-3 days. If the patient is not given operative treatment (intubation, tracheostomy), asphyxia develops. Asphyxia is characterized by marked anxiety of the child which is then followed by drowsiness, and cyanosis of the lips, the nose and the nails. Respiration is fast and shallow, pulse is weak and arrhythmic, arterial pressure decreases, the forehead is covered with cold sweat; convulsions develop and the patient dies of suffocation. Nasal diphtheria. This disease is usually seen in infants. The body temperature is subfebrile or normal, nasal breathing is impeded, the nasal discharge is serosanguineous. Excoriation and fissures appear at the nostrils. Membranes and ulcers covered with crusts develop on the nasal mucosa. Toxaemia is mild. Diphtheria of rare location occurs mostly in infants due to secondary faucial and nasal diphtheria. The clinical picture of diphtheria has substantially changed in connection with vaccination of children. Faucial diphtheria often runs the same course as catarrhal or lacunar tonsillitis. Complications. The common complications of diphtheria are insufficiency of the hypothalamic- pituitary system with collapse, myocarditis, peripheral paralysis and paresis. Complications usually develop after the toxic form of diphtheria. Early and late myocardites are distinguished. Early myocarditis develops in 2-5 days after the onset of the disease and is characterized by tachycardia, dysrhythmia, transient elevation and then fall of arterial pressure (diastolic pressure is especially low). The pulse is small and thready; the skin is pallid; adynamia develops. The patient can die of collapse. Late circulatory disorders develop in the end of the first or on the second or third week of the disease. Peripheral paralysis of the soft palate, accommodation, and polyneuritis can develop in 2-4 weeks after the onset of the disease. Muscles of the larynx and pharynx, and of the trunk and extremities are paralyzed less frequently. Nephrosis is also among the complications. It is characterized by albuminuria, cylindruria, and the presence of single erythrocytes. Diagnosis. The diagnosis is based on clinical, epidemiologic and laboratory findings. The bacteriologic method is very important in identification of diphtheria. Sterile cotton tampons are used to take materials from the tonsils and the nasal mucosa (separate tampon for each smear). The material is taken in the morning before meals or at least 2 hours after meals. When taking material for a tonsillar smear, it is necessary that the tampon should not touch the tongue, the buccal mucosa or the teeth. A spatula should therefore be used. In the presence of membranes, the material is taken at the border between the affected and healthy tissues. A nasal specimen is taken by one tampon which is first passed into one and then the other nostril. The tampons should be delivered to the laboratory not later than in three hours. If it takes longer time to deliver the material to the laboratory, tampons soaked n glycerol (5 per cent solution) should be used. The material should be protected from cooling. The label must indicate the name of the patient, the place from which the material is taken (fauces, nose, skin), and other necessary information. The material taken from the fauces, tonsils, nose and other involved sites should be used to inoculate solid nutrient media (Clauberg's II, tellurite agar with blood) in Petri dishes. A preliminary result is ready in 1-2 days (colonies are studied in a binocular stereomicroscope; tests for toxicity and other rapid tests are performed). The final result can be obtained in three days. Treatment. The main treatment is early administration of antidiphtheritic serum (diphtheria antitoxin). Before administering the serum, the patient should obligatory be tested for sensitivity to foreign protein (intracutaneous test). The dose of the serum depends on the clinical form of the disease, its severity, and duration. The severer the disease and the longer its duration, the greater the dose. The first single dose for faucial diphtheria is 10 000-30 000 U; if the disease is diffuse, 30 000-40 000 U; and if its form is toxic, the dose should be 50000-120000 U. Injections should be repeated at 8-12 hour intervals, and then given every day, until signs of toxaemia disappear and the fauces are cleared of the membranes. Depending on severity of the disease, the daily dose for laryngeal diphtheria during the first day of the therapy should be from 15 000 to 30 000 U. Administration of the diphtheria antitoxin should be combined with antibiotics: the tetracyclines and erythromycin, in common doses depending on the age of the patient (for seven days). Detoxicating therapy of faucial diphtheria of the first and second degree includes haemodez and rheopolyglucin with a 10 per cent glucose solution (intravenous drip), the injection dose is 20-30 ml/kg. Ascorbic acid, cocarboxylase, and insulin should be added to the solution. Diuretics should also be given. Operative treatment (intubation and tracheostomy) is necessary in croup patients with severe stenosis, if conservative treatment fails (thermal procedures, steam inhalations, oxygen therapy, etc.), and if the second stage transforms into the third stage (asphyxia). Intubation consists in passing a tube into the lumen of the constricted larynx. In this time, diphtheritic croup is rare. After abatement of acute symptoms, patients with mild diphtheria are allowed to leave their beds. Patients with toxic diphtheria should be kept in hospital regardless of the absence or presence of complications. Patients with subtoxic forms and toxaemia of the first degree should remain in bed for at least a month, with toxic diphtheria of the second degree, 40-45 days, and of the third degree, 50-60 days. Prevention and control. Active immunization is the main prophylactic measure against diphtheria. Epidemiologic efficacy of immunization depends on timely vaccination of the entire children's population. Primary immunization in infants (in the absence of contraindications) should be conducted at the age of 3 months, using adsorbed vaccine (combined vaccine against pertussis, diphtheria, and tetanus). The vaccination includes three intramuscular injections of 0.5 ml doses given at 45-day intervals. The first revaccination should be done in 18-24 months after the vaccination (0.5 ml dose). The second and third revaccinations are given at the age of 9 and 16 years: 0.5 ml doses of the adsorbed diphtheria-tetanus anatoxin with decreased content of antigens (ADS-M toxoid). Subsequent revaccinations (0.5 ml) are given each decade, i. e., at the age of 26, 36, 46 and 56 years. If a child develops a complication in response to the first vaccination with adsorbed diphtheria and tetanus toxoids and pertussis vaccine, next vaccination should be done with the ADS-M toxoid. In order to prevent diphtheria spread, a constant epidemiologic supervision is necessary. It includes: control of the immunologic structure of population, control of circulating diphtheria agent among population; early detection of diphtheria cases, epidemiologic analysis and evaluation of efficacy of antidiphtheria measures. The obtaining data are used as the basis for planning and carrying out of prophylactic and anti-epidemic measures. Control of the epidemiologic structure of population includes comparison of the vaccination reports with the condition of immunity against diphtheria in children and adolescents. This condition is determined by the direct haemagglutination reaction with diphtheria diagnosticum. In order to prevent formation of diphtheria foci, and for timely detection of patients and carriers, children should be inspected by a otorhinolaryngologist before formation of collective bodies (schools and the like). The screened patients should be treated. Routes of infection spread should be disrupted by proper sanitary and hygienic measures, especially in children's institutions and food industry and catering. Measures in the focus. Before the patient is taken to hospital, current disinfection should be done. A final disinfection with obligatory decontamination of the fomites and the bedding is necessary after hospitalization. The main object of the anti-epidemic measures in the focus is timely detection of diphtheria patients, persons suspected for diphtheria, carriers of toxigenic bacteria, and persons with otorhinolaryngologic diseases that were not immunized against diphtheria. The source of infection is revealed by questioning the patient and his contacts about the presence of diphtheria patients or persons suspected for diphtheria in their surroundings. If a person who contacted a diphtheria patient or a carrier is revealed in the infection focus, he or she must be examined bacteriologically and observed for 7 days from the moment of isolation of the patient or the carrier, and after final disinfection. If toxigenic bacteria of diphtheria are revealed after the first bacteriologic examination, the contacts should be given repeated examinations until no carriers are revealed any longer. Taking material from the fauces and the nose should be combined with examination of the contacts by otorhinolaryngologist. Persons with various skin lesions (furuncles, pyoderma, excoriations, crusts, and the like) should also undergo bacteriologic examination. In order to prevent diphtheria among contacts, preventive immunization should be performed in the focus of infection. Children in whom the term of vaccination has expired, adolescents under 16 years of age, and older persons, who were not immunized during the past decade and to whom vaccination is not contraindicated, should be immunized. The AD-M or ADS-M toxoids are used. They are given in a single 0.5 ml dose. All other contacts aged from 3 to 16 years should be examined (direct haemagglutination reaction). Children in schools and preschool institutions, and also workers of food industry and food catering establishments, should be admitted to their jobs only after obtaining a negative result of the test for the carrier state. Health education of population is also helpful. Groups of children in which diphtheria cases or carriers were revealed, should be dismissed. All contacts (children and the personnel) should be tested for the carrier state by examining their smears (specimens taken from the fauces and the nose). The group can be re-collected after final disinfection if the results of testing are negative and if acute inflammatory processes in the fauces or the nasopharynx are absent. If laboratory examinations are infeasible, the children can gather in groups again in 7 days after isolation of the patient and in the absence of inflammation in the fauces or the nasopharynx. The children and the personnel should be observed for 7 days: two medical examinations during a day with obligatory thermometry. Taking material for bacteriologic studies should be combined with examination of all contacts by a otorhinolaryngologist.

Now the Herpesviridae family contains more than 100 viruses. These viruses parasitize on various vertebrates - monkeys, horses, cattle, sheep, pigs, rabbits, cats, dogs, mice, rats, birds, guinea- pigs and the human beings. Each host type can be infected by different herpesviruses having the different characteristics. Herpesviruses can be subdivided into several classes depending on the type of the infected cells and the natural host persistence. All herpesviruses have an intracellular parasitizing cycle that takes place in a nucleus and a cytoplasm of the infected cell. During this cycle the inclusions of virus particles accumulate within the nucleus that cause an enlargement both the nucleus and the cell as a whole (a giant cell pathogeny). The herpesvirus infection can cause various human diseases (see the table). The tissue tropism and the ability to a persistence and a latency in the infected organism are the unique biological properties of all human herpesviruses. Subfamily Virus type and its Primary diseases associated designation with this herpesvirus type α-herpesviruses have a short Herpes simplex Labial and genital herpes. reproduction cycle with a cytopathic virus type 1, Herpetic gingivostomatites. effect on the infected cell cultures. They HSV-1 Mucocutaneous herpes. persist in CNS, supporting a latent Ophthalmoherpes. infection, and cause mucocutaneous forms of diseases and respiratory tract Herpes encephalitis. involvements. Pneumonitis.

In the cause of virusemia of pregnant women - stillbirth, premature birth, spontaneous abortion. Herpes simplex Genital herpes. Neonatal virus type 2, herpes. HSV-2 Disseminated herpes. Varicella-zoster Chicken pox. Shingles. virus (herpes zoster Disseminated chicken pox. varicellosis) - human herpes virus type 3, VZV β-herpesviruses Cytomegalovirus Congenital anomalies. (CMV) have a slow reproduction rate and a strict Retinopathies. pathogenicity for the only one host type. It causes less intensive changes of cell Hepatitis. cultures. Pneumonitis.

AIDS or post-transplantation immunodeficiency cytomegalia.

Retinite, colitis or neuroinfections in the case of AIDS γ-herpesviruses have a tropism to B- and Epstein-Barr virus Kissing disease (infectious T-lymphocytes and persist within these (human herpes mononucleosis). Burkitt's cells for a long time. virus type 4), lymphoma. Rhinopharyngeal EBV carcinoma. Hairy leukoplakia.

B-cell lymphoproliferation. Human herpes B-cell lymphoma. virus type 6, HHV-6 Erythema of the newborn.

Sudden exanthema.

Post-transplantation systemic diseases. Human herpes Erythema of the newborn. virus type 7, HHV-7 Chronic tiredness syndrome. Human herpes Kaposi's sarcoma of HIV- virus type 8, seronegative patients. HHV-8 Kaposi's sarcoma associated with AIDS and HIV-infection. Human herpesviruses: Human herpesviruses can be subdivided on A-, B- and G-viruses. A-viruses (HSV, shingles) are located in neurons, B-viruses (CMV) - in myelocytes and G-viruses (EBV) - in lymphocytes. HSV: herpes simplex is one of the most common human virus infections. There are two types of this virus. HSV-1 usually causes the oral cavity lesions, and HSV-2 is detected mainly at the genital lesions. About 90% of all people are infected by HSV type 1 or 2 and about 20% of them have any clinical signs of the infection. VZV: Varicella-zoster virus is a DNA herpesvirus. It causes two types of lesions - the chicken pox (varicella) and the shingles (zoster). Varicella-zoster virus causes only human diseases; animals are immune to it. CMV: cytomegaloviral infection is very common human viral infection. About 90% of urban population and 60% of rural population are the latent carriers of this virus. CMV is the most dangerous to the fetus and the newborn. It is one of the most common viruses causing a prenatal infection, and it belongs to the TORCH infection group. Clinical signs of the CMV infection (CMVI) of the newborn can include the , pneumonia, cachexy, microcephalia, chorioretinitis, gastroenteritis, mental retardation, deafness, heart and liver pathology, etc. About 2% of newborns were infected by CMV during a prenatal period; up to 10% of these children perish in the course of year. The CMVI signs are diagnosed for approximately 10% of infected children after their birth. Among the asymptomatic infected children approximately 10-20% will have in future such serious consequences as the mental retardation, visual and hearing impairments. 10-60% of children get the infection during their birth or during first 6 months from the mother's milk. CMVI usually accompanies the immunodeficiency state. CMVI develops for 40% of AIDS patients, especially if the number of SV-4 T-lymphocytes decrease below the certain level. In the absence of an opportune treatment the death-rate of CMV-pneumonia patients after the bone marrow transplantation runs up to 85%. The cytomegalovirus destroys human cell structures, causing a formation of clobs from the nucleus, mitochondria, endoplasmic reticulum, Golgi complex and lysosomes. After such destruction the cell is filled with fluid and becomes inflated, taking a specific form of "owl's eye". The "owl's eye" symptom has been discovered in 1881 by Ribbert. In 1921 Goodpasture and Tolbert have assumed the possible viral nature of the cytomegaly ("cyto" - the cell; "mega" - large dimensions). EBV ( EBV ): Epstein-Barr virus (human herpes virus type 4) has been found in 1964 in the tumor samples sent by Dr. Denis Parson Berkitt, an English surgeon working in Uganda. Several years earlier he has presented a scientific report testifying that in some Africa countries with the hot and wet climate there can be found a special oncologic disease of children with a frequency of 8 morbid events per 100000 of population. Later this disease has been called as "Berkitt lymphoma". Trying to clear up the causes of this disease with the help of an electron microscopy, Epstein, Barr and Achong have detected an unknown herpesvirus called as Epstein-Barr virus. There is no any precise information about the frequency of EBV infection. After an initial infection the Epstein-Barr virus remains in an organism for life. About 15-25% of healthy EBV-positive adults excrete a virus from the fauces. The higher frequency of some types of malignant tumors (just those tumors that presumably can be caused by EBV) is registered for regions with the heightened frequency of the kissing disease (infectious mononucleosis). HHV-6: human herpes virus type 6 was isolated from peripheral blood lymphocytes of the patients suffering from lymphoproliferative diseases (including AIDS patients). HHV-7: human herpes virus type 7 was found in 1990, now is actively investigated. HHV-8: human herpes virus type 8; it is possible that this virus takes part in a Kaposi's sarcoma pathogeny. This sarcoma is the main type of malignant tumors (up to 40-60%), striking the patients with the HIV-infection. In this connection it is proposed to add Kaposi's sarcoma to the list of viral infection. Latence and persistence: A persistence is an ability of herpesviruses to reproduce (replicate) itself continuously or cyclically within infected cells of tropic tissues that produces a constant threat of an infectious process development. An infection of sensory ganglions by HSV is one of the important stages of the herpesviral infection pathogeny. The virus penetrates into sensory nerve-endings and then through the centripetal nerve fibres comes into paravertebral ganglions. In the case of a facial herpes there will be trifacial sensory ganglions; for a genital herpes there will be lumbosacral ganglions, becoming the viral reservoirs for its sexual transmission. In the case of a normal virus-specific immune response the resolution of an initial disease and the HSV elimination from tissues and organs takes place in 2-4 weeks after the infection. However, in paravertebral ganglions the virus can transform itself into the non-capsulated L- and PREP-particles and persist in such form in nervous cells for a long time. In such latent phase herpesviruses remains in human ganglions for all life. The clinical latent stage is characterized by a presence of specific antiviral IgG (seropositivity), though usually during this stage the virus can not be detected in a peripheral blood of people with the normal immune status, even with the help of such high-sensitive technique as PCR. Because of the features of their enzymatic systems herpesviral strains have different abilities to the persistence and latence and the different sensitivity to anti-herpetic preparations. Each herpesvirus has its own persistence and latence rates. In this respect the most active among the investigated viruses are viruses of herpes simplex, the least active is the Epstein-Barr virus.

8. Materials for activating students during a lecture: 1. Characteristics of the causative agent of diphtheria. 2. Source, mechanism, transmission pathways for diphtheria. 3. The nature of immunity in diphtheria. 4. What organs are affected by diphtheria? 5. Classification of diphtheria. 6. What is combined diphtheria, give an example. 7. Classification of diphtheria croup. 8. Features of films with diphtheria of the larynx. 9. In what infectious diseases, besides diphtheria and tonsillitis, is the impression of tonsils. 10. Name the main factors of aggression of diphtheria bacillus. 11. The main links in the pathogenesis of diphtheria. 12. Clinic for general intoxication syndrome with diphtheria. 13. Clinic of localized membranous diphtheria of tonsils. Changes in the oropharynx with islet diphtheria of the tonsils. 14. Changes in the oropharynx in patients with localized diphtheria of the tonsils and lacunar tonsillitis are characteristic. Indicate changes. 15. Features of the course of diphtheria of the larynx. 16. Specific laboratory diagnosis of diphtheria. Nonspecific laboratory tests for diphtheria. 17. List the complications that can occur with diphtheria. Specific complications of diphtheria. 18. Causes of death with diphtheria. 19. The principles of treatment of diphtheria. Etiotropic therapy of diphtheria. Rules for the introduction of antidiphtheria serum. 20. Prevention of diphtheria. What anti-epidemic measures are carried out in the focus of diphtheria? 21. What group of infectious diseases does herpesvirus infection belong to? 22. Routes of transmission of herpes virus infections. 23. Stages of the pathogenesis of various manifestations of herpes virus infections. 24. Clinical classification of herpes virus infections. 25. The main symptoms of various nosological forms of herpes virus infections. 26. Features of the course of various manifestations of herpes virus infections in AIDS patients. 27. Complications of various manifestations of herpes virus infections. 28. The main causes of death in various nosological forms of herpes virus infections. 29. Examination plan for a patient with various forms of herpes virus infections. 30. Changes in cerebrospinal fluid with lesions of the nervous system caused by herpes viruses. 31. Methods for the specific diagnosis of herpes virus infections. 32. Interpretation of results depending on the duration of the disease and research material. 33. Etiotropic therapy of herpes virus infections: doses, routes of administration, duration of treatment. 34. Principles of the pathogenetic treatment of herpes virus infections 35. Rules for extracting convalescents from the hospital. 36. Etiological structure of infectious mononucleosis. 37. Classification of infectious mononucleosis. 38. Clinical variants of the course of infectious mononucleosis. 39. Complications and consequences of infectious mononucleosis. 40. Features of the defeat of the oropharynx with infectious mononucleosis. 41. Features of liver damage in infectious mononucleosis. 42. The main clinical manifestations of infectious mononucleosis. 43. The nature of the changes in the hemogram with infectious mononucleosis. 44. Criteria for the severity of infectious mononucleosis. 45. Ultrasound diagnosis for infectious mononucleosis. 46. The main stages of pathogenesis in infectious mononucleosis. 47. The principles of treatment of infectious mononucleosis. 48. Rules for discharge of patients with infectious mononucleosis. Task 1 A 17-year-old patient, was admitted to the infectious ward on the 4th day of illness. The disease is associated with hypothermia, when there was a severe sore throat, which persists today. From the first day of the disease there is a high (39.0 - 39.5 ° C) fever. Local use of antiseptics to improve the condition did not lead. About-but: In the oropharynx - bright hyperemia of the mucous membrane, hypertrophy (II degrees) of the tonsils, covered with purulent layers, which are easily removed with a spatula and do not go beyond them. Enlarged cervical lymph nodes. From other organs and systems of pathology it is not revealed. 1. Formulate a clinical diagnosis. 2. Diagnostics 3.Treatment Task 2 A 15-year-old patient was admitted to the infectious ward on the 5th day of illness. The disease began acutely with sore throat, symptoms of general intoxication. Up to 3 days of illness, all groups of lymph nodes, especially the cervical ones, increased in size. Ob-but: In the oropharynx - ulcerative necrotic tonsillitis. Sclera and skin are subicteric. The enlarged liver and spleen are palpated. In a : leukocytosis, lymphomonocytosis, and virocytosis. ESR - 14 mm / hour. 1. Formulate a clinical diagnosis. 2. Diagnostics. 3. Treatment. A. Test tasks for self-control. 1. Which two pathogens are not belong to group of Herpesviridae? a) Hantavirus; b) HSV-1 and HSV-2; c) Cytomegalovirus; d) Bunjavirus; e) Epstein-Barr virus; 2. Which one of following pathomorphological peculiarities is typical for herpetic encephalitis? a) formation of intracellular insertions (Negri bodies); b) myelinoclasis of nerves; c) hemorrhagic vasculitis; d) detachable neurons affection; e) disturbance of the synthesis of acethylcholine in synapses. 3. What way of transmittion is not typical for HSV-infection? a) contact; b) sexual; c) through the blood; d) transplacentar; e) perinatal. 4. What are the typical course and prognosis of the herpetic encephalitis? a) mild; b) moderate; c) severe; d) favorable; e) unfavorable; 5. What are the typical course and prognosis of the herpetic meningitis? a) mild; b) moderate; c) severe; d) favorable; e) unfavorable; 6. To what genus belongs pathogen of diphtheria? a) Neisseria; b) Corynebacteria; c) Campilobacteria; d) Streptococci; e) Staphylococci. 7. What are the properties of Cl. Diphtheria? a) spore-forming and Gram-negative bacteria; b) Gram-negative and nonspore-forming bacteria; c) nonspore-forming and Gram-positive bacteria; d) Gram-positive and spore-forming bacteria; 8. What is the stability of Cl. Diphteria in environment? a) unstable; b) poorly stable; c) considerably stable; 9. What is a main source of infection with diphtheria? a) healthy bacteria carriers; b) patients with atypical forms of disease; c) patients with typical forms of disease; d) patients with severe forms of disease. 10. What are the two main way of transmission of diphtheria? a) contact; b) air-droplet; c) transplacenter; d) alimentary; e) through the bites of insects.

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 2. Viral hepatitis B, C, D: etiology, epidemiology, clinical picture. 3. Types of the course of the prodromal period of viral hepatitis B, C, D. 4. Describe the main clinical syndromes characteristic of the peak of viral hepatitis. 5. What complications arise with hepatitis B, C, D. 6. What laboratory diagnostic methods confirm the diagnosis of viral hepatitis. 7. Treatment of patients with viral hepatitis. 8. Prevention of hepatitis B, C, D. 9. Chronic viral hepatitis B, C: etiology, epidemiology, clinical presentation 10. Describe the main clinical syndromes characteristic of the exacerbation and latency of chronic viral hepatitis. 11. Specific therapy for chronic hepatitis C. 12. Specific therapy for chronic hepatitis B. 13. What complications arise with chronic hepatitis B, C, diagnosis, treatment. 14. What laboratory diagnostic methods confirm the diagnosis of chronic viral hepatitis. 15. Treatment of patients with chronic viral hepatitis. 16. The HIV epidemic in Ukraine and the world. Normative documents on preventing the spread of HIV infection and social protection of the population. The social consequences of the spread of HIV. 17. Etiology and pathogenesis of HIV infection, classification of the stages of the disease. Extended definition of AIDS in adults and adolescents. Classification of clinical stages, diagnosis criteria are large and small. 18. The role of HIV infection in the formation of lymphadenopathy syndrome, differential diagnosis of this syndrome. 19. HIV infection: laboratory diagnosis, features of its implementation, differential diagnosis, complications, treatment principles. The psychological basis of communication with such patients. Principles and approaches to the treatment of HIV patients. General characteristics of the groups of drugs used in the treatment of HIV infection. 20. General and specific prevention of HIV infection. Safety measures and the organization of the doctor’s work to prevent HIV infection of medical workers. Safety measures for invasive manipulations. Measures in case of contamination with infectious material at the workplace. Forecast. The order of hospitalization, examination, medical examination. HIV-associated infections and diseases: features of the clinical course, laboratory and instrumental diagnostics, differential diagnosis, treatment principles

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Infectious diseases with airborne transmission. Topic Diphtheria. Meningococcal disease Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. According to the World Health Organization (WHO), diphtheria epidemics remain a health threat in developing nations. The largest epidemic recorded since widespread implementation of vaccine programs was in 1990-1995, when a diphtheria epidemic emerged in the Russian Federation, rapidly spreading to involve all Newly Independent States (NIS) and Baltic States. This epidemic caused more than 157,000 cases and 5000 deaths according to WHO reports. Disproportionately high rates of death were observed in individuals older than 40 years, and 5,000 deaths were reported. This epidemic accounted for 80% of cases reported worldwide during this time period. From 1993-2003, a decade long epidemic in Latvia resulted in 1359 reported cases of diphtheria with 101 deaths. The incidence fell from 3.9 cases per 100,000 cases in 2001 to 1.12 cases per 100,000 population in 2003. Most cases were registered in unvaccinated adults. From 1995-2002, 17 cases of cutaneous diphtheria due to toxigenic strains were reported in the United Kingdom. Overall rates of infection have decreased in Europe from 2000 to 2009, according to the Diphtheria Surveillance Network. This has been attributed to improved vaccination rates creating herd immunity. However, issues with vaccinations still occur, especially in eastern European countries and Russia, and are thought to contribute to the ongoing outbreaks. Many case reports in the literature describe epidemics in sub-Saharan Africa, France, India, and the United States. Meningococcal meningitis is observed in a range of situations, from sporadic cases, small clusters, to huge epidemics throughout the world, with seasonal variations. The disease can affect anyone of any age, but mainly affects babies, preschool children and young people. The geographic distribution and epidemic potential differ according to the serogroup. There are no reliable estimates of global meningococcal disease burden due to inadequate surveillance in several parts of the world. The largest burden of meningococcal disease occurs in an area of sub- Saharan Africa known as the meningitis belt, which stretches from Senegal in the west to Ethiopia in the east (26 countries). During the dry season between December to June, dust winds, cold nights and upper respiratory tract infections combine to damage the nasopharyngeal mucosa, increasing the risk of meningococcal disease. At the same time, transmission of N. meningitidis may be facilitated by overcrowded housing. This combination of factors explains the large epidemics which occur during the dry season in the meningitis belt.

2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of viruses, methods for the specific diagnosis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. Symptoms internal diseases and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. Etiology,pathophysisology of diphtheria; 2. Clinical presentation of diphtheria; 3. Diagnosis and treatment of diphtheria; 4. Prevention of diphtheria; 5. Etiology,pathophysisology of meningococcal infection; 6. Clinical presentation of meningococcal infection; 7. Diagnosis and treatment of meningococcal infection; 8. Prevention of meningococcal infection;

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: DIPHTHERIA Etiology. C. diphtheria is a nonencapsulated, nonmotile, gram-positive bacillus; this is shown in the image below. Pathogenic strains can result in severe localized upper respiratory infection, localized cutaneous infections, and rarely systemic infection. Exotoxins are associated with both invasive localized and systemic forms of this disease; however, case reports of invasive disease in absence of the exotoxin release have been documented. Exotoxins are encoded in viral bacteriophages, which are transmitted from bacteria to bacteria. The 3 isolated strains of C diphtheria include gravis, intermedius, and mitis. Intermedius is thought to be responsible for systemic elaboration of the disease, as it is most often associated with the exotoxin. However, all 3 strains are capable of producing toxins. Pathophysiology Overcrowding, poor health, substandard living conditions, incomplete immunization, and immunocompromised states facilitate susceptibility to diphtheria and are risk factors associated with transmission of this disease. Human carriers are the main reservoir of infection; however, case reports have linked the disease to livestock. Infected patients and asymptomatic carriers can transmit C diphtheria via respiratory droplets, nasopharyngeal secretions, and rarely fomites. In the case of cutaneous disease, contact with wound exudates may result in the transmission of the disease to the skin as well the respiratory tract. Immunity from exposure or vaccination wanes over time. Inadequate boosting of previously vaccinated individuals may result in increased risk of acquiring the disease from a carrier, even if adequately immunized previously. Additionally, since the advent of widespread vaccination, cases of nontoxigenic strains causing invasive disease have increased. C. diphtheria adheres to mucosal epithelial cells where the exotoxin, released by endosomes, causes a localized inflammatory reaction followed by tissue destruction and necrosis. The toxin is made of two joined proteins. The B fragment binds to a receptor on the surface of the susceptible host cell, which proteolytically cleaves the membrane lipid layer enabling segment A to enter. Molecularly, it is suggested that the cellular susceptibility is also due to diphthamide modification, dependent on human leukocyte antigen (HLA) types predisposing to more severe infection. The diphthamide molecule is present in all eukaryotic organisms and is located on a histidine residue of the translation elongation factor 2 (eEF2). eEF2 is responsible for the modification of this histidine residue and is the target for the diphtheria toxin (DT). Fragment A inhibits an amino acid transfer from RNA translocase to the ribosomal amino acid chain, thus inhibiting protein synthesis is required for normal host cell functioning. DT causes a catalytic transfer of NAD to diphthamide, which inactivates the elongation factor, resulting in the inactivation eEF2, which results in protein synthesis blockage and subsequent cell death. Local tissue destruction enables the toxin to be carried lymphatically and hematologically to other parts of the body. Elaboration of the diphtheria toxin may affect distant organs such as the myocardium, kidneys, and nervous system. Nontoxigenic strains tend to produce less severe infections; however, since widespread vaccination, case reports of nontoxigenic strains of C. diphtheria causing invasive disease have been documented. Clinical presentation. Onset of symptoms of respiratory diphtheria typically follows an incubation period of 2-5 days (range, 1-10 d). Symptoms initially are general and nonspecific, often resembling a typical viral upper respiratory infection (URI). Respiratory involvement typically begins with sore throat and mild pharyngeal inflammation. Development of a localized or coalescing pseudomembrane can occur in any portion of the respiratory tract. The pseudomembrane is characterized by the formation of a dense, gray debris layer composed of a mixture of dead cells, fibrin, RBCs, WBCs, and organisms; the pseudomembrane is shown in the image below. Removal of the membrane reveals a bleeding, edematous mucosa. The distribution of the membrane varies from local (eg, tonsillar, pharyngeal) to widely covering the entire tracheobronchial tree. The membrane is intensely infectious, and droplet and contact precautions must be followed when examining or caring for infected patients. A combination of cervical adenopathy and swollen mucosa imparts a "bull's neck" appearance to many of the infected patients; this is shown in the image below. The most frequent cause of death is airway obstruction or suffocation following aspiration of the pseudomembrane. Cutaneous diphtheria is a disease characterized by indolent, nonhealing ulcers covered with a gray membrane. The ulcers are often co-infected with Staphylococcus aureus and group A streptococci. This form of the disease is seen with increasing frequency in poor inner-city dwellers and alcoholics. The lesions of cutaneous diphtheria are infectious, and bacteria from cutaneous lesions have been found to cause pharyngeal infections and thus serve as a reservoir for infection. Patients with diphtheria may present with the following complaints:  Low-grade fever (rarely >103°F) (50-85%) and chills  Malaise, weakness, prostration  Sore throat (85-90%)  Headache  Cervical lymphadenopathy and respiratory tract pseudomembrane formation (about 50%)  Serosanguineous or seropurulent nasal discharge, white nasal membrane  Hoarseness, (26-40%)  Dyspnea, respiratory stridor, wheezing, cough Respiratory diphtheria may quickly progress to respiratory failure due to airway obstruction or aspiration of pseudomembrane into the tracheobronchial tree. Cutaneous diphtheria often develops at a site of previous trauma or a primary dermatologic disease. It follows an indolent course, typically lasting weeks to months. Occasionally, it may cause respiratory diphtheria. Physical General: Patient has a low-grade fever but is toxic in appearance, and also may have a swollen neck. Pharyngeal diphtheria:  Patients may present with general symptoms of fever, halitosis, tachycardia, and anxiety.  Tonsils and pharynx: Pharyngeal erythema and edema, thick, gray, leathery membrane variably covers the tonsils, soft palate, oropharynx, nasopharynx, and uvula. Attempts at scraping the pseudomembrane causes bleeding of the underlying mucosa.  Neck: Extensive anterior and submandibular cervical lymphadenopathy imparts a bull's neck appearance. The patient may hold his or her head in extension. It can occasionally also be associated with dysphonia.  Respiratory distress manifesting as stridor, wheezing, cyanosis, accessory muscle use, and retractions. Cardiac toxicity typically occurs after 1-2 weeks of illness following improvement in the pharyngeal phase of the disease. It may manifest as follows:  Myocarditis is seen in as many as 60% of patients (especially if previously unimmunized) and can present acutely with congestive heart failure (CHF), circulatory collapse, or more subtly with progressive dyspnea, diminished heart sounds, cardiac chamber dilatation, and weakness.  Atrioventricular blocks, ST-T wave changes, and various dysrhythmias may be evident.  Endocarditis may be present, especially in the presence of an artificial valve. Neurologic toxicity is proportional to the severity of the pharyngeal infection. Most patients with severe disease develop neuropathy. Deficits include the following:  Cranial nerve deficits including oculomotor, ciliary paralysis, facial, and pharyngeal, or laryngeal nervous dysfunction.  Occasionally, a stocking and glove peripheral sensory neuropathy pattern can be observed.  Most C diphtheriae associated neurologic dysfunction eventually resolves.  Peripheral neuritis develops anywhere from 10 days to 3 months after the onset of pharyngeal disease. It manifests initially as a motor defect of the proximal muscle groups in the extremities extending distally. Various degrees of dysfunction exist, ranging from diminished DTRs to paralysis. Laboratory Studies To establish the diagnosis of C diphtheriae, it is vital to both isolate C diphtheriae in culture media and to identify the presence of toxin production. Bacteriologic testing Gram stain shows club-shaped, nonencapsulated, nonmotile bacilli found in clusters. Immunofluorescent staining of 4-hour cultures or methylene blue–stained specimen may sometimes allow for a speedy identification. Cultures Inoculation of tellurite or Loeffler media with swabs taken from the nose, pseudomembrane, tonsillar crypts, any ulcerations, or discolorations. Identification is accomplished through observation of colony morphology, microscopic appearance, and fermentation reactions. Any diphtheria bacilli isolated must be tested for toxin production. Obtain throat and pharyngeal swabs from all close contacts. Toxigenicity Toxigenicity testing is aimed to determine the presence of toxin production. Elek test detects the development of an immunoprecipitin band on a filter paper impregnated with antitoxin and then is laid over an agar culture of the organism being tested. Polymerase chain reaction (PCR) assays for detection of DNA sequence encoding the A subunit of tox+ strain are both rapid and sensitive. Once diphtheria infection has been established, the Centers for Disease Control and Prevention (CDC) should be contacted, and further testing may be requested. Other laboratory studies  CBC may show moderate leukocytosis.  Urinalysis (UA) may demonstrate transient proteinuria.  Serum antibodies to diphtheria toxin prior to administration of antitoxin: Low levels cannot exclude the possibility of the disease; high levels may protect against severe illness (concentrations of 0.1 to 0.01 IU are thought to confer protection). [10]  Serum troponin I levels seem to correlate with the severity of myocarditis. Imaging Studies  Chest radiograph and soft tissue neck radiography/CT or ultrasonography may show prevertebral soft tissue swelling, enlarged epiglottis, and narrowing of the subglottic region.  Echocardiography may demonstrate valvular vegetations; however, this systemic manifestation of diphtheria is rare.  ECG may show ST-T wave changes, variable heart block, and dysrhythmia. Procedures

The following procedures may be necessary:  Endotracheal intubation  Surgical airway - Cricothyroidotomy or tracheostomy  Laryngoscopy, bronchoscopy as indicated in intubated patients  Electrical pacing for high-grade conduction disturbances Treatment Treatment of diphtheria should be initiated even before confirmatory tests are completed due to the high potential for mortality and morbidity. Isolate all cases promptly and use universal and droplet precautions to limit the number of possible contacts. Secure definite airway for patients with impending respiratory compromise or the presence of laryngeal membrane. Early airway management allows access for mechanical removal of tracheobronchial membranes and prevents the risk of sudden asphyxia through aspiration. Consider involving ENT or operating room personnel for intubation and securing of airway if there is suspicion for loss of the airway or respiratory failure. Maintain close monitoring of cardiac activity for early detection of rhythm abnormalities. Initiate electrical pacing for clinically significant conduction disturbance and provide pharmacologic intervention for arrhythmias or for heart failure. Provide 2 large-bore IVs for patients with a toxic appearance; provide invasive monitoring and aggressive resuscitation for patients with septicemia. Initiate prompt antibiotic coverage (erythromycin or penicillin) for eradication of organisms, thus limiting the amount of toxin production. Antibiotics hasten recovery and prevent the spread of the disease to other individuals. Neutralize the toxin as soon as diphtheria is suspected. Diphtheria antitoxin is a horse-derived hyperimmune antiserum that neutralizes circulating toxin prior to its entry into the cells. It prevents the progression of symptoms. The dose and route of administration (IV vs IM) are dependent on the severity of the disease. This antitoxin must be obtained directly from the Centers for Disease Control and Prevention (CDC) through an Investigational New Drug (IND) protocol. The patient must be tested for sensitivity to the antitoxin before it is given. Diphtheria disease does not confer immunity; thus, initiation or completion of immunization with diphtheria toxoid is necessary. Obtain throat and nasal swabs from persons in close contact with the suspected diphtheria victim; administer age-appropriate diphtheria booster. Initiate antibiotic therapy with erythromycin or penicillin for chemoprophylaxis in a patient with suspected exposure. Throat cultures should be repeated in 2 weeks after treatment. Prevention The widespread use of the diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine in childhood has significantly decreased the incidence of diphtheria. However, childhood immunity wanes, requiring an updated booster vaccine. The CDC recommends either DTaP, Tdap, or DT at least every 10 years to maintain immunity. Meningococcal disease describes infections caused by the bacterium Neisseria meningitidis (also termed meningococcus). It has a high mortality rate if untreated but is vaccine-preventable. While best known as a cause of meningitis, it can also result in sepsis, which is an even more damaging and dangerous condition. Meningitis and meningococcemia are major causes of illness, death, and disability in both developed and under-developed countries. Meningococcal meningitis (International Classification of Disease-9 [ICD-9] code: 036.0) has been recognized as a serious problem for almost 200 years. It was first identified definitely by Vieusseux in Geneva in 1805. Meningococcal disease still is associated with a high mortality rate and persistent neurologic defects, particularly among infants and young children. The first successful treatment of meningitis with intravenous and intrathecal penicillin was reported in 1944, and the first clinical trials using high doses of intravenous penicillin as monotherapy for the treatment of meningitis were reported in 1950. Since then, penicillin has remained the drug of choice for the treatment of meningococcal meningitis. However, current IDSA guidelines list ceftriaxone or cefotaxime as the drugs of choice. Etiology. The causative organism, Neisseria meningitidis, is a gram-negative, aerobic, encapsulated diplococcus that grows best on enriched media, such as Mueller-Hinton or chocolate agar, at 37°C and in an atmosphere of 5-10% carbon dioxide. Meningococci make up numerous serogroups that are based on the composition of their polysaccharide capsular antigens. They differ in their agglutination reactions to sera directed against polysaccharide antigens. At least 13 serogroups have been described: A, B, C, D, E, H, I, K, L, W- 135, X, Y, and Z. Serogroups B and C have caused most cases of meningococcal meningitis in the United States since the end of World War II; before that, group A was more prevalent. More than 99% of meningococcal infections are caused by serogroups A, B, C, 29E, or W-135. In Europe and the Americas, serogroup B is the predominant agent causing meningococcal disease, followed in frequency by serogroup C. Historically, serogroup A was the main cause of epidemic meningococcal disease globally, and it is still the predominant cause of meningococcal meningitis in Africa and Asia. Transmission and pathogenesis. Individuals acquire meningococcal infections if they are exposed to virulent bacteria and have no protective bactericidal antibodies. The natural habitat and reservoir for meningococci is the mucosal surfaces of the human nasopharynx and, to a lesser extent, the urogenital tract and anal canal. Approximately 5-10% of adults are asymptomatic nasopharyngeal carriers, but that number increases to as many as 60-80% of members of closed populations (eg, military recruits in camps). The modes of infection include direct contact or respiratory droplets from the nose and throat of infected people. Meningococcal disease most likely occurs within a few days of acquisition of a new strain, before the development of specific serum antibodies. The incubation period averages 3-4 days (range 1-10 days), which is the period of communicability. Bacteria can be found for 2-4 days in the nose and pharynx and for up to 24 hours after starting antibiotics. Treatment with penicillin may not eradicate the bacteria from the nasopharyngeal carriers. After adherence to the nasopharyngeal mucosa, meningococci are transported to membrane- bound phagocytic vacuoles. Within 24 hours, they can be seen in the submucosa, close to vessels and local immune cells. In most cases, meningococcal colonization of mucosal surfaces leads to subclinical infection or mild symptoms. In approximately 10-20% of cases, N meningitidis enters the bloodstream. In the vascular compartment, the bacterium may be killed by bactericidal antibodies, complement, and phagocytic cells, or it may multiply, initiating the bacteremic phase. Organisms replicate rapidly. Systemic disease appears with the development of meningococcemia and usually precedes meningitis by 24-48 hours. This can lead to systemic infection in the form of bacteremia, metastatic infection that commonly involves the meninges, or severe systemic infection with circulatory collapse and DIC. Meningococcemia leads to diffuse vascular injury, which is characterized by endothelial necrosis, intraluminal thrombosis, and perivascular hemorrhage. Risk factors. Meningococci that elaborate a capsule can lead to invasive disease. The capsule protects them from desiccation and from host immune mechanisms. Adhesins and endotoxins also enhance their pathogenic potential. Dysfunctional properdin (ie, component of the alternative pathway of complement), HIV infection, functional or anatomical asplenia, and congenital complement deficiencies predispose individuals to meningococcal disease. Clinical presentation. Classification of the clinical forms of meningococcal infection: I. Primarily localized forms: a) meningococcal carrier state b) acute nasopharyngitis; c) pneumonia. II. Gematogenously generalized forms: a) meningococcemia: typical acute meningococcal sepsis; chronic; b) meningitis; meningoencephalitis; c) mixed forms (meningococcemia + meningitis, meningoencephalitis). d) rare forms (endocarditis, arthritis, iridocyclitis). In meningococcal carriers the clinical manifestations are absent. Clinical current of meningococcal nasopharingitis. The most common complains of the a patients are headache, mainly in the frontal-parietal region, sore throat, dry cough, blocked nose, fatigue, weakness, loss of appetite, violation of the sleep. In most of the patients body temperature rises upto subfebrile and lasts for not more than 3-7 days, sometimes 5-7 days. The skin is pale, conjunctival vessels and sclera are injected. There are hyperemia and edema of the mucous membrane of the nose. In many patients the posterior wall of the pharynx seem to be covered by mucous or mucous – purulent exudation. Inflammatory changes in the nasopharynx can be noticed after 5-7 days, hyperplasion of lymphoid follicles lasts longer (till 14-16 days). In the peripheral blood temperate leukocytosis with neutrophylosis and a shift of leukocytaric formula to the left, increase in ERS may be revealed. Nasopharyngitis precedes to development of generalized forms of the disease. Diagnostics. The diagnosis of meningococcal carrier is possible only by use of bacteriological method. The material for analysis is the mucus from proximal portions of upper respiratory tract. In diagnostics of meningococcal nasopharyngitis epidemiological and bacteriological methods occupy the main place. Clinical differention of meningococcal nasopharyngitis from nasopharyngitis of the other genesis is no possible or very difficult. Meningococcal meningitis is characterized by acute onset of intense headache, fever, nausea, vomiting, photophobia, and stiff neck. Elderly patients are prone to have an altered mental state and a prolonged course with fever.  Lethargy or drowsiness in patients frequently is reported. Stupor or coma is less common. If coma is present, the prognosis is poor.  Patients also may complain of skin rash, which usually points to disease progression.  The clinical pattern of bacterial meningitis is quite different in young children. Bacterial meningitis in these patients usually presents as a subacute infection that progresses over several days.  Projectile vomiting may occur in children.  Seizures occur in 40% of children with meningitis, typically during the first few days. The majority of seizures have a focal onset.  In infants, the illness may have an insidious onset; stiff neck may be absent. In children, even when the combination of convulsive status epilepticus and fever is present, the classic signs and symptoms of acute bacterial meningitis may not be present.  The Waterhouse-Friderichsen syndrome may develop in 10-20% of children with meningococcal infection. This syndrome is characterized by large petechial hemorrhages in the skin and mucous membranes, fever, septic shock, and DIC. Physical Examination  Neurologic signs of meningococcal meningitis include nuchal rigidity (eg, Kernig sign, Brudzinski sign), lethargy, delirium, coma, and convulsions.  Irritability is a common presenting feature in children.  A petechial or purpuric rash usually is found on the trunk, legs, mucous membranes, and conjunctivae. Occasionally, it is on the palms and soles. The rash may progress to purpura fulminans, when it usually is associated with multiorgan failure (ie, Waterhouse-Friderichsen syndrome). The petechial rash may be difficult to recognize in dark-skinned patients. Meningococcemia Meningococcemia is defined as dissemination of meningococci (Neisseria meningitidis) into the bloodstream (see the image below). Patients with acute meningococcemia may present with (1) meningitis (2) meningitis with meningococcemia, or (3) meningococcemia without clinically apparent meningitis. The clinical presentation of meningococcemia may include any of the following:

 A nonspecific prodrome of cough, headache, and sore throat  The above followed by a few days of upper respiratory symptoms, increasing temperature, and chills  Subsequent malaise, weakness, myalgias, headache, nausea, vomiting, and arthralgias  The characteristic petechial skin rash is usually located on the trunk and legs and may rapidly evolve into purpura  In fulminant meningococcemia, a hemorrhagic eruption, hypotension, and cardiac depression, as well as rapid enlargement of petechiae and purpuric lesions

Meningococcemia is characterized by the following :  Fever  Initial rash that may be erythematous or maculopapulars, short lived, followed by petechiae and purpura  Vomiting  Headache  Myalgias that may be quite severe  Sore throat  Abdominal pain  Tachycardia/tachypnea  Hypotension  Cool extremities  Initially normal level of consciousness  Early symptoms are similar to those of viral illness, such as influenza or streptococcal pharyngitis; however, this infection accelerates at a rate matched by few other infections. Physical findings may include the following:  Dermatologic manifestations: Petechiae, rash, ecchymoses, purpura  Meningococcal meningitis: Pain and resistance to neck flexion, other signs of meningeal irritation, petechiae, fever (of variable intensity)  Fulminant meningococcemia: Purpuric eruption, hemorrhages on buccal mucosa and conjunctivae, no signs of meningitis, cyanosis, hypotension, profound shock, high fever, pulmonary insufficiency  Meningococcal septicemia: Fever, rash, tachycardia, hypotension, cool extremities, initially normal level of consciousness

Workup Laboratory examination of the cerebrospinal fluid (CSF) usually confirms the presence of meningitis. In the US, a neuroimaging study (either MRI or CT scanning) prior to lumbar puncture is mandatory in all patients in whom meningitis is suspected. However, this rule is relaxed in several other countries (see CT scanning and MRI). CSF Examination Typical CSF abnormalities in meningitis include the following:  Increased opening pressure (>180 mm water)  Pleocytosis of polymorphonuclear leukocytes (white blood cell [WBC] counts between 10 and 10,000 cells/µL, predominantly neutrophils)  Decreased glucose concentration (< 45 mg/dL)  Increased protein concentration (>45 mg/dL)

Gram stain and culture of CSF identify the etiologic organism, N meningitides. In bacterial meningitis, Gram stain is positive in 70-90% of untreated cases, and culture results are positive in as many as 80% of cases. More specialized laboratory tests, which may include culture of CSF and blood specimens, are needed for identification of N meningitidis and the serogroup of meningococci, as well as for determining its susceptibility to antibiotics. Polymerase Chain Reaction The polymerase chain reaction (PCR) may be used to complement standard laboratory procedures for the diagnosis of meningococcal meningitis. The IS1106 PCR is a rapid and sensitive test for confirmation of the diagnosis; its sensitivity is not affected by prior antibiotic treatment. PCR of the nspA gene was also reported to be a fast diagnostic test. CT Scanning and MRI Head CT scan findings are usually normal but may reveal signs of intracranial hypertension, edema, and intracerebral hemorrhage. In several parts of the world, imaging is an important cause of delay of therapy. In the US, due to the large availability of brain imaging, the performance of a head CT scan is mandatory. In other countries, this rule is relaxed, and indications for performing CT scanning prior to lumbar puncture include altered level of consciousness, papilledema, focal neurological deficits, and/or focal or generalized seizure activity. MRI with contrast is preferred to CT scanning, because MRI better demonstrates meningeal lesions, cerebral edema, and cerebral ischemia. T1 may show obliterated cisterns. Contrast enhances the cisterns, and extension of enhancing subarachnoid exudate deep into the sulci may be seen in severe cases. Treatment. Institute antimicrobial therapy as soon as possible after the lumbar puncture is performed. Long delays may occur in the emergency department before initiation of antibiotics in patients with suspected bacterial meningitis. In general, these delays appear to be physician generated and, to a great extent, potentially avoidable. Standard empirical therapy At presentation, meningitis due to N meningitidis may be impossible to differentiate from other types of meningitis. Thus, empirical treatment with an antibiotic with effective CNS penetration should be based on age and underlying disease status, since delay in treatment is associated with adverse clinical outcome. Initial empirical therapy until the etiology is established should include dexamethasone, a third-generation cephalosporin (eg, ceftriaxone, cefotaxime), and vancomycin. Acyclovir should be considered according to the results of the initial cerebrospinal fluid (CSF) evaluation. Doxycycline should also be added during tick season in endemic areas. A 7-day course of intravenous ceftriaxone or penicillin is adequate for uncomplicated meningococcal meningitis. If imaging studies are indicated before lumbar puncture, draw blood for culture and begin administration of empiric antibiotics. Administration of empiric antibiotics is unlikely to decrease diagnostic sensitivity if CSF is tested for bacterial antigens early in the course of the illness. Treatment following diagnosis Once an accurate diagnosis of meningococcal meningitis is established, appropriate changes can be made. Currently, a third-generation cephalosporin (ceftriaxone or cefotaxime) is the drug of choice for the treatment of meningococcal meningitis and septicemia. Penicillin G, ampicillin, chloramphenicol, fluoroquinolone, and aztreonam are alternatives therapies (IDSA guidelines). The use of dexamethasone in the management of bacterial meningitis in adults remains controversial. It may be used in children, especially in those with meningitis caused by Haemophilus influenzae. In adults with suspected bacterial meningitis, especially in high-risk cases, the adjunctive use of dexamethasone may be beneficial. Prevention Vaccination. Licensed vaccines against meningococcal disease have been available for more than 40 years. Over time, there have been major improvements in strain coverage and vaccine availability, but to date no universal vaccine against meningococcal disease exists. Vaccines are serogroup specific and confer varying degrees of duration of protection.

There are three types of vaccines available:

 Polysaccharide vaccines are used during a response to outbreaks, mainly in Africa: o They are either bivalent (serogroups A and C), trivalent (A, C and W), or tetravalent (A, C, Y and W). o They are not effective before 2 years of age. o They offer a 3-year protection but do not induce herd immunity.  Conjugate vaccines are used in prevention (into routine immunization schedules and preventive campaigns) and outbreak response: o They confer longer-lasting immunity (5 years and more), prevent carriage and induce herd immunity. o They can be used as soon as of one year of age. o Available vaccines include: . Monovalent C . Monovalent A . Tetravalent (serogroups A, C, Y, W).  Protein based vaccine, against N. meningitidis B. It has been introduced into the routine immunization schedule (one country as of 2017) and used in outbreak response.

Chemoprophylaxis. Antibiotic prophylaxis for close contacts, when given promptly, decreases the risk of transmission.

 Outside the African meningitis belt, chemoprophylaxis is recommended for close contacts within the household.  In the meningitis belt, chemoprophylaxis for close contacts is recommended in non-epidemic situations.

Ciprofloxacin antibiotic is the antibiotic of choice, and ceftriaxone an alternative.

8. Materials for activating students during a lecture:

1. What is diphtheria? 2. What are common presenting complaints in patients with diphtheria? 3. What is the clinical course of respiratory diphtheria? 4. What are the general clinical findings in diphtheria? 5. Which lab studies definitively diagnose diphtheria? 6. When should treatment of diphtheria be initiated? 7. Why is it important to secure an airway in patients with diphtheria? 8. How effective is diphtheria vaccination, and how often are booster vaccines recommended? 9. What is meningococcal infection? What is meningococcal meningitis? What is meningococcemia? 10. What are serogroups of meningococci that cause meningococcal infection? 11. What are the clinical types of meningococcal infection 12. What are the signs and symptoms of meningococcal nasopharyngitis? 13. What are the signs and symptoms of meningococcal meningitis? 14. What are the signs and symptoms of meningococcemia? 15. How is a diagnosis of meningococcal infection confirmed? 16. What are the differential diagnoses for Meningococcal Meningitis? 17. How is meningococcal meningitis prevented? 18. What is the role of CT/MRI scanning in the workup of meningococcal meningitis? 19. What is the role of empiric therapy in the treatment of meningococcal meningitis? 20. What is the prognosis of meningococcal infection?

Task 1 The patient was 34 years old, was admitted to the infectious department on the 5th day of illness with complaints of severe general weakness, moderate headache and sore throat when swallowing, nasal breathing difficulties, fever - 38.0 - 38.60C, unpleasant sensations in the heart, aches in muscles and joints. Objective: pale skin, cyanosis of the lips and nasolabial triangle. Oropharyngeal mucosa - slightly hyperemic, cyanotic, pronounced edema. The tonsils have fibrinous layers that extend to the posterior wall of the pharynx and tongue. Rhinoscopy - on the background of slight edema and cyanosis of the mucosa revealed gray films. Submandibular lymph nodes are palpated (0.5-1 cm) and edema of the submandibular and cervical tissue is determined. Tachycardia, deaf heart tones. AD 100 \ 60mm.rt.st. The abdomen is soft, painless. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment.

Task 2 Patient K., 21. The disease began with a high temperature up to 39.0 ° C, headache, chills, repeated vomiting. Objectively: body temperature 39.3 ° C, pulse 76 beats. for hv., stresses. Stiff neck, positive Kernig symptom. Liquor analysis: turbid, flows under the high pressure, cytosis 1237 in 1 μl. (84% neutrophils, 16% lymphocytes), Pandey ++ reaction, protein 0.66 g / l. Bacterioscopic analysis: gram-negative cocci intracellularly were detected. 1. Formulate a preliminary diagnosis. 2. Diagnostics 3. Treatment. Test control. 1. The genesis of late diphtheria myocarditis is associated with: A. toxin B. histamine C. corynebacteria D. autoantibodies E. metabolic factors

2. The cause of death from diphtheria can be: A. asphyxia B. infectious-toxic shock C. myocarditis D. polyneuritis E. hypovolemic shock

3. What plaque location is typical for combined form of diphtheria? A. only on the palate B. only on the tonsils, braces and tongue C. only on the laryngeal mucosa D. only on the tonsils E. on the tonsils, laryngeal mucosa and / or nose

4. The effectiveness of diphtheria treatment is primarily determined by the early appointment: A. antibiotic therapy B. pathogenetic therapy C. diphtheria serum D. antibiotics and diphtheria serum E. antibiotics and pathogenetic therapy

5. Diphtheria-associated myocarditis is characterized by: A. moderate pain in the sternum B. decrease in voltage of teeth on an ECG C. increase in blood pressure D. bradycardia E. tachycardia

6. Rules for discharge of a patient with a generalized form of meningococcal infection from the hospital are following: A. Complete clinical recovery B. Two negative results of bacteriological examination of nasopharyngeal mucus C. Three negative results of bacteriological examination of nasopharyngeal mucus D. Two negative results of bacteriological blood test E. Not earlier than 3 weeks after the onset of the disease

7. Pathogenesis of cerebral coma in generalized forms of meningococcal infection is characterized by: A. Consequence of intoxication (disorders of protein metabolism, amino acid imbalance, etc.) B. Development of encephalitis C. Increased intracranial pressure D. Hemorrhages in the adrenal glands E. Swelling of the meninges

8. The main factors of meningococcal pathogenicity are: A. Endotoxin B. Exotoxin C. Capsule D. Ig A protease E. Hyaluronidase

9. Characteristics of the rash in meningococcal disease: A. Roseola-petechial B. Hemorrhagic-necrotic stellate C. Appears on day 3-5 of the disease D. Appears in the first 5-15 hours of the disease E. The phenomenon of "pouring" is not typical

10. Material for bacteriological examination in suspected meningococcal meningitis: A. Liquor B. Blood C. Swabs from the nasopharynx D. Saliva E. Urina

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What is the virology of hepatitis A virus (HAV)? 2. What is the pathophysiology of viral replication in hepatitis A virus (HAV)? 3. What is the incubation period of hepatitis A virus (HAV)? 4. What are the risk factors for the acquisition of hepatitis A? 5. What is the prognosis of hepatitis A virus (HAV) infection? 6. What is the association between age and illness severity in hepatitis A virus (HAV) infection? 7. What are the rare complications of hepatitis A virus (HAV) infection? 8. What is the basic diagnostics of hepatitis A virus (HAV) infection? 9. What is the basic treatment of hepatitis A virus (HAV) infection? 10. How should travelers be educated about hepatitis A? 11. What is the virology of hepatitis E virus (HEV)? 12. What is the incubation period of hepatitis E virus (HEV)? 13. What are the risk factors for the acquisition of hepatitis E? 14. What is the prognosis of hepatitis E virus (HEV) infection? 15. What is the association between age and illness severity in of hepatitis E virus (HEV) infection ? 16. What is the basic diagnostics of hepatitis E virus (HEV) infection? 17. What is the basic treatment of hepatitis E virus (HEV) infection? 18. How should travelers be educated about hepatitis E? 19. How should patients with hepatitis A virus (HAV) infection be educated?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases and epidemiology Module № Infectious diseases and epidemiology Topic HIV infection. HIV-associated infection and infestation.Viral hepatitis with parenteral mechanism of transmission. Course 4 Faculty Stomatological

Number of teaching hours: 2

Poltava 2019

1. Scientific and methodological substantiation of the topic. Viral hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E) affects millions of people around the globe; hepatitis B and C result in chronic infections and disproportionately impact certain countries. The World Health Organization (WHO) estimates that in 2015: 257 million people worldwide had hepatitis B;71 million people worldwide had hepatitis C. Both of these types of hepatitis can lead to lifelong infection. WHO estimated that during the same year, 1.34 million people died from liver cancer, cirrhosis, and other conditions caused by chronic viral hepatitis. All types of viral hepatitis can be controlled or prevented. Hepatitis C can be cured; a once- daily medication taken by mouth for as few as 8 weeks can cure most people who are infected with hepatitis C. Hepatitis B medications are available to help prevent liver damage and slow progression of the disease. Safe and effective vaccines to protect against hepatitis A and hepatitis B are available. Hepatitis A vaccine is used in only a few countries; greater use of the vaccine has the potential to control outbreaks. In 2015, global coverage with three doses of hepatitis B vaccine was 84%, and 39% of children received a dose at birth, which is necessary to prevent mother-to-child transmission of this infection. Improving rates of vaccination coverage, especially among including infants and children, will reduce hepatitis B infection, which can lead to liver disease and death. Even though affordable, safe, and effective treatments can prevent liver disease and liver cancer among people living with hepatitis B and cure those living with hepatitis C, WHO estimated that only 10% of people with hepatitis B and 20% of people with hepatitis C worldwide knew they were infected in 2015. Of these, less than 10% had received treatment. Today it is generally recognized that the HIV infection has become a medical and social problem of vital importance, for apart from its social consequences (millions of people infected and dying from AIDS) the disease seriously affects a country economic and political welfare. This has made the HIV infection one of the most considerable modern sociopathies. It is universally acknowledged that social and ecological characteristics are the most important factors influencing peoples health. To this extent the effect of any infectious disease, the HIV infection among them is to be assessed in terms of epidemiological surveillance. Global HIV statistics:37.9 million people globally were living with HIV (end 2018);1.7 million people became newly infected with HIV (end 2018); 770 000 people died from AIDS- related illnesses (end 2018); 74.9 million people have become infected with HIV since the start of the epidemic (end 2018); 32.0 million people have died from AIDS-related illnesses since the start of the epidemic (end 2018); 24.5 million people were accessing antiretroviral therapy (end of June 2019).

2. The educational goals of the lecture. Explain the etiology of hepatitis A, hepatitis B, hepatitis B, hepatitis B, hepatitis B, hepatitis C, HIV; epidemiology of hepatitis A, hepatitis B, hepatitis B, hepatitis B, hepatitis C, hepatitis C, HIV, and features of the current epidemiological process; pathogenesis; classification of the clinical forms of hepatitis A, hepatitis B, hepatitis B, hepatitis B, hepatitis C, hepatitis C, HIV; the course of hepatitis C, hepatitis B, hepatitis C, hepatitis C, hepatitis C, HIV, depending on the clinical forms and type of pathogen; possible complications of hepatitis C, hepatitis C, hepatitis C, hepatitis C, hepatitis C their appearance; diagnostic methods for hepatitis A, hepatitis B, hepatitis B, hepatitis B, hepatitis C, HIV, the principles of treatment for patients with hepatitis A, hepatitis B, hepatitis B, hepatitis C, hepatitis C, HIV, management of patients in case of emergency; principles of prevention; rules for discharge of convalescents from the hospital; rules of medical examination of convalescents. Analyze the etiology and epidemiology, adhere to the basic sanitary and anti-epidemic rules of work near the bedside of a patient with hepatitis A, hepatitis B virus, hepatitis B virus, hepatitis B virus, hepatitis C virus, HIV; to collect a medical history, evaluate epidemic data; examine the patient and identify the main symptoms and syndromes of hepatitis A, hepatitis B, hepatitis B virus, hepatitis B virus, hepatitis C virus, HIV, substantiate a preliminary diagnosis; identify the presence of specific complications in the patient; differential diagnosis of hepatitis A, hepatitis B virus, hepatitis B virus, hepatitis B virus, hepatitis C virus infection, HIV with diseases that occur with similar symptoms; make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination, including specific diagnostic methods; add up an individual treatment plan taking into account the epidemiological data, the clinical form of the disease, the severity of the course, the presence of complications, an allergic history, concomitant pathologies, and prescribe prescriptions; provide emergency assistance if necessary; put together a plan of anti-epidemic and preventive visits in the center of infection; give recommendations regarding the regimen, diet, examination. To interpret the basic rules of work at the bedside of an infectious patient; to collect a medical history with an assessment of the epidemiological data characteristic of these infections; apply the rules for hospitalization of patients with diphtheria in compliance with the rules of anti-epidemic and personal safety; physically examine the patient with suspected diphtheria in compliance with the rules of anti- epidemic safety; identify the main symptoms and the timing of their appearance, the localization of the pathological process; draw up medical documentation on the fact of establishing a preliminary diagnosis of hepatitis A, hepatitis B virus, hepatitis B virus, hepatitis B virus, hepatitis C virus, hepatitis C virus, HIV (emergency notification to the sanitary-epidemiological station (SES)) evaluate macroscopic changes during examination and collect material for bacteriological examination; make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination, including specific diagnostic methods; to make a preliminary diagnosis according to the existing classification, justify it according to the epidemiological history, medical history, objective examination; prescribe the necessary laboratory and instrumental examination in compliance with the rules of anti-epidemic safety, give an interpretation of the results to substantiate the final clinical diagnosis according to the clinical classification; conduct differential diagnosis with other similar infectious and non-infectious diseases; draw up a treatment plan depending on age, clinical form, course characteristics and complications that have arisen premorbid background; provide assistance in case of emergency conditions inherent in the hepatitis A virus, hepatitis B virus, hepatitis B virus, hepatitis B virus, hepatitis C virus, hepatitis C virus, outline a preventive plan for the outbreak give recommendations for follow-up, regimen, diet, treatment in the period of convalescence. 3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork

Autonomy and No. Competence Awareness Skill Communication responsibility 7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. protect the environment Autonomy and No. Competence Awareness Skill Communication responsibility 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. 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Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system, GIT, liver, biliar tract Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea, GIT, liver, biliary tract Microbiology Properties of HIV, HBV, HCV, methods for the specific diagnosis of viral hepatitis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. The etiology of HIV infection, viral hepatitis with a parenteral transmission mechanism 2. Epidemiology of HIV infection, viral hepatitis with a parenteral transmission mechanism 3. The pathogenesis of HIV infection, viral hepatitis with a parenteral transmission mechanism 4. Clinic of HIV infection, viral hepatitis with a parenteral transmission mechanism 5. Diagnosis of HIV infection, viral hepatitis with a parenteral transmission mechanism 6. Treatment of HIV infection, viral hepatitis with parenteral transmission 7. Prevention of HIV infection, viral hepatitis with a parenteral transmission mechanism 1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: Viral hepatitis B, C, D

ETIOLOGY HBV: hepatitis B virus; partially double stranded DNA virus, enveloped., hepadnavirus HCV: hepatitis C virus; ssRNA, enveloped, flavivirus HDV: hepatitis D virus; ssRNA, associated with HBV, a viriod All the information below is for HBV unless otherwise noted.

 Several antigens can be found in the blood at various times during viral infection.  HBsAg or Australia antigen - includes 3 glycoproteins (L, M, and S). HBsAg is an envelope protein eliciting neutralizing antibodies in the patient. This antigen is composed of a group (a) and type specific (termed d or y and w or r) determinants. Eight different subtypes of HBV exists. The most common combination of HBV surface antigens is either adw or ady. These type specific determinants are useful in epidemiology.  Other antigens: Incomplete viral particles that may be present in the patient's serum include: o HBcAg: HBV core antigen o HBeAg: HBV soluble antigen = a minor component of the virion. HBeAg and HBcAg have nearly identical amino acid sequences. HBeAg is processed differently by the cell, is primarily secreted into the serum, does not self assemble like an HBcAg, and expressed different antigenic determinants. o viral DNA o DNA polymerase o protein kinase  Dane particle: the infectious HBV virion.  Other spherical and filamentous, non-infectious viral particles can also be found in patient serum.

Delta agent: HDV, named for the delta antigen. To be infective, delta agent must be coated with HBsAg. Thus, delta agent is only found in concurrent HBV infections.

EPIDEMIOLOGY Distribution is worldwide, but uneven. Hepatitis B virus (HBV) infection is a serious global health problem, with 2 billion people infected worldwide, and 350 million suffering from chronic HBV infection. Approximately 15-40% of infected patients will develop cirrhosis, liver failure, or hepatocellular carcinoma (HCC). It is the 10th leading cause of death worldwide, HBV infections result in 500,000 to 1.2 million deaths per year due to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCC accounts for 320,000 deaths per year. Acute viral hepatitis in the US has been well characterized. About 55% is caused by HAV, 32% by HBV, and 12% by HCV. HBV and HCV play some role in 64% of patients with chonic liver disease. 80% of all cases of Primary Hepatocellular Carcinoma (HPC) is attributed to chronic HBV infections. HBV infects 140,000-320,000 people/yr with 70,000-160,000 symptomatic infections/yr. Of symptomatic HBV infections, 8400-19,000 hospitalizations/yr and 140-320 (0.2%) deaths/yr. Of all HBV infections, 8,000-32,000 (6%-10%) chronic infections/yr, and 5,000-6,000 deaths/yr from chronic liver disease including primary liver cancer. Estimated 1-1.25 million Americans are chronically infected with HBV. HBV costs the American people an estimated $700 million (1991 dollars)/yr (medical and work loss). There are 36,000 new HCV infections/yr with 25-30% being symptomatic. Chronic infection occurs in >85% of persons infected with HCV. 70% of persons infected with HCV develop chronic liver disease. Deaths from chronic liver disease: 8,000-10,000/yr. Infection with HCV is the leading infectious indication for liver transplantation. About 3.9 million (1.8%) Americans have been infected with HCV of whom 2.7 million are chronically infected. HCV infections cost the American people an estimated $600 million (1991 dollars)/year (medical and work loss, excluding transplantation). HDV infection can be acquired either as a coinfection with HBV or as a superinfection of patients with chronic HBV infection. Patients with HBV-HDV coinfection may have more severe acute disease and a higher risk of fulminant hepatitis (2%-20%) compared with those infected with HBV alone. However, chronic HBV infection appears to occur less frequently in persons with HBV- HDV coinfection. Chronic HBV carriers who acquire HDV superinfection usually develop chronic HDV infection. In long-term studies of chronic HBV carriers with HDV superinfection, 70%-80% have developed evidence of chronic liver diseases with cirrhosis compared with 15%-30% of patients with chronic HBV infection alone.

Hosts: Humans and possibly other primates seem to be the only hosts, and chronic carriers are the reservoir. 5-15% of persons in tropical countries are carriers, while only 0.1-0.5% are carriers in the U.S.

HBV Transmission: Hepatitis B virus is present in the blood, saliva, semen, vaginal secretions, menstrual blood, and to a lesser extent, perspiration, breast milk, tears, and urine of infected individuals. A highly resilient virus, HBV is resistant to breakdown, can survive outside the body. It is easily transmitted through contact with infected body fluids. In areas of high endemicity, the most common route of transmission is perinatal or the infection is acquired during the preschool years. The route of transmission has important clinical implications, because there is a very high probability of developing chronic hepatitis B (CHB) if the infection is acquired perinatally or in the preschool years. The virus can be spread by percutaneous routes (e.g. needle sharing, acupuncture, ear piercing, tattooing, transfusions, receiving blood products) and through very close personal contact involving the exchange of blood or secretions (e.g. sex, child birth). The most common means of transmission of HBV in the U.S. is via the sexual route. The pattern of transmission of HBV varies with chronic HBV prevalence. In areas where chronic infections (chronic hepatitis) are highly endemic (East and Southeast Asia and Sub-Saharan Africa), transmission is usually perinatal (from a carrier mother to her newborn) or by close contact between children (horizontal transmission). Perinatal transmission of HBV usually occurs during or soon after delivery following contact of the infant with maternal blood and other body fluids. In areas of low endemicity (Western Europe and North America), perinatal transmission is less common and transmission occurs mainly through blood and by sexual contact between adults. There is no evidence that breastfeeding from a chronically infected mother poses an additional risk of HBV infection to her infant, even without immunization. However, damage to the breast as a result of breastfeeding, such as cracked or bleeding nipples or lesions with serous exudates, could however expose the infants to infectious doses of HBV. Therefore, neonates born to chronically infected women should be given hepatitis B immunoglobulin at birth along with the first dose of the hepatitis B recombinant vaccine. The remaining doses of vaccine should be given at 1 and 6 months of age. At high risk for HBV infection:

 intravenous drug users  patients undergoing blood transfusions or hemodialysis lab  personnel in contact with blood and blood products  individuals with multiple sexual contacts (heterosexual and homosexual)  immunosuppressed individuals  infants born to mothers with chronic HBV  residents and staff members of institutions for the mentally handicapped  People from endemic regions (i.e., China, parts of Africa, Alaska, Pacific Islands)

HCV Transmission: HCV infections are mainly associated with injecting drug use (60%). HCV can also be transmitted by sexual contact (15%) however the efficiency of sexual transmission is quite low. People with increased risk factors for sexual transmission of HCV are those that participate in unprotected sex with multiple sexual partners, begin sexual activity at an early age, have an infected sexual partner, have a history of other STD's, and/or experience sex with trauma. HCV is the most common infectious reason patients need liver transplants; 2.7 million people are chronic carriers of HCV. HDV Transmission: HDV infections are usually due to percutaneous exposures. Most commonly found in IV drug users. Sexual transmission of HDV is less efficient than for HBV. Perinatal HDV transmission is rare.

PATHOGENESIS HBV replicates within liver cells, within 3 days following bloodstream acquisition. Replication of the virus is not cytopathic; symptoms may not be observed for 45 days or longer, depending on the dose of HBV, the route of infection, and the individual. HBV genomes integrate into host chromosomes during replication; the basis of latent infections. Large amounts of HBsAg are released into the blood as well as complete virions. Immune complexes formed by HBsAg and specific antibody are responsible for hypersensitivity reactions seen as arthritis, rash, liver damage, vasculitis, arthralgia (acute paroxysmic joint pain), or kidney problems. Liver parenchyma degeneration results from cellular swelling and necrosis. Resolution of the infection allows the liver parenchyma to regenerate. Fulminant infections, activation of chronic infections, or coinfection with the delta agent can lead to permanent liver damage or cirrhosis. Resolution of disease: Both cell mediated immunity and inflammation are responsible for the resolution of HBV infection and its symptoms. Acute cases of HBV disease are usually of short duration with significant symptomology. Chronic Hepatitis B infection or CHB is the presence of Hepatitis S antigen (HbsAg) in the bloodstream following infection by Hepatitis B virus for at least 6 months. The early phase of chronic Hepatitis B virus (CHB) infection is characterized by the presence of hepatitis B e antigen (HBeAg) and high serum levels of HBV DNA (referred to as HBeAg-positive CHB). After infection the CHB patient’s immune system attempts to clear the HBV by destroying infected hepatocytes. This leads to increasing circulatory blood levels of alanine aminotransferase (ALT). Most patients will clear HBeAg (and produce anti-HBe antibodies) and achieve a state of nonreplicative infection, characterized by low or undetectable serum levels of HBV DNA and normal ALT levels. High HBV DNA and ALT levels may persist in some anti-HBe-positive patients (referred to as HBeAg-negative CHB) because of the presence of an HBV variant that is unable to produce HBeAg (HBeAg-negative variant, also called HBV precore stop codon mutant). Severe disease progresses quickly with HBeAg-negative HBV; 60% of patients with this form of disease develop cirrhosis within 6 years. Over time, 25% of persons who acquire HBV as children will develop primary liver cancer or cirrhosis as adults. Cirrhosis may develop as a consequence of repeated immune system attacks. Once established, cirrhosis cannot be cured; however, its progress may be stopped if the cause (in this case, HBV infection) is removed. Without treatment, the typical progression is from compensated cirrhosis to decompensated cirrhosis. The latter is characterized by cessation of enzymatic processes in the liver and subsequent severe clinical complications such as fluid retention in the abdomen (), jaundice, internal bleeding, and hepatic encephalopathy. Patients with decompensated cirrhosis are candidates for liver transplantation, without which death results from end-stage liver disease.

MANIFESTATIONS Incubation period. 7 to 160 days. Anicteric infections. about 65% of the time. Acute Infection. about 25% of time with HBV;  less severe in children than adults.

 early symptoms

 fatigue

 anorexia; recovery follows regaining appetite.

 nausea pain and fullness in the upper right quadrant

 fever

 loss of fever signifies recovery. Later symptoms arthritis and rash, cholestasis; symptoms tend to be more severe those seen in HAV infections. Fulminant hepatitis.  occurs in 1% of acutely infected individuals; more likely if HBV and HDV coinfect.

 more severe symptoms, can be fatal.

 severe liver damage: ascites and bleeding;

 liver shrinkage rather than . Chronic infection. (not seen with HAV) more common with HCV (50-70% of acutely ill patients) Occurs in 5-10% of HBV infections. Usually follows mild or inapparent initial disease. Usually detected by elevated liver enzyme levels on a routine blood analysis. 10% of chronic hepatitis HBV patients suffer from liver cirrhosis and liver failure. Chronic HBV infections are the major reservoir. HBV and HDV can infect a person at the same time (coinfection). HDV can also infect a person after they have been infected with HBV (superinfection). Chonic HBV patients are more likely to develop fulminant hepatitis or a more severe hepatitis when superinfected by HDV. 20% of chronic HCV patients suffer from liver cirrhosis and 20% of these cirrhotic patients have liver failure. Primary hepatocellular carcinoma. Chronic HBV infection is associated with 80% of cases of liver carcinoma (one of the three most common causes of cancer mortality, worldwide). Liver carcinoma follows HBV infection after 9-35 years. Chronic HCV infection can also result in hepatocellular carcinoma.

DIAGNOSIS Initial diagnosis

 Cholestasis  Altered liver enzyme profiles in the blood; ALT, AST  Alkaline phosphatase elevated  bilirubin elevated

Confirmatory diagnosis (hepatitis panel for serologies)

 HBsAg and HBeAg are detectable by clinical laboratory assays.  HBsAg only: predicts minimal liver damage  HBsAg and HBeAg predicts more liver damage, cirrhosis.  IgM for HBcAg and/or HBsAg is usually the best indication of an acute HBV infection.  IgM or IgG specific for delta antigen indicate HDV infection. Occasionally delta antigen, itself is tested for.  Antibodies for HCV are also detectable.

Convalescence sign: An increase in Anti-HBs and Anti-HBe.

Chronic infection: A patient has chronic hepatitis if HBsAg is present for more than 6 months. Chronic Active Hepatitis (CAH) patients have HBsAg, HBeAg, and Anti-HBc. Chronic Persistant Hepatitis (CPH) patients have HBsAg, Anti-HBe, and Anti-HBc.

THERAPY The main goal of therapy for patients with chronic HBV infection is to improve survival and quality of life by preventing disease progression, and consequently HCC development. Additional goals of antiviral therapy are to prevent mother to child transmission, hepatitis B reactivation and the prevention and treatment of HBV-associated extrahepatic manifestations. Human interferon alpha (IFN, 3TC and adefovir dipivoxil may be used to treat chronic HBV. IFNhas immunostimulatory activity as well as antiviral activity. 3TC and adefovir dipivoxil are nucleoside/nucleotide analogues that suppress HBV replication through inhibition of HBV DNA polymerase. HbeAg positive chronic hepatitis patients usually respond better to therapy than HbeAg negative chronic hepatitis patients. Treatment with conventional IFNα not only results in loss of and normalization of liver enzymes, but also improves long-term outcomes and survival, and alters the natural history of the disease. HbeAg positive IFNfor 4-6 months/3 injections per week= 20-50% loss in HbeAg. Response to treatment with conventional IFNα is sustained, as approximately 90% of end-of-treatment responders maintain a positive response. HBeAg loss was followed by loss of HBsAg in 87% of patients after conventional IFNα therapy. Conventional IFNα has been shown to have beneficial long-term effects on disease outcome, incidence of HCC development and complication-free survival. 3TC after 12 months of therapy at 100 mg daily, end-of-treatment seroconversion rates (disappearance of HBeAg and appearance of anti-HBe) range from 17 to 21%. However, reversion to HBeAg-positive status after cessation of lamivudine therapy has been observed, and a positive response (sustained response 2 years after cessation of therapy) is maintained in 50% of end-of- treatment responders to lamivudine therapy. Mutant HBV viruses do develop and are resistant to 3TC therapy. HbeAg negative

This type of CHB is less susceptible to therapy than HBeAg-positive 'wild-type' virus and is associated with a poorer prognosis. Therefore, treatment needs to be given early during the natural course of HBV infection before mutation to the HBeAg-negative variant occurs. This will prevent the HBeAg-negative variant from becoming the prevalent form of the virus. After up to 12 months of IFNα therapy, approximately 50-70% of showed a positive response (normalization of ALT values and disappearance of HBV DNA). However, sustained response rates are highly variable, with 6-24% of patients maintaining a sustained response (12-18 months after cessation of therapy). 3TC demonstrates a positive response (ALT normalization and HBV DNA suppression) in 65- 87% of patients after 12 months of therapy, and in 40% of patients at the end of 30 months of continuous treatment. However, in the majority of patients, a positive response is not maintained when treatment is stopped. Only 13-17% of patients show a sustained response 6 months after cessation of therapy. Adefovir dipivoxil has been used with less success than what was seen with IFN and 3TC in both HbeAg positive and negative patients. However it appears useful in treating patients that have 3TC resistant HBV.

The goal of therapy of HCV infection is to cure it, in order to: prevent the complications of HCV-related liver and extra-hepatic diseases, including hepatic necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death; improve quality of life and remove stigma; and prevent onward transmission of HCV. Two different management strategies for chronic HCV patients exist: 1. Immediate treatment with interferon and ribavirin for up to 48 weeks 2. Watchful waiting with liver biopsy every 3 years, with therapy initiated if hepatitis progressed to a moderate stage or cirrhosis. One study has demonstrated that the immediate treatment with inteferon and ribavirin may be more cost effective than watchful waiting. Unfortunately, about 25% of patient must stop the Interferon alpha/ribavirin treatment due to thrombocyopenia. A recent study using a platelet cell growth factor IL-11 (oprelvekin) was able to raise platelet levels in patients and allow them to continue their treatment for the HCV infection. The use of IL-11 is still experimental. In a recent study patients were given PEG-interferon (PEG-Intron) with ribavirin for 48 weeks (4 years) and then they were followed for the presence of Hepatitis C virus for 24 weeks (6 months). They found that nearly 61 percent of the patients treated in this way were still negative for Hepatitis C virus. In fact, some of the investigators are even pointing to the possibility that these patients may have been CURED. This treatment may give new hope to chronic HCV patients. PREVENTION For HBV and HDV. Active immunization. There are two HBV vaccines available. The most commonly used vaccine Energix-B or Recombivax HB are HBs antigen produced in yeast. The vaccines are given to all children at 0-2 month, 1 to 4 months, and 6 to 18 months (three different immunizations). Passive immunization. HBV Immune Globulin prepared from plasma with a high titer of HBs antibody, but no detectable HBsAg. This treatment is often used in combination with vaccination for infants born to HBV positive mothers and for persons who were accidentally exposed to HBV as above. Protection of neonates born from mothers with chronic HBV. Neonates should be given hepatitis B immunoglobulin at birth along with the first dose of the hepatitis B recombinant vaccine. The remaining doses of vaccine should be given at 1 and 6 months of age. HIV-infection. AIDS AIDS is an acronym for Acquired Immunodeficiency Syndrome or Acquired Immune Deficiency Syndrome and is defined as a collection of symptoms and infections resulting from the depletion of the immune system caused by infection with HIV. Although treatments for both AIDS and HIV exist, there is no known cure. The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility, immune function, health care, the presence of co-infections and peculiarities of the viral strain. The official date for the beginning of the AIDS epidemic is marked as June 18, 1981, when the US Center for Disease Control and Prevention reported a cluster of Pneumocystis carinii pneumonia (now classified as Pneumocystis jiroveci pneumonia) in five gay men in Los Angeles in the early 1980s. Originally dubbed GRID, or Gay Related Immune Difficiency, health authorities soon realized that nearly half of the people identified with the syndrome were not gay. Reporter Randy Shilts discovered the name of an extremely sexually active man, Gaetan Dugas, who epidemiologists at the time suspected to be the first carrier of what was first called "gay-plague", but later research failed to track the epidemic to any individual carrier. In 1982, the CDC introduced the term AIDS to describe the newly recognized syndrome. Three of the earliest known instances of HIV infection are as follows: 1. A plasma sample taken in 1959 from an adult male living in what is now the Democratic Republic of Congo. 2. HIV found in tissue samples from an American teenager who died in St. Louis in 1969. 3. HIV found in tissue samples from a Norwegian sailor who died around 1976. Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is more virulent and more easily transmitted. HIV-1 is the source of the majority of HIV infections throughout the world, while HIV- 2 is less easily transmitted and is largely confined to West Africa. Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-2 has been established to be the sooty mangabey (Cercocebus atys), an Old World monkey of Guinea Bissau, Gabon, and Cameroon. The origin of HIV-1 is a chimpanzee subspecies: Pan troglodytes troglodytes. HIV is transmitted through penetrative (anal or vaginal) and oral sex; blood transfusion; the sharing of contaminated needles in health care settings and through drug injection; and, between mother and infant, during pregnancy, childbirth and breastfeeding. AIDS is thought to have originated in sub-Saharan Africa during the twentieth century and is now a global epidemic. The World Health Organization estimated that, worldwide, between 2.8 and 3.5 million people with AIDS died in 2004. Global epidemic UNAIDS and the WHO estimated that between 36 and 44 million people around the world were living with HIV in December 2004. It was estimated that during 2004, between 4.3 and 6.4 million people were newly infected with HIV and between 2.8 and 3.5 million people with AIDS died. Sub- Saharan Africa remains by far the worst-affected region, with 23.4 million to 28.4 million people living with HIV at the end of 2004. Just under two thirds (64%) of all people living with HIV are in sub-Saharan Africa, as are more than three quarters (76%) of all women living with HIV. South & South East Asia are second most affected with 15%. AIDS accounts for the deaths of 500,000 children. Estimated adult prevalence of Estimated adult and World region HIV infection child deaths (ages 15–49) during 2004 Sub-Saharan Africa 6.9% to 8.3% 2.1 to 2.6 million Caribbean 1.5% to 4.1% 24,000 to 61,000 Asia 0.3% to 0.6% 350,000 to 810,000 Eastern Europe and Central Asia 0.5% to 1.2% 39,000 to 87,000 Latin America 0.5% to 0.8% 73,000 to 120,000 Oceania 0.1% to 0.3% fewer than 1,700 Middle East and North Africa 0.1% to 0.7% 12,000 to 72,000 North America, Western and 0.3% to 0.6% 15,000 to 32,000 Central Europe Source: UNAIDS and the WHO 2004 estimates. The ranges define the boundaries within which the actual numbers lie, based on the best available information. Prevention The effective use of condoms and screening of blood transfusion in North America, Western and Central Europe is credited with the low rates of AIDS in these regions. Adopting these effective prevention methods in other regions has proved controversial and difficult. The Vatican opposes the use of condoms and many countries do not screen blood transfusions for HIV antibodies. Safer sex The male latex condom is the single most efficient available technology to reduce the sexual transmission of HIV and other sexually transmitted infections. With consistent and correct use of condoms, there is a very low risk of HIV infection. Studies on couples where one partner is infected show that with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year. The US government and US health organizations both endorse the ABC Approach to lower the risk of acquiring AIDS during sex:  Abstinence or delay of sexual activity, especially for youth,

 Being faithful, especially for those in committed relationships,

 Condom use, for those who engage in risky behavior. This approach has been very successful in Uganda, where HIV prevalence has decreased from 15% to 5%. However, the ABC approach is far from all that Uganda has done, as "Uganda has pioneered approaches towards reducing stigma, bringing discussion of sexual behavior out into the open, involving HIV-infected people in public education, persuading individuals and couples to be tested and counseled, improving the status of women, involving religious organizations, enlisting traditional healers, and much more." (Edward Green, Harvard medical anthropologist). Also, it must be noted that there is no conclusive proof that abstinence-only programs have been successful in any country in the world in reducing HIV transmission. This is why condom use is heavily co-promoted. There is also considerable overlap with the CNN Approach. This is:  Condom use, for those who engage in risky behavior.

 Needles, use clean ones

 Negotiating skills; negotiating safer sex with a partner and empowering women to make smart choices The ABC approach has been criticized, because a faithful husband or wife of an unfaithful partner is at risk of AIDS. Many think that the combination of the CNN approach with the ABC approach will be the optimum prevention platform. HIV blood screening In those countries where improved donor selection and antibody tests have been introduced, the risk of transmitting HIV infection to blood transfusion recipients has been effectively eliminated. According to the WHO, the overwhelming majority of the world's population does not have access to safe blood and "between 5% and 10% of HIV infections worldwide are transmitted through the transfusion of infected blood and blood products." Medical procedures Medical workers who follow universal precautions or body substance isolation such as wearing latex gloves when giving injections and washing the hands frequently can help prevent infection of HIV. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV infected person though is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce that small risk. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training. The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections. Because of this, the United Nations General Assembly, supported by universal medical opinion on the matter, has urged the nations of the world to implement universal precautions to prevent HIV transmission in health care settings. Universal precaution gets its name from the idea that precautions are to be used every single time, and not merely when the healthcare worker thinks that a patient might be high-risk for a transmissable disease. Intravenous drug use HIV can be transmitted by the sharing of needles by users of intravenous drugs. Cumulative data from 1981 to 2001 has shown that 31.5% of people with AIDS in the United States are injection drug users. All AIDS-prevention organisations advise drug-users not to share needles and to use a new or properly sterilized needle for each injection. Information on cleaning needles using bleach is available from health care and addiction professionals and from needle exchanges. In the United States and other western countries, clean needles are available free in some cities, at needle exchanges or safe injection sites. Mother to child transmission There is a 30% risk of transmission of HIV from mother to child during pregnancy, labour and delivery. A number of factors influence the risk of infection, particularly the viral load of the mother at birth (the higher the load, the higher the risk). Breastfeeding increases the risk of transmission by 10–15%. This risk depends on clinical factors and may vary according to the pattern and duration of breastfeeding. Studies have shown that antiretroviral drugs, cesarean delivery and formula feeding reduce the chance of transmission of HIV from mother to child. (Sperlin et al., 1996) When replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV- infected mothers are recommended to avoid breast feeding their infant. Otherwise, exclusive breastfeeding is recommended during the first months of life and should be discontinued as soon as possible. Transmission and infection Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Patterns of HIV transmission vary in different parts of the world. In sub-Saharan Africa, which accounts for an estimated 60% of new HIV infections worldwide, controversy rages over the respective contribution of medical procedures, heterosexual sex and the bush meat trade. In the United States, sex between men (35%) and needle sharing by intravenous drug users (15%) remain prominent sources of new HIV infections. In January 2005, Anthony S. Fauci, M.D., director of NIAID said, "Individual risk of acquiring HIV and experiencing rapid disease progression is not uniform within populations". NIH press release Some epidemiological models suggest that over half of HIV transmission occurs in the weeks following primary HIV infection before antibodies to the virus are produced. Investigators have shown that viral loads are highest in semen and blood in the weeks before antibodies develop and estimated that the likelihood of sexual transmission from a given man to a given woman would be increased about 20-fold during primary HIV infection as compared with the same couple having the same sex act 4 months later. Most people who are infected typically suffer from days to weeks of fever with or without muscle and joint aches, fatigue, headache, sore throat, swollen glands and sometimes rash. This "acute retroviral syndrome" is rarely diagnosed because it is difficult to distinguish from other very common ailments. The Centers for Disease Control (CDC) in the United States reported a cluster of HIV infections in 13 of 42 young women who reported sexual contact with the same HIV infected man in a rural county in upstate New York between February and September 1996 The risk of oral sex has always been controversial. Most of the early AIDS cases could be attributed to anal sex or vaginal sex. As the use of condoms became more widespread, there were reports of AIDS acquired by oral sex. Unprotected oral sex is widely understood to be less risky than unprotected vaginal sex, which in turn is less risky than unprotected anal sex. Heterosexual transmission of HIV-1 depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. Each 10 fold increment of seminal HIV RNA is associated with an 81% increased rate of HIV transmission. During 2003 in the United States, 19% of new infections were attributed to heterosexual transmission. The argument about the exact incidence of HIV transmission per act of intercourse is academic. Infectivity depends critically on social, cultural, and political factors as well as the biological activity of the agent. Whether the epidemic grows or slows depends on infectivity plus two other variables: the duration of infectiousness and the average rate at which susceptible people change sexual partners. Genetic susceptibility CDC has released findings that genes influence susceptibility to HIV infection and progression to AIDS. HIV enters cells through an interaction with both CD4 and a chemokine receptor of the 7 Tm family. They first reviewed the role of genes in encoding chemokine receptors (CCR5 and CCR2) and chemokines (SDF-1). While CCR5 has multiple variants in its coding region, the deletion of a 32- bp segment results in a nonfunctional receptor, thus preventing HIV entry; two copies of this gene provide strong protection against HIV infection, although the protection is not absolute. This gene is found in up to 20% of Europeans but is rare in Africans and Asians; researchers and scientists believe that HIV had a similar viral shell as the bacteria which caused the black plague (1347-1350), leading to the decimation of one-third of the European population, possibly explaining why the CCR5-32 receptor gene is more prevalent in Europeans than Africans and Asians. Multiple studies of HIV- infected persons have shown that presence of one copy of this gene delays progression to the condition of AIDS by about 2 years. And it is possible that a person with the CCR5-32 receptor gene will not develop AIDS, although they will still carry HIV. Diagnosis The majority of people infected with HIV, if not treated, develop signs of AIDS within 8-10 years. However, 1-2% of HIV-infected individuals retain functional immune systems, despite being infected with HIV for a number of years. These individuals are known as HIV longterm non- progressors. The Centers for Disease Control has, since 1993, defined an AIDS diagnosis in adults and adolescents in the USA as when a person presents with HIV infection and either a CD4+ T cell the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV entry; two copies of this gene provide strong protection against HIV infection, although the protection is not absolute. This gene is found in up to 20% of Europeans but is rare in Africans and Asians; researchers and scientists believe that HIV had a similar viral shell as the bacteria which caused the black plague (1347-1350), leading to the decimation of one-third of the European population, possibly explaining why the CCR5-32 receptor gene is more prevalent in Europeans than Africans and Asians. Multiple studies of HIV-infected persons have shown that presence of one copy of this gene delays progression to the condition of AIDS by about 2 years. And it is possible that a person with the CCR5-32 receptor gene will not develop AIDS, although they will still carry HIV. In developing countries, AIDS in adults and adolescents is identified on the basis of certain infections, grouped by the World Health Organization (WHO):  Stage I HIV disease is asymptomatic and not categorized as AIDS

 Stage II (includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections)

 Stage III (includes unexplained chronic diarrhoea for longer than a month, severe bacterial infections and pulmonary tuberculosis) or

 Stage IV (includes of the brain, Candidiasis of the oesophagus, trachea, bronchi or lungs and Kaposi's Sarcoma) HIV disease are used as indicators of AIDS. Treatment There is currently no cure or vaccine for HIV or AIDS. Current optimal treatment options consist of combinations ("cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of anti-retroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor or a non nucleoside reverse transcriptase inhibitor (NNRTI). This treatment is frequently referred to as HAART (highly-active anti-retroviral therapy). Anti-retroviral treatments, along with medications intended to prevent AIDS- related opportunistic infections, have played a part in delaying complications associated with AIDS, reducing the symptoms of HIV infection, and extending patients' life spans. Over the past decade the success of these treatments in prolonging and improving the quality of life for people with AIDS has improved dramatically. However, treatment guidelines are changing constantly. The current guidelines for antiretroviral therapy from the World Health Organization reflect the 2003 changes to the guidelines and recommend that in resource-limited settings (i.e., developing nations), HIV-infected adults and adolescents should start ARV therapy when HIV-infection has been confirmed and one of the following conditions is present:  Clinically advanced HIV disease:

 WHO Stage IV HIV disease, irrespective of the CD4 cell count;

 WHO Stage III disease with consideration of using CD4 cell counts <350/Вµl to assist decision-making.

 WHO Stage I or II HIV disease with CD4 cell counts <200/Вµl The US Department of Health and Human Services, the federal agency responsible for overseeing HIV/AIDS healthcare policies in the United States, have recently stated on April 7, 2005 that:  All patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART.

 Antiretroviral therapy is also recommended for asymptomatic patients with <200 CD4+ T cells/Вµl

 Asymptomatic patients with CD4+ T cell counts of 201 - 350 cells/Вµl should be offered treatment.  For asymptomatic patients with CD4+ T cell of >350 cells/Вµl and plasma HIV RNA >100,000 copies/ml most experienced clinicians defer therapy but some clinicians may consider initiating treatment.

 Therapy should be deferred for patients with CD4+ T cell counts of >350 cells/Вµl and plasma HIV RNA <100,000 copies/mL. The preferred initial regimens are either:  efavirenz + lamivudine or emtricitabine + zidovudine or tenofovir; or

 lopinavir boosted with ritonavir + zidovudine + lamivudine or emtricitabine.

The DHHS also recommends that doctors should assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to begin treatment. There are several concerns about antiretroviral regimens. The drugs can have serious side effects (Saitoh et al., 2005). Regimens can be complicated, requiring patients to take several pills at various times during the day. If patients miss doses, drug resistance can develop. Also, anti-retroviral drugs are costly, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS. Research to improve current treatments includes decreasing side effects of current drugs, simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Vaccine research As there is no known cure for AIDS, the search for a vaccine against the etiological agent, HIV, has become part of the struggle against the disease. Only a vaccine will be able to halt the pandemic. This would possibly cost less, thus being affordable for developing countries, and would not require daily treatments. However, after over 20 years of research, HIV remains a difficult target for a vaccine and there is still no vaccine available; a June 2005 study estimates that $682 million is spent on AIDS vaccine research annually.

8. Materials for activating students during a lecture: 1. Viral hepatitis B, C, D: etiology, epidemiology, clinical picture. 2. Types of the course of the prodromal period of viral hepatitis B, C, D. 3. Describe the main clinical syndromes characteristic of the peak of viral hepatitis. 4. What complications arise with hepatitis B, C, D. 5. What laboratory diagnostic methods confirm the diagnosis of viral hepatitis. 6. Treatment of patients with viral hepatitis. 7. Prevention of hepatitis B, C, D. 8. Chronic viral hepatitis B, C: etiology, epidemiology, clinical presentation 9. Describe the main clinical syndromes characteristic of the exacerbation and latency of chronic viral hepatitis. 10. Specific therapy for chronic hepatitis C. 11. Specific therapy for chronic hepatitis B. 12. What complications arise with chronic hepatitis B, C, diagnosis, treatment. 13. What laboratory diagnostic methods confirm the diagnosis of chronic viral hepatitis. 14. Treatment of patients with chronic viral hepatitis. 15. The HIV epidemic in Ukraine and the world. Normative documents on preventing the spread of HIV infection and social protection of the population. The social consequences of the spread of HIV. 16. Etiology and pathogenesis of HIV infection, classification of the stages of the disease. Extended definition of AIDS in adults and adolescents. Classification of clinical stages, diagnosis criteria are large and small. 17. The role of HIV infection in the formation of lymphadenopathy syndrome, differential diagnosis of this syndrome. Task 1 Patient Z. of 42 years was hospitalized with the infectious disease ward on the 23rd day of the disease with complaints of general weakness, absence of appetite, sickness and periodical vomiturition. The disease progressed gradually and began with general weakness, sickness, deterioration of appetite and pain in joints. Several days later: vomiturition especially in response to smell of cooking food, anorexia, heaviness in the epigatsric area; on the 16th day of the disease, the patient observed dark urine, and during the following days – typical signs of jaundice. The patient was operated 3 months ago for colonic intussusception with hemotransfusion in the postoperative period. Objective data: grave condition. Answered to questions apathetically. Vomiting during the examination. Significant signs of jaundice, scratches on the skin. Meteorism. Liver is 4cm below the costal margin. The lower pole of spleen is palpated. Faeces are light. 1. Provisional diagnosis. 2. Examination plan. 3. Treatment.

Task 2 A fifteen-year-old drug user presented with rapidly growing weakness, arthralgia, nausea, anorexia, and after 6 days - bright jaundice, vomiting, insomnia, dizziness, nosebleeds, slight tachycardia, subfebrile condition, enlargement of the spleen, liver, soreness, testiformity of its edge, hyperaminotransfera. On the 10th day of the disease: excited, inadequate, bright jaundice, painful, pasty liver, palpable under the costal arch, tachycardia, arterial hypotension. In the blood - moderate neutrophilic leukocytosis, ESR of 20 mm / h, direct bilirubin predominates slightly, ALT - 1650 IU / l, LF - 280 IU / l, AST - 1240 IU / l, γ GTP - 140 IU / l, creatinine - 90 mmol / l 1. Preliminary diagnosis. 2. The survey plan. 3. The treatment plan.

Test-control. 1. Which one of the following secrets contains maximal quantity of the hepatitis A virus? A. sperm; B. feces; C. urine; D. saliva; E. all mentioned. 2. What is the most typical syndrome for the preicteric period of the viral hepatitis A? A. astheno-vegetative syndrome; B. polyarthralgia; C. dyspeptic syndrome; D. influenza-like syndrome; E. mixed; 3. What is the most frequent clinical form of viral hepatitis A? A. subclinical; B. unicteric; C. cholestatic; D. icteric; E. fulminant. 4. In what group of patients lethal outcome of viral hepatitis E are observed more often? A. pregnant women; B. homosexuals; C. drag–abused; D. recipients of blood E. immunosupressed patients. 5.. What is the basic method of therapy of viral hepatitis A? A. symptomatic; B. pathogenetic; C. immunocorrection; D. antiviral; E. all mentioned. 6. What is the source of infection in viral hepatitis В? A. person sick in viral hepatitis B. B. carrier of HBsAg. C. person sick in chronic hepatitis D. D. cattle. E. person sick in chronic hepatitis C. 7. Syndromes of pre-jaundice period of acute viral hepatitis B. A. asthenovegetative. B. jaundice. C. arthralgic. D. catarrhal. E. allergic. 8. Typical features of viral hepatitis D (co-infection): A. fever. B. high risk of acute hepatic encephalopathy development. C. catarrhal syndrome. D. ascitic type. E. mainly, jaundice-free forms. 9. The most important diagnostic proteins of the shell of the human immunodeficiency virus are: A. All answers are correct B. p24, p18 C. p7, p9 D. p17, gp41 E. gp 41, gp120 10. The most important distinguishing feature of all retroviruses are: A. the presence of the shell B. Integration into the host genome C. the presence of DNA D. the presence of RNA E. Lymphotropy

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8)

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Viral hepatitis. HIV infection. Topic Viral hepatitis with predominantly fecal-oral transmission mechanism (A and E) Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. Hepatitis A is a liver disease caused by the hepatitis A virus (HAV). The virus is primarily spread when an uninfected (and unvaccinated) person ingests food or water that is contaminated with the faeces of an infected person. The disease is closely associated with unsafe water or food, inadequate sanitation, poor personal hygiene and oral-anal sex. Unlike hepatitis B and C, hepatitis A does not cause chronic liver disease and is rarely fatal, but it can cause debilitating symptoms and fulminant hepatitis (acute liver failure), which is often fatal. Overall, WHO estimated that in 2016, 7 134 persons died from hepatitis A worldwide (accounting for 0.5% of the mortality due to viral hepatitis). Hepatitis A occurs sporadically and in epidemics worldwide, with a tendency for cyclic recurrences. The hepatitis A virus is one of the most frequent causes of foodborne infection. Epidemics related to contaminated food or water can erupt explosively, such as the epidemic in Shanghai in 1988 that affected about 300 000 people1. They can be also prolonged, affecting communities for months through person-to-person transmission. Hepatitis A viruses persist in the environment and can withstand food-production processes routinely used to inactivate and/or control bacterial pathogens. Persons aged 5-14 years are most likely to acquire acute HAV infection before the vaccination programs. Over the past 40 years, the average age of infected persons has steadily increased. Evidence of past infection is more prevalent in adults (approximately 40%) than in children (approximately 10%), which supports acquisition during school-aged years. Individuals in the high-risk populations currently account for many sporadic cases of HAV infection. These groups include contacts of recently infected individuals, foreign travelers (particularly those to developing nations), male homosexuals, childcare workers, institutionalized individuals, and those living in poverty. Health measures implemented for these high-risk groups will likely modify the evolving epidemiology. Hepatitis E has many similarities with hepatitis A. Hepatitis E has been associated with chronic hepatitis in solid-organ transplant recipients, patients infected by human immunodeficiency virus (HIV), and in an individual on rituximab treatment for non-Hodgkin lymphoma. A study has shown that among patients receiving hemodialysis, the seroprevalence of anti- HEV immunoglobulin G (IgG) was found to be high. However, no evidence of chronic infection was found. The global disease burden of hepatitis E has been reported to be at least 20 million cases/year with 70,000 fatalities and 3,000 stillbirths. Hepatitis E has worldwide distribution, but predominating factors include tropical climates, inadequate sanitation, and poor personal hygiene. It is found most often in developing countries near the equator, in both the Eastern and Western hemispheres. Regions with a prevalence rate of more than 25% include Central America, the Middle East, and large parts of Africa and Asia.

2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system, gastrointestinal tract Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea, gastrointestinal tract Microbiology Properties of bacteria, methods for the specific diagnosis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. Symptoms internal diseases and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of antimicrobials, Pharmacology pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. Etiology,pathophysisology of hepatitis A; 2. Clinical presentation of hepatitis A; 3. Diagnosis and treatment of hepatitis A; 4. Prevention of hepatitis A; 5. Etiology, pathophysiology of hepatitis E; 6. Clinical presentation of hepatitis E; 7. Diagnosis and treatment of hepatitis E; 8. Prevention of hepatitis E;

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: VIRAL HEPATITIS A Etiology. HAV is a single-stranded, positive-sense, linear RNA enterovirus of the Picornaviridae family. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in the liver cells. Virus acquisition results almost exclusively from ingestion (eg, fecal-oral transmission), although isolated cases of parenteral transmission have been reported.

HAV is an icosahedral nonenveloped virus, measuring approximately 28 nm in diameter. Its resilience is demonstrated by its resistance to denaturation by ether, acid (pH 3.0), drying, and temperatures as high as 56°C and as low as -20°C. The hepatitis A virus can remain viable for many years. Boiling water is an effective means of destroying it. Chlorine and iodine are similarly effective.

Various genotypes of HAV exist; however, there appears to be only 1 serotype. Virion proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization. No antibody cross- reactivity has been identified with other viruses causing acute hepatitis. Evidence in recent years appears to show that the exosomes play a dual role in the transmission of HAV and HCV, allowing these viruses to evade antibody-mediated immune responses but, paradoxically, can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production.

Pathogenesis. Hepatocyte uptake involves a receptor, identified by Kaplan et al, on the plasma membrane of the cell, and viral replication is believed to occur exclusively in the hepatocytes. The demonstration of HAV in the saliva has raised questions about this exclusivity. After entry into the cell, viral RNA is uncoated, and the host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase. Assembled virus particles are shed into the biliary tree and excreted in the feces. Minimal cellular morphologic changes result from hepatocyte infection. The development of an immunologic response to infection is accompanied by a predominantly portal and periportal lymphocytic infiltrate and a varying degree of necrosis. Many authorities believe that hepatocyte injury is secondary to the host’s immunologic response. This hypothesis is supported by the lack of cytotoxic activity in tissue culture and correlations between immunologic response and the manifestations of hepatocyte injury. Person-to-person contact is the most common means of transmission and is generally limited to close contacts. Transmission through blood products has been described. The period of greatest shedding of HAV is during the anicteric prodrome (14-21 d) of infection and corresponds to the time when transmission is the highest (see the image below). Recognizing that the active virus is shed after the development of jaundice is important, although the quantity falls rapidly.

The incubation period usually lasts 2-6 weeks, and the time to the onset of symptoms may be dose related. The presence of disease manifestations and the severity of symptoms after HAV infection directly correlate with the patient's age. In developing nations, the age of acquisition is before age 2 years. In Western societies, acquisition is most frequent in persons aged 5-17 years. Within this age range, the illness is more often mild or subclinical; however, severe disease, including fulminant hepatic failure, does occur. Transmission. The hepatitis A virus is transmitted primarily by the faecal-oral route; that is when an uninfected person ingests food or water that has been contaminated with the faeces of an infected person. In families, this may happen though dirty hands when an infected person prepares food for family members. Waterborne outbreaks, though infrequent, are usually associated with sewage-contaminated or inadequately treated water. The virus can also be transmitted through close physical contact (such as oral-anal sex) with an infectious person, although casual contact among people does not spread the virus. Anyone who has not been vaccinated or previously infected can get infected with hepatitis A virus. In areas where the virus is widespread (high endemicity), most hepatitis A infections occur during early childhood. Risk factors include:

 poor sanitation;  lack of safe water;  living in a household with an infected person;  being a sexual partner of someone with acute hepatitis A infection;  use of recreational drugs;  sex between men;  travelling to areas of high endemicity without being immunized. Clinical presentation History. Along with outlining the presenting complaint and its severity and sequelae, the history should also initiate a search for the source of exposure (eg, overseas travel, lack of immunization, intravenous [IV] drug use) and attempt to exclude other possible causes of acute hepatitis (eg, accidental acetaminophen overdose). The incubation period is 2-6 weeks (mean, 4 wk). Shorter incubation periods may result from higher total dose of the viral inoculum.

Discussion focusing on excluding other potential causes should be undertaken early in order to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has hepatitis A virus (HAV) infection. Some of the important differential diagnoses for acute hepatitis warrant early and specific management. Prodrome. In the prodrome, patients may have mild flulike symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually < 39.5°C), myalgia, and mild headache. Smokers often lose their taste for tobacco, like persons presenting with appendicitis. Icteric phase. In the icteric phase, dark urine appears first (bilirubinuria). Pale stool soon follows, although this is not universal. Jaundice occurs in most (70%-85%) adults with acute HAV infection; it is less likely in children and is uncommon in infants. The degree of icterus also increases with age. Abdominal pain occurs in approximately 40% of patients. Itching (pruritus), although less common than jaundice, is generally accompanied by jaundice. Arthralgias and skin rash, although also associated with acute HAV infection, are less frequent than the above symptoms. Rash more often occurs on the lower limbs and may have a vasculitic appearance. Physical Examination. The physical examination focuses on detecting features that support a diagnosis of acute hepatitis and should include an assessment of features of chronic liver disease and, similarly, assessment of any evidence of decompensation. Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40°C. Workup. Nucleic acid testing (NAT) is the gold standard for the diagnosis of viremic stages of hepatitis infection. Central to the prevention of any legal problem is establishing the correct diagnosis, which comes from a combination of careful history and subsequent examination. Appearances may be deceiving; therefore, always exclude drugs, particularly acetaminophen, as a cause of acute liver injury. One of the most common reasons for the misdiagnosis of hepatitis A infection is misinterpretation of the serology tests. After establishing a diagnosis of hepatitis A virus (HAV) infection, tracing contacts and notifying local public health authorities are important steps for preventing further cases. Omitting these measures may place the practitioner in a vulnerable situation. Complete blood count Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection. Indices of low-grade hemolysis are not uncommon. Prothrombin time The prothrombin time (PT) usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring. In the presence of encephalopathy, an elevated PT has ominous implications (eg, fulminant hepatic failure [FHF]). Liver Function Tests Rises in the levels of ALT and aspartate aminotransferase (AST) are sensitive for hepatitis A. Levels may exceed 10,000 mIU/mL, with ALT levels generally greater than AST levels. These levels usually return to reference ranges over 5-20 weeks. Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels. Hepatic synthetic function Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. Levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic HAV infection. Older individuals have higher bilirubin levels. Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection. Modest falls in serum albumin level may accompany the illness. Serologic Tests Anti-hepatitis A virus immunoglobulin M The diagnosis of acute HAV infection is based on serologic testing for immunoglobulin M (IgM) antibody to HAV. Test results for anti-HAV IgM are positive at the time of onset of the symptoms and usually accompany the first rise in the alanine aminotransferase (ALT) level. This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. In patients with relapsing hepatitis, IgM persists for the duration of this pattern of disease. False-positive results are uncommon and should be considered in the event that anti-HAV IgM persists. Anti-hepatitis A virus immunoglobulin G Anti-HAV immunoglobulin G (IgG) appears soon after IgM and generally persists for many years. The presence of anti-HAV IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. IgG provides protective immunity. Ultrasonography Imaging studies are usually not indicated in HAV infection. However, ultrasonography may be required when alternative diagnoses must be excluded. The goals should be to assess vessel patency and to evaluate any evidence supporting the presence of unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with FHF. Treatment There is no specific treatment for hepatitis A. Treatment generally involves supportive care, with specific complications treated as appropriate. The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents used include analgesics, antiemetics, vaccines, and immunoglobulins. Liver transplantation, in selected cases, is an option if the patient has fulminant hepatic failure (FHF). Patients at risk of developing acute hepatitis A virus (HAV) infection should undergo immunization for the virus. In addition, immunization of those at greater risk for morbidity from acute HAV infection is important. A German study of immunization rates in patients with autoimmune liver disease identified that seroconversion rates in this population were lower; however, more importantly, the study identified that vaccination was not offered to a large proportion of this population. It is not difficult to identify a low risk-benefit ratio in patients with chronic liver disease, and the author recommends vaccination for HAV in all who have no contraindication. The advent of new antiviral agents, such as direct-acting antivirals (DAAs) and host-targeting agents (HTAs), has expanded the potential therapeutic options available against HAV. Prevention Improved sanitation, food safety and immunization are the most effective ways to combat hepatitis A. The spread of hepatitis A can be reduced by:  adequate supplies of safe drinking water;  proper disposal of sewage within communities; and  personal hygiene practices such as regular hand-washing before meals and after going to the bathroom.

Several injectable inactivated hepatitis A vaccines are available internationally.  Hepatitis A vaccine, inactivated, and hepatitis B vaccine (Twinrix) - this combined hepatitis A–hepatitis B vaccine is used for active immunization of persons older than 18 years against disease caused by HAV and infection by all known subtypes of hepatitis B virus (HBV).  Hepatitis A vaccine, inactivated (Havrix, Vaqta) - may be administered with immunoglobulin injections without affecting efficacy.  Immune globulin IM (Gamunex, Octagam, Gammaplex) - neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase cerebrospinal fluid immunoglobulin G (10%). It is effective when administered within 14 days of exposure. If the patient is likely to be returning to areas of high endemicity, concurrent vaccination is recommended. For situations in which exposure is likely to occur before vaccination would be effective, both agents may be administered without reducing the efficacy of the HAV vaccine.

All are similar in terms of how well they protect people from the virus and their side-effects. No vaccine is licensed for children younger than 1 year of age. In China, a live oral vaccine is also available. Nearly 100% of people develop protective levels of antibodies to the virus within 1 month after injection of a single dose of vaccine. Even after exposure to the virus, a single dose of the vaccine within 2 weeks of contact with the virus has protective effects. Still, manufacturers recommend 2 vaccine doses to ensure a longer-term protection of about 5 to 8 years after vaccination. Millions of people have received injectable inactivated hepatitis A vaccine worldwide with no serious adverse events. The vaccine can be given as part of regular childhood immunizations programmes and also with other vaccines for travellers.

VIRAL HEPATITIS E Etiopathophysiology The hepatitis E virus (HEV) genome contains three open reading frames (ORFs). The largest, ORF-1, codes for the nonstructural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is unknown, but the antibodies directed against ORF-3 epitopes have been identified. Hepatitis E results from HEV infection and is spread by fecally contaminated water within endemic areas. However, in nonendemic areas, the major mode of the spread of HEV is foodborne, especially consumption of undercooked pork, raw liver, and sausages. HEV is an RNA virus of the genus Hepevirus. It was discovered during electron microscopy of feces contaminated with enteric non-A, non-B hepatitis. The virus is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometers, and it contains a single strand of RNA approximately 7.5 kilobases in length. Five HEV genotypes have been identified. Genotypes 1 and 2 are considered human viruses; genotypes 3 and 4 are zoonotic and have been isolated from humans and animals (eg, pigs, boars, deer), and genotype 7 primarily infects dromedaries (single-humped camel). Prognosis No chronic cases of acute hepatitis E have been reported. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. The overall case fatality rate is 4%. Among pregnant women, the case fatality rate is 20%, and this rate increases during the second and third trimesters. Reported causes of death include encephalopathy and disseminated intravascular coagulation. The rate of fulminant hepatic failure in infected pregnant women is high. In a 3-year (2010-2013) prospective observational study of 55 symptomatic anti-HEV IgM- positive Indian women, the overall maternal mortality was 5%, including one antenatal death. The most common fetal complications were prematurity (80%) and premature rupture of membranes (11%), with a 28% rate of vertical transmission. Liver transplant recipients may be at a greater risk for hepatitis E virus (HEV) infection, which can lead to chronic hepatitis and rapid progression of liver fibrosis. The presence of anti-HEV-IgG titer in pretransplantation measurements do not lead to protection of hepatitis E in posttransplantation patients. Clinical presentation. History The incubation period ranges from 15-60 days. The course of infection has two phases, the prodromal phase and the icteric phase. The prodromal phase usually is of short duration. Prodromal-phase symptoms include the following:  Myalgia  Arthralgia  Fever with mild temperature elevations (25%-97%)  Anorexia (66%-100%)  Nausea/vomiting (30%-100%)  Weight loss (typically 2-4 kg)  Dehydration  Right upper quadrant pain that increases with physical activity (abdominal pain is reported in 35%-80% of patients) Icteric-phase symptoms may last days to several weeks and include the following:  Jaundice - May be difficult to see with some patients’ natural skin color; serum bilirubin level is usually higher than 3 mg/dL; scleral icterus is present; usually occurs between the fifth and eighth week after infection  Dark urine  Light-colored stools (20%-40%)  Pruritus (50%) Other features include the following  Malaise (most common)  Arthritis  Pancreatitis  Aplastic anemia  Thrombocytopenia  Neurologic symptoms of polyradiculopathy, Guillain–Barré syndrome, Bell palsy, peripheral neuropathy, ataxia, and mental confusion  Membranoproliferative glomerulonephritis and membranous glomerulonephritis In nonendemic (autochthonous) type of acute hepatitis E infection, the majority of patients have subclinical manifestations and mild symptoms, especially in women and young persons. One report of an outbreak of hepatitis E on a cruise ship revealed only 7 of 33 patients had jaundice (21%) and most cases occurred in elderly men. Autochthonous hepatitis E also has a striking spectrum of serious complications, including “acute-on-chronic” liver failure, neurologic disorders, and chronic hepatitis. Acute-on-chronic disease refers to hepatitis with a rapid appearance of signs of liver failure such as ascites and encephalopathy in a person with preexisting liver disease. Physical Examination Physical examination should focus on the following:  Icteric sclera  Right upper quadrant tenderness  Possible enlarged liver (palpable edges; hepatomegaly is noted in 10%-85% of patients)  Possible signs of advanced chronic liver disease - Spider angiomata, , ascites, prominent collateral veins over the abdominal wall, palmar erythema Workup Basic Laboratory Studies Elevation in the serum aminotransferase levels is the laboratory hallmark of acute viral hepatitis. Serum alanine aminotransferase (ALT) level is usually higher than the serum aspartate aminotransferase (AST) level. The levels of aminotransferases may range from 10 times the upper limit of normal to more than 20 times the upper limit of normal. They increase rapidly and peak within 4-6 weeks of onset but generally return to normal within 1-2 months after the peak severity of the disease has passed. The serum alkaline phosphatase level may be normal or slightly increased (< 3 times upper limit of normal). Serum bilirubin level usually ranges from 5-20 mg/dL, depending on the extent of hepatocyte damage. The patient may develop leukopenia with neutropenia or lymphopenia. Prolonged prothrombin time, decreased serum albumin, and very high bilirubin are signs of impending hepatic failure requiring referral to a liver transplantation center. Perform blood cultures if the patient is febrile and hypotensive with an elevated white blood cell (WBC) count. Obtain serum acetaminophen levels if overdose is suspected. Serologic Testing Acute hepatitis E virus (HEV) infection is diagnosed in immunocompetent individuals based on the detection of anti-HEV immunoglobulin M (IgM). The anti-HEV IgM usually starts rising 4 weeks after infection and remains detectable for 2 months after the onset of illness. Detection of elevated reactivity in a specific IgG assay indicates the presence of acute hepatitis E. (The worldwide population seroprevalence of HEV IgG ranges between 5% and 50%.) However, the determination of immunity or previous exposure to HEV by detection of IgG antibodies is problematic. Polymerase chain reaction After exposure, viral RNA can be detected just before the onset of clinical symptoms in both blood and stool samples. HEV RNA does not persist for long, becoming undetectable in blood about 3 weeks after the onset of symptoms. The virus is shed in stool for a further 2 weeks. [40, 41] The window of detectable RNA is, therefore, narrow, and if patients present late in their illness, an undetectable HEV RNA result does not exclude recent infection. Treatment. Acute hepatitis E in immunocompetent persons usually only requires symptomatic treatment, as almost all of them are able to clear the virus spontaneously. A report showed significant improvement of liver enzymes and functions in a patient with severe acute hepatitis E who was treated with ribavirin for 21 days. Although ribavirin therapy is contraindicated in pregnancy owing to teratogenicity, the risks of untreated HEV to the mother and fetus are high, and trials of antiviral therapy might be worthwhile. Prevention Management should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish. Heating pork to an internal temperature of 71°C for 20 minutes is necessary to completely inactivate the hepatitis E virus (HEV). Care should be taken in the preparation of uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown. Hepatitis E is preventable by vaccination. Studies in Nepal and China have shown 95% efficacy of a recombinant genotype 1 HEV vaccine in preventing infection and clinical disease. Not only did the vaccine prevent the genotype 1 (Hecolin) HEV infection, genotype 4 HEV was also prevented with the vaccination, indicating cross-protection against different HEV genotypes. At this time, the vaccine efficacy against HEV genotype 3 is not known. A vaccine developed from HEV genotype 1 HEV vaccine was approved in China in December 2011. A study showed long-term efficacy of this vaccine, as it induced a sustained level of antibodies and protection against hepatitis E for up to 4.5 years. However, further evaluation of these vaccines is required to determine their efficacy in special risk groups, such as patients with end-stage liver disease or immunosuppressed individuals, to define the anti-HEV titers that can be considered protective, and to know the duration of their protective effect.

8. Materials for activating students during a lecture:

Task 1 The 17-year-old patient was admitted to the clinic on the 6th day of illness. Ill acutely with an increase in body temperature to 39oC, weakness, on the 2nd day of the disease decreased appetite, the temperature was maintained for 4 days, then decreased to normal, on the 5th day of the disease - darkened urine Circumstances: T-36,8oC, skin and mucous membranes subicteric, without rash. The abdomen on palpation is soft, painless, the liver is enlarged, the spleen is not palpable. Heart rate - 64 beats / min. Blood pressure - 110/70 mm Hg 1. Formulate the preliminary diagnosis. 2. Prescribe additional diagnostics. 3. Treatment. Task 2. Patient O., 32 years old, returned from Afghanistan at the 8th month of pregnancy. She served there for 2 years in the military unit. The first pregnancy, without complications, continued to work until the departure. She felt ill on the road: nausea, weakness, vomiting, loss of appetite. About 7 days after the illness, jaundice appeared, in connection with which she was hospitalized. At the moment of hospitalization the condition is relatively satisfactory, but after a few days intoxication and jaundice increased. Childbirth began prematurely, in connection with which on the 10th day of the disease was transferred to the maternity ward. There was significant bleeding during delivery. A viable girl was born. The general condition of the patient continued to deteriorate: increased general weakness, almost constant nausea, repeated vomiting. After transfer to the infectious department: the condition is serious. Hepatic odor from the mouth. Drowsiness. Vaguely oriented in space, time and place. Liver +1 cm, soft edge. 1. Formulate the preliminary diagnosis. 2. Prescribe additional diagnostics. 3. Treatment. Test control. 1. The source of HAV infection is: A. is ill during jaundice B. patient in the pre-jaundice period C. the patient in the period of convalescence D. rodents E. pets

2. The risk group for severe VHE: A. children aged 2 to 6 years B. infants C. immunodeficient adults D. children aged 6 to 12 years E. pregnant women

3. Manifestations of general intoxication syndrome in HAV infection is: A. tracheobronchitis B. laryngitis C. nasopharyngitis D. alveolitis E. increase in body temperature

4. Choose the main symptoms of moderate pertussis of HAV infection without complications during the heat: A. normal body temperature B. fever C. vomiting D. jaundice E. conjunctivitis

5. Changes in the general analysis of blood at uncomplicated HAV infection: A. relative lymphocytosis B. leukopenia C. leukocytosis D. shift the formula to the right E. anemia

6. Complications of HAV infection: A. orchitis B. pancreatitis C. otitis D. pneumonia E. thrombocytopenic purpura

7. Specific diagnosis of HAV infection in the midst of the disease: A. Cytological method B. ELISA on Anti HAV IgM C. ELISA Anti HAV IgG D. Buck sowed on the causative agent of measles E. virological method

8. The color of urine in CAA in the midst of jaundice A. "beer color" B. light yellow C. red D. saturated yellow E. colorless

9. Water transmission is leading to: A. hepatitis A B. hepatitis B C. Lyme disease D. flu E. botulism

10. Clinical syndromes of the pre-jaundice period of CAA A. General intoxication B. Dyspeptic C. Meningeal D. Respiratory E. Generalized lymphadenopathy

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What is hepatitis B (HBV) (Hep B)? 2. What is acute hepatitis B (HBV) (Hep B)? 3. How is hepatitis B (HBV) (Hep B) transmitted? 4. What is the pathogenesis of hepatitis B (HBV) (Hep B)? 5. What are the signs and symptoms of icteric hepatitis in patients with hepatitis B (HBV) (Hep B)? 6. What are the signs and symptoms of fulminant and subfulminant hepatitis in patients with hepatitis B (HBV) (Hep B)? 7. What is the outcome of infection? 8. What is the role of lab testing in the workup of hepatitis B (HBV) (Hep B)? 9. What is the treatment for acute and chronic hepatitis B (HBV) (Hep B) infection? 10. What is hepatitis C (hep C)? 11. What are symptoms of acute hepatitis C (hep C) infection? 12. Which physical finding are characteristic acute hepatitis C (hep C) infection? 13. What are common extrahepatic manifestations of hepatitis C (hep C) infection? 14. Which baseline studies are performed in patients with suspected hepatitis C (hep C) infection? 15. Which lab tests detect hepatitis C virus (HCV) infection? 16. What are the treatment options for acute and chronic hepatitis C virus (HCV) infection? 17. What is the prognosis of hepatitis C (hep C) infection?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Viral hepatitis. HIV infection. Topic Viral hepatitis with predominantly parenteral transmission (B and C) Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. The term viral hepatitis can describe either a clinical illness or the histologic findings associated with the disease. Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure. Adults with acute hepatitis A or B are usually symptomatic. Persons with acute hepatitis C may be either symptomatic or asymptomatic (ie, subclinical). Providing that acute viral hepatitis does not progress to fulminant hepatic failure many cases resolve over a period of days, weeks, or months. Acute HBV infection is generally considered resolved once an individual has developed antibodies to the hepatitis B surface antigen (anti-HBs) and has cleared hepatitis B surface antigen (HBsAg) from their serum. Alternatively, acute viral hepatitis may evolve into chronic hepatitis. HBV infection is considered to have progressed to chronic infection when HBsAg, hepatitis B e antigen (HBeAg), and high titers of hepatitis B viral DNA are found to persist in the serum for longer than 6 months. Hepatitis C infection is considered to have progressed to chronic infection when HCV RNA persists in the blood for longer than 6 months. The likelihood of progressing to chronic hepatitis B infection varies with the age at the time of infection. Chronic hepatitis B infection develops in up to 90% of individuals infected as neonates; however only 1-5% of individuals infected with HBV as adults develop chronic hepatitis B infection. Patients with chronic HBV infection who are coinfected with HDV also tend to develop chronic HDV infection. Chronic coinfection with HBV/HDV often leads to rapidly progressive subacute or chronic hepatitis, with as many as 70-80% of these patients eventually developing cirrhosis. Chronic hepatitis C infection develops in 75-85% of patients infected with hepatitis C. Individuals infected with HCV at a younger age are less likely to develop chronic hepatitis C infection. Some patients with chronic hepatitis remain asymptomatic for their entire lives. Other patients report fatigue (ranging from mild to severe) and dyspepsia. Individuals with chronic hepatitis B or hepatitis C infection may go on to develop cirrhosis, with histologic changes of severe fibrosis and nodular regeneration. In their study of serologic markers in patients with cirrhosis and hepatocellular carcinoma, Perz et al estimated that 57% of cirrhosis and 78% of hepatocellular carcinoma worldwide was attributable to chronic infection with either hepatitis B or C. Although some patients with cirrhosis are asymptomatic, others develop life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months, years, or decades to evolve.

2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of gastrointestinal tract, liver Histology The structure of the mucous membrane of gastrointestinal tract Microbiology Properties of viruses, which are causing viral hepatitis, methods for the specific diagnosis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of gastrointestinal tract and hepatocytes. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of antivirals, Pharmacology pathogenetic therapy. Neurology Pathogenesis, clinical signs of encephalopathy, toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. Etiology,pathophysisology of hepatitis B; 2. Clinical presentation of hepatitis B; 3. Diagnosis and treatment of hepatitis B; 4. Prevention of hepatitis B; 5. Etiology, pathophysiology of hepatitis C; 6. Clinical presentation of hepatitis C; 7. Diagnosis and treatment of hepatitis C; 8. Prevention of hepatitis C;

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: Hepatitis B infection is a worldwide healthcare problem, especially in developing areas. The hepatitis B virus (HBV) is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. An acute hepatitis B infection may last up to six months (with or without symptoms) and infected persons are able to pass the virus to others during this time. A simple blood test can let a person know if the hepatitis B virus is in their blood or if they have successfully gotten rid of the virus. Until your health care provider confirms that the blood test shows that there is no more hepatitis B virus in your blood, it is important to protect others from a possible infection. It is also important to have your sexual partner(s) and family members (or those you live in close household contact) get tested for hepatitis B. If they have not been infected – and have not received the hepatitis B vaccine – then they should also start the hepatitis B vaccine series. Symptoms of an acute infection may include loss of appetite, joint and muscle pain, low- grade fever, and possible stomach pain. Although most people do not experience symptoms, they can appear 60-150 days after infection, with the average being 90 days or 3 months. Some people may experience more severe symptoms such as nausea, vomiting, jaundice (yellowing of the eyes and skin), or a bloated stomach that may cause them to see a health care provider. If treatment for an acute hepatitis B infection is required, a person may be hospitalized for general support. Rest and managing symptoms are the primary goals of this medical care. A rare, life- threatening condition called “fulminant hepatitis” can occur with a new acute infection and requires immediate, urgent medical attention since a person can go into sudden liver failure. Simple tips for taking care of your liver during a new infection is to avoid alcohol, stop or limit smoking, eat healthy foods, avoid greasy or fatty foods, and talk to your health care provider about your prescriptions, over-the-counter medications and ask any other questions you may have during this time. The use of vitamins and liver health supplements will likely not assist your recovery and may actually cause more harm than good to the liver. Be sure to follow-up with your health care provider for any additional blood tests that are needed to confirm your recovery from an acute infection. Etiology. Hepatitis B infection, caused by the hepatitis B virus (HBV), is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. Consequently, sexual contact, accidental needle sticks or sharing of needles, blood transfusions, and organ transplantation are routes for HBV infection. Infected mothers can also pass the infection to their newborns during the delivery period. Hepatitis B virus (HBV) is a hepadnavirus (see the following image), with the virion consisting of a 42-nm spherical, double-shelled particle composed of small spheres and rods and with an average width of 22 nm. It is an exceedingly resistant virus, capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at –20°C, for 24 months at – 80°C, for 6 months at room temperature, and for 7 days at 44°C. Indeed, the approximately 400-year- old mummified remains of a child found on a mountain top in Korea had HBV in the liver that could be sequenced, and a viral genotype C was identified. Viral genome The viral genome of hepatitis B consists of a partially double-stranded, circular DNA molecule of 3.2 kilobase (kb) pairs that encodes the following 4 overlapping open reading frames:  S (the surface, or envelope, gene): Encodes the pre-S1, pre-S2, and S proteins  C (the core gene): Encodes the core nucleocapsid protein and the e antigen; an upstream region for the S (pre-S) and C (pre-C) genes has been found  X (the X gene): Encodes the X protein  P (the polymerase gene): Encodes a large protein promoting priming ribonucleic acid (RNA) ̶ dependent and DNA-dependent DNA polymerase and ribonuclease H (RNase H) activities.

Surface gene The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigens (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important and identify the serotypes. Core gene The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, which is also produced from the region in and near the core gene, is a marker of active viral replication. It serves as an immune decoy and directly manipulates the immune system; it is thus involved in maintaining viral persistence. HBeAg can be detected in patients with circulating serum HBV DNA who have “wild type” infection. As the virus evolves over time under immune pressure, core promotor and precore mutations emerge, and HBeAg levels fall until the level is not measurable by standard assays. Individuals who are infected with the wild type virus often have mixed infections, with core and precore mutants in up to 50% of individuals. They often relapse with HBeAg-negative disease after treatment. X gene The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis. Antibody production The production of antibodies against HBsAg (anti-HBs) confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated. Antibody to HBcAg (anti-HBc) is detected in almost every patient with previous exposure to HBV and indicates that there is a minute level of persistent virus, as demonstrated by the risk of reactivation in individuals who undergo immune suppression regardless of their anti-HBs status. The immunoglobulin M (IgM) subtype of anti-HBc is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. The activity of the disease cannot be understood using this marker alone, however. Antibody to HBeAg may be suggestive of a nonreplicative state if there is undetectable HBV DNA or the emergence of the core/precore variants and of chronic HBV HBeAg-negative disease. Variants of HBV With the newest polymerase chain reaction (PCR) assay techniques, scientists are able to identify variations in the HBV genome (variants) as far back as 1995, even in patients who are positive for HBeAg. Mutations of various nucleotides such as the 1896, 1764, and 1768 (precore/core region) processing the production of the HBeAg have been identified (HBeAg-negative strain). The prevalence of the HBeAg-negative virus varies from one region to another. Estimates indicate that among patients with chronic HBV infection, 50-60% of those from Southern Europe, the Middle East, Asia, and Africa, as well as 10-30% of patients in the United States and Europe, have been infected with this strain. Immune response The pathogenesis and clinical manifestations of hepatitis B infection are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury, the result of an immunologic reaction when activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides on the surface of the hepatocytes. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T-cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes. The final state of HBV disease is cirrhosis. With or without cirrhosis, however, patients with HBV infection are likely to develop hepatocellular carcinoma (HCC). In the United States, the most common presentation of these patients with HCC is that they are of Asian origin and acquired HBV disease as newborns (vertical transmission). Viral life cycle The 5 stages that have been identified in the viral life cycle of hepatitis B infection are briefly discussed below. Different factors have been postulated to influence the development of these stages, including age, sex, immunosuppression, and coinfection with other viruses. Stage 1: Immune tolerance This stage, which lasts approximately 2-4 weeks in healthy adults, represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness. Stage 2: Immune active/immune clearance In the immune active stage, also known as the immune clearance stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline in the levels of HBV DNA is seen in some patients who are clearing the infection. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops, immune clearance takes place, HCC develops, or the chronic HBeAg-negative variant emerges. Stage 3: Inactive chronic infection In the third stage, the inactive chronic infection stage, the host can target the infected hepatocytes and HBV. Viral replication is low or no longer measurable in the serum, and anti-HBe can be detected. Aminotransferase levels are within the reference range. It is most likely at this stage that an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present in the serum. Stage 4: Chronic disease The emergence of chronic HBeAg-negative disease can occur from the inactive chronic infection stage (stage 3) or directly from the immune active/clearance stage (stage 2). Stage5: Recovery In the fifth stage, the virus cannot be detected in the blood by DNA or HBsAg assays, and antibodies to various viral antigens have been produced. The image below depicts the serologic course of HBV infection.

Serologic course of hepatitis B virus (HBV) infection. The flat bars show the duration of seropositivity in self-limited acute HBV infection. The pointed bars show that HBV DNA and e antigen (HBeAg) can become undetectable during chronic infection. Only immunoglobulin G (IgG) antibodies to the HBV core antigen (anti-HBc) are predictably detectable after resolution of acute hepatitis or during chronic infection. Antibody to hepatitis B surface antigen (anti-HBs) is generally detectable after resolution of acute HBV infection but may disappear with time. It is only rarely found in patients with chronic infection and does not indicate that immunologic recovery will occur or that the patient has a better prognosis. ALT = alanine transaminase. (Adapted from Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582-92.) Genotypes and disease progression Ten different genotypes (A through J), representing a divergence of the viral DNA of about 8%, have been identified. The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated and the response to treatment with antiviral agents is less favorable for patients infected by genotype C, compared with those infected by genotype B. However, much of this can be explained by the presence of core and precore mutations found in multivariate analysis. It has been confirmed that the risk of HCC is related to higher HBV DNA levels in the serum, when DNA is present for longer periods—with an even higher risk if there is an increasing level of hepatitis B viral load, the presence of genotype C, and the presence of mutations in the precore and basal core promoter regions. Hepatocellular carcinoma Even the presence of hepatitis B surface antibody (anti-HBs) in the absence of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC, although surveillance for HCC is not recommended in the affected group unless cirrhosis is present. In the United States, the estimated annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. In Taiwan, the annual incidence of this malignancy in patients with hepatitis B and cirrhosis is 2.8%. Familial clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska. HBV and HCV coinfection The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) coinfection is higher than in those with a single infection. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. These findings point to a probable synergistic effect on the risk of HCC. HBV and HDV coinfection Individuals coinfected with hepatitis D (delta) virus (HDV) are thought to have a higher rate of HCC and cirrhosis, with the virus reportedly increasing the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis. Worldwide, the prevalence of HDV coinfection among patients infected with HBV is 0-30%, with the highest prevalence in Mongolia, Southeast Turkey, and the Orinoco River in South America. The speculation that HDV may promote hepatocarcinogenesis in these patients has been investigated with varying results. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different in one study, whereas most other investigations show the delta virus to be more aggressive, with higher rates of cirrhosis and cancer. Clinical presentation. History The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to fulminant, acute, and subacute hepatitis during the acute phase, and from an asymptomatic chronic infection state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase. Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, most commonly in children with acute infection. The following multisystem manifestations may occur in hepatitis B virus (HBV) infection:  Pleural effusion and hepatopulmonary and portopulmonary syndrome may occur in patients with cirrhosis  Diffuse intravascular coagulation may occur in patients with fulminant hepatitis  Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis  Arthralgias and arthritic (serum sickness) subcutaneous nodules may also occur, but these are rare  Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B  Pancreatitis may develop  Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon A variety of cutaneous manifestations have been recognized during the early course of viral hepatitis, including hives and a fleeting maculopapular rash. These various lesions are episodic, palpable, and, at times, pruritic. A discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities. Women are more prone to developing cutaneous manifestations. Acute phase The incubation period is 1-6 months in the acute phase of hepatitis B infection. Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic, but patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Icteric hepatitis is associated with a prodromal period, during which a serum sickness –like syndrome can occur. The symptomatology is more constitutional and includes the following:  Anorexia  Nausea  Vomiting  Low-grade fever  Myalgia  Fatigability  Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)  Right upper quadrant and epigastric pain (intermittent, mild to moderate) Patients with fulminant and subfulminant hepatitis may present with the following:  Hepatic encephalopathy  Somnolence  Disturbances in sleep pattern  Mental confusion  Coma  Ascites  Gastrointestinal (GI) bleeding  Coagulopathy

Physical Examination The physical examination findings in hepatitis B disease vary from minimal to impressive (in patients with hepatic decompensation), according to the stage of disease. Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:  Low-grade fever  Jaundice (10 days after appearance of constitutional symptomatology, lasting for 1-3 mo)  Hepatomegaly (mildly enlarged, soft liver)  Splenomegaly (5-15%)  Palmar erythema (rarely)  Spider nevi (rarely) Workup. The current AASLD recommendations for the initial evaluation of HBsAg-positive patients is summarized below. History and physical examination: Thoroughly evaluate for the following:  Alcohol, metabolic, and other risk factors for HBV infection  Patient's HBV vaccination status  Family history of HBV infection and hepatocellular carcinoma  The presence of symptoms/signs of cirrhosis Routine laboratory studies  CBC, platelet count; INR  Levels of AST, ALT, total bilirubin, ALP, and albumin Serologic/virologic studies  Hepatitis B e antigen (HBeAg)/anti-HBe  HBV DNA level  Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination) Imaging/staging studies  Abdominal ultrasonography  Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma- GGT, total bilirubin])

High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within a range of 1000-2000 IU/mL, is the hallmark of this stage of HBV disease, although values 100 times above the upper limit of normal (ULN) can be also be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels. Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the ULN. Albumin levels can be slightly low, and serum iron levels may be elevated as an acute phase reactant. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR). Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the international normalized ratio (INR). Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum in acute disease. Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) follows. For patients who recover, seroconversion to hepatitis B surface antibody (anti-HBs) and hepatitis B e antibody (anti-HBe) is observed. The anti-HBc is of the IgG class. Patients with persistent HBsAg lasting more than 6 months are considered to have chronic hepatitis. Marker Incubation Acute Past/resolved Chronic Vaccination period infection infection infection Primary diagnostic tests HBsAg ± + – + –* Anti-HBs – – + – +

Anti- HBc- – ± + + – Total Anti- – + – ±† – HBc-IgM Prognostic or

monitoring tests HBeAg ± + – ± – Anti-HBe – – ± ± ‡ – HBV- ±§ + ±§ +§ – DNA § *Recent HBV vaccination within one to two weeks can lead to a false-positive test. The vaccine antigen can be detected at low levels; †May be positive in chronically infected individuals; ‡Patients with chronic HBV infection usually have detectable Hepatitis B e antigen (HBeAg) or antibody to hepatitis B e protein (anti-HBe). Rarely, both HBeAg and anti-HBe can be detected simultaneously; §Methods differ in sensitivity and standardization. Anti-HBc Antibody to hepatitis B core protein; Anti-HBs Antibody to hepatitis B surface protein; HBsAg Hepatitis B surface antigen; IgM Immunoglobulin M; + Implies positive; – Implies negative; ± May be positive or negative

Histologic findings The hallmark of acute hepatitis B is liver cell death. Scattered within the lobule are small, individual clusters of dying hepatocytes in apoptosis. (When the nucleus is extruded, it is an eosinophilic, or Councilman, body). Many of the surviving hepatocytes show hydropic swelling known as . Lymphocytes diffusely infiltrate the lobule, with macrophages and neutrophils seen occasionally. Treatment. There is no specific treatment for acute hepatitis B. Therefore, care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids lost from vomiting and diarrhoea. Most important is the avoidance of unnecessary medications. Acetaminophen/Paracetamol and medication against vomiting should not be given. Prevention The hepatitis B vaccine is the mainstay of hepatitis B prevention. WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours. Routine infant immunization against hepatitis B has increased globally with an estimated coverage (third dose) of 84% in 2017. The low prevalence of chronic HBV infection in children under 5 years of age, estimated at 1.3% in 2015, can be attributed to the widespread use of hepatitis B vaccine. In most cases, 1 of the following 2 options is considered appropriate:  a 3-dose schedule of hepatitis B vaccine, with the first dose (monovalent) given at birth and the second and third doses (monovalent or combined vaccine) given at the same time as the first and third doses of diphtheria, pertussis (whooping cough), and tetanus – (DTP vaccine); or  a 4-dose schedule, where a monovalent birth dose is followed by 3 monovalent or combined vaccine doses, usually given with other routine infant vaccines. The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. Protection lasts at least 20 years and is probably lifelong. Thus, WHO does not recommend booster vaccinations for persons who have completed the 3 dose vaccination schedule. All children and adolescents younger than 18 years and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. In those settings it is possible that more people in high-risk groups may acquire the infection and they should also be vaccinated. This includes:  people who frequently require blood or blood products, dialysis patients and recipients of solid organ transplantations;  people in prisons;  people who inject drugs;  household and sexual contacts of people with chronic HBV infection;  people with multiple sexual partners;  healthcare workers and others who may be exposed to blood and blood products through their work; and  travellers who have not completed their HBV series, who should be offered the vaccine before leaving for endemic areas. The vaccine has an excellent record of safety and effectiveness. Since 1982, over 1 billion doses of hepatitis B vaccine have been used worldwide. In many countries where 8–15% of children used to become chronically infected with the hepatitis B virus, vaccination has reduced the rate of chronic infection to less than 1% among immunized children. In addition to infant vaccination, implementation of blood safety strategies, including quality- assured screening of all donated blood and blood components used for transfusion, can prevent transmission of HBV. Worldwide, in 2013, 97% of blood donations were screened and quality assured, but gaps persist. Safe injection practices, eliminating unnecessary and unsafe injections, can be effective strategies to protect against HBV transmission. Unsafe injections decreased from 39% in 2000 to 5% in 2010 worldwide. Furthermore, safer sex practices, including minimizing the number of partners and using barrier protective measures (condoms), also protect against transmission. CHRONIC HEPATITIS B INFECTION

Background. People who test positive for the hepatitis B virus for more than six months (after their first blood test result) are diagnosed as having a chronic infection. This means their immune system was not able to get rid of the hepatitis B virus and it still remains in their blood and liver. The risk of developing a chronic hepatitis B infection is also directly related to the age at which one first becomes exposed to the hepatitis B virus:  90% of infected newborns and babies will develop a chronic hepatitis B infection  Up to 50% of infected children (1-5 years) will develop a chronic hepatitis B infection  5-10% of infected adults will develop a chronic hepatitis B infection (that is, 90% will recover) Learning that you have a chronic hepatitis B infection can be very upsetting. Because most people do not have symptoms and can be diagnosed decades after their initial exposure to the hepatitis B virus, it can be a shock and a surprise to be diagnosed with a chronic hepatitis B infection. The good news is that most people with chronic hepatitis B should expect to live a long and healthy life. There are effective drug therapies that can control and even stop the hepatitis B virus from further damaging a liver. There are also promising new drugs in the research pipeline that could provide a cure in the very near future. Although the risk of developing a serious liver disease or liver cancer is higher for those living with chronic hepatitis B than those who are not infected, there are still many simple things a person can do to help reduce their risks. Risk factors for progression of chronic HBV include the following:  Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections  Male sex  Older age  Family history of HCC  Alcohol use  Elevated alpha-fetoprotein (AFP)  Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

Clinical presentation History. Patients with chronic hepatitis B disease can be immune tolerant or have an inactive chronic infection without any evidence of active disease; they are also asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:  Symptoms similar to those of acute hepatitis  Fatigue  Anorexia  Nausea  Mild upper quadrant pain or discomfort If progressive liver disease is present, the following symptomatology may appear:  Hepatic decompensation  Hepatic encephalopathy  Somnolence  Disturbances in sleep pattern  Mental confusion  Coma  Ascites  GI bleeding  Coagulopathy

Physical examination The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:  Hepatomegaly  Splenomegaly  Muscle wasting  Palmar erythema  Spider angioma  Vasculitis (rarely) Patients with cirrhosis may have the following findings:  Ascites  Jaundice  History of variceal bleeding  Peripheral edema  Gynecomastia  Testicular atrophy  Abdominal collateral veins (caput medusa)

Workup. The current AASLD recommendations for the initial evaluation of HBsAg-positive patients is summarized below. History and physical examination: Thoroughly evaluate for the following:  Alcohol, metabolic, and other risk factors for HBV infection  Patient's HBV vaccination status  Family history of HBV infection and hepatocellular carcinoma  The presence of symptoms/signs of cirrhosis Routine laboratory studies  CBC, platelet count; INR  Levels of AST, ALT, total bilirubin, ALP, and albumin Serologic/virologic studies  Hepatitis B e antigen (HBeAg)/anti-HBe  HBV DNA level  Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination) Imaging/staging studies  Abdominal ultrasonography  Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma- GGT, total bilirubin])

Inactive hepatitis B disease The term “healthy carriers” is no longer used due to the fact that a person who is positive for HBsAg has a high risk of cirrhosis and hepatocellular carcinoma (HCC) and, therefore, cannot be defined as healthy. Such individuals have normal AST and ALT levels, with markers of infectivity, such as HBeAg, being negative and HBV DNA going undetected or being detected at very low levels (usually below 2,000 IU/ml). HBsAg, anti-HBc of IgG type, and anti-HBe are present in the serum. A minimum follow-up of these patients for 1 year with laboratory evaluation every 3 to 4 months is recommended. Chronic active hepatitis B disease Chronic active HBV disease is categorized into HBeAg-positive and HBeAg-negative disease. Subtype “wild type” or HBeAg-positive disease Patients have mild to moderate elevation of the aminotransferases (≤5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time [PT]). HBV DNA levels are high during this phase. HBsAg and anti-HBc of IgG or IgM type (in case of reactivation) are identified in the serum. If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be considered. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue- nonspecific antibodies, such as anti–smooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present, indicating the presence of cryoglobulins on further assessment. Subtype chronic HBV HBeAg-negative disease Note that although the HBeAg result is negative in this stage, HBeAg negativity can be associated with greater HBV DNA replication and more rapid disease progression in patients who carry mutations in either the precore or the basic core promoter region of the HBV genome. Cirrhosis In the early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet and white blood cell counts, and AST levels higher than ALT levels can be identified. Alkaline phosphatase (ALP) and GGT levels can be slightly elevated. Histologic findings The hallmark of chronic hepatitis B infection is lymphoid inflammation, mostly involving the portal tracts. However, occasional Councilman bodies are seen in the lobule. Hepatocytes that are distended with viral particles may acquire an unusual “ground-glass” appearance on the hematoxylin and eosin (H&E) stain (see the following image). Ground-glass cells are seen in approximately 50- 75% of affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg). Immunohistochemical staining of the specimen can help to identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection). As the severity of the histologic changes advance, interface hepatitis (piecemeal necrosis) appears, with erosion of the limiting plate by chronic inflammation from the portal side of the lobule. Over time, this ongoing type of inflammation may lead to increasing degrees of fibrosis that spreads out from that portal tract to connect with other nearby portal tracts (bridging fibrosis). When the fibrosis advances further in severity, regenerating nodules of hepatocytes appear; this constitutes cirrhosis. Staging. Liver damage is graded according to the inflammatory component and is described as follows:  Grade 0 – Portal inflammation only, no activity  Grade 1 – Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis  Grade 2 – Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage  Grade 3 – Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change  Grade 4 – Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent, diffuse hepatocellular damage Liver damage staging (ie, fibrosis) is described as follows:  Stage 0 – No fibrosis  Stage 1 – Portal fibrosis  Stage 2 – Periportal fibrosis  Stage 3 – Septal, bridging fibrosis  Stage 4 – Cirrhosis Treatment.

The goals of pharmacotherapy in patients with hepatitis B disease are to reduce the risk of progression of disease, prevent transmission to others, and decrease complications. Currently, pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are the first-line agents in the treatment of hepatitis B disease.

The National Institutes of Health (NIH) recommends nucleos(t)ide therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression.

In general, for hepatitis B e antigen (HBeAg)-positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL (105 copies/mL) (or, per the EASL, >2,000 IU/mL ) and when serum ALT is elevated for 3-6 months.

For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL (104 copies/mL) and the serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

ACUTE HEPATITIS C

Infection with hepatitis C virus (HCV) is self-limited in 15% to 50% of patients. In a review of HCV infection, it was reported that chronic infection developed in 70%-80% of patients. Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection. The onset of chronic hepatitis C infection early in life often leads to less serious consequences. Hepatitis B virus (HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis. Etiology. The HCV genome consists of a single, open reading frame and two untranslated, highly conserved regions, 5'-UTR and 3'-UTR, at both ends of the genome. The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see the image below).

Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest that at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C. The proteolytic cleavage of the virus results in two structural envelope glycoproteins (E1 and E2) and a core protein. Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, believed to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV. HCV core protein is an important risk factor in the development of liver disease; it can modulate several signaling pathways affecting cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress, and lipid metabolism. Other viral components are nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7), whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. These nonstructural proteins are necessary for viral propagation and have been the targets for newer antiviral therapies, such as the direct-acting antiviral agents (DAAs). NS2/3 and NS3/4A are proteases responsible for cleaving the HCV polyprotein. NS5A is critical for the assembly of the cytoplasmic membrane-bound replication complex; one region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity– determining region. NS5B is an RNA dependent RNA polymerase required for viral replication; it lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1%-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development. Genotypes HCV genomic analysis by means of an arduous gene sequencing of many viruses has led to the division of HCV into six genotypes based on homology. Numerous subtypes have also been identified. Arabic numerals denote the genotype, and lower-case letters denote the subtypes for lesser homology within each genotype. Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40%-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of hepatocellular carcinoma. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. Genotype details are as follows:  Genotype 1a occurs in 50%-60% of patients in the United States.  Genotype 1b occurs in 15%-20% of patients in the United States; this type is most prevalent in Europe, Turkey, and Japan.  Genotype 1c occurs in less than 1% of patients in the United States.  Genotypes 2a, 2b, and 2c occur in 10%-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication.  Genotypes 3a and 3b occur in 4%-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland.  Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa.  Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa.  Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao. Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse injection drugs. Transmission Transfusion of blood contaminated with hepatitis C virus (HCV) was once a leading means of HCV transmission. Since 1992, however, the screening of donated blood for HCV antibody sharply reduced the risk of transfusion-associated HCV infection. With the advent of more advanced screening tests for HCV such as polymerase chain reaction (PCR), the risk is considered to be less than 1 per 2 million units transfused. The newer assays have decreased the window after infection to 1-2 weeks. Persons who inject illicit drugs with nonsterile needles are at the highest risk for HCV infection. In developed countries, most of the new HCV infections are reported in injection drug users (IDUs). The most recent surveys of active IDUs in the United States indicate that approximately one third of young (aged 18–30 years) IDUs are HCV-infected. Older and former IDUs typically have a much higher prevalence (approximately 70%-90%) of HCV infection, attributable to needle sharing during the 1970s and 1980s, before greater understanding of the risks of blood-borne viruses and the implementation of public educational strategies. The additional risk of acquiring hepatitis C infection from noninjection (snorted or smoked) cocaine use is difficult to differentiate from that associated with injection drug use and sex with HCV-infected partners. Transmission of HCV to healthcare workers may occur via needle-stick injuries or other occupational exposures. Needle-stick injuries in the healthcare setting result in a 3% risk of HCV transmission. According to Rischitelli et al, however, the prevalence of HCV infection among healthcare workers is similar to that of the general population. Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992. HCV may be transmitted via sexual transmission. However, studies of heterosexual couples with discordant serostatus have shown that such transmission is extremely inefficient. A higher rate of HCV transmission is noted in men who have sex with men (MSM), particularly those who practice unprotected anal intercourse and have infection with the human immunodeficiency virus (HIV). HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The use of disposable needles for acupuncture, now the standard practice in the United States, should eliminate this transmission route. Maternal-fetal HCV transmission may occur at a rate of approximately 4%– 5%. Breastfeeding is not associated with transmission. Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.

Clinical presentation Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin. In a large study of the extrahepatic manifestations of HCV, 74% of medical workers with HCV infection demonstrated extrahepatic manifestations, of which the following were the most common:  Arthralgias (23%)  Paresthesias (17%)  Myalgias (15%)  Pruritus (15%)  Sicca syndrome (11%) In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection. Risk factors for manifestations of extrahepatic chronic hepatitis C infection include advanced age, female sex, and liver fibrosis. Treatment Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. Monitoring for spontaneous clearance for a minimum of 6 months before initiating treatment is therefore recommended. Patients with acute HCV infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). However, IFN-sparing regimens are safer and are currently recommended for the treatment of acute HCV infection as with chronic HCV infection. CHRONIC HEPATITIS C

Hepatitis C is an infection caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation. The World Health Organization (WHO) estimates that about 71 million people globally have chronic hepatitis C, with approximately 399,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma. The image below depicts the HCV genome. Most patients with acute and chronic infection are asymptomatic. Patients and healthcare providers may detect no indications of these conditions for long periods; however, chronic hepatitis C infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Astute observation and integration of findings of extrahepatic symptoms, signs, and disease are often the first clues to the underlying HCV infection. Although acute HCV infection is usually mild, chronic hepatitis develops in at least 75% of patients. Although liver enzyme levels may be in the reference range, the presence of persistent HCV- RNA levels discloses chronic infection. Biopsy samples of the liver may reveal chronic liver disease. Cirrhosis develops in 20-50% of patients with chronic hepatitis C infection. Liver failure and HCC (11%-19%) can eventually result. Clinical presentation History Acute hepatitis C virus (HCV) infection becomes chronic in 70% of patients, which represents a high rate of chronicity for a viral infection. Most patients with chronic hepatitis C are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus. Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distention (ascites), and hematemesis or melena (variceal bleeding). Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin. In a large study of the extrahepatic manifestations of HCV, 74% of medical workers with HCV infection demonstrated extrahepatic manifestations, of which the following were the most common  Arthralgias (23%)  Paresthesias (17%)  Myalgias (15%)  Pruritus (15%)  Sicca syndrome (11%) In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection. Risk factors for manifestations of extrahepatic chronic hepatitis C infection include advanced age, female sex, and liver fibrosis. Patients also present with symptoms that are less specific and are often unaccompanied by discrete dermatologic findings. Pruritus and urticaria are examples of less specific clues to underlying HCV infection in the appropriate setting (eg, posttransfusion, organ transplantation, surgery, injection drug use, injury of the nasal mucosa from snorting cocaine through shared straws). Patients with ongoing pathology associated with chronic hepatitis C that eventually results in organ failure can present with symptoms and signs in the skin. Pruritus, dryness, palmar erythema, and yellowing of the eyes and skin are examples of less specific findings in patients with end-stage liver disease with cirrhosis; these findings provide clues that lead to further evaluation of the underlying causes. Chronic hepatitis C has a strong association with pruritus. Indeed, some authorities believe that all patients with unexplained pruritus should be investigated for HCV infection. Physical Examination Most patients with hepatitis C virus (HCV) infection do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis. Signs in patients with decompensated liver disease include the following:  Hand signs: Palmar erythema, Dupuytren contracture, asterixis, leukonychia, clubbing  Head signs: Icteric sclera, temporal muscle wasting, enlarged parotid, cyanosis  Fetor hepaticus  Gynecomastia, small testes  Abdominal signs: Paraumbilical , ascites, caput medusae, , abdominal bruit  Ankle edema  Scant body hair  Skin signs: Spider nevi, petechiae, excoriations due to pruritus Other common extrahepatic manifestations include the following:  Cryoglobulinemia  Membranoproliferative glomerulonephritis  Idiopathic thrombocytopenic purpura  Lichen planus  Keratoconjunctivitis sicca  Raynaud syndrome  Sjögren syndrome  Porphyria cutanea tarda  Necrotizing cutaneous vasculitis Approximately 10%-15% of affected patients have symptoms/signs such as weakness, arthralgias, and purpura; these are often related to vasculitis. The precise pathogenesis of these extrahepatic complications has not been determined, although most are the clinical expression of autoimmune phenomena.

Workup 1. Hepatitis C Antibody Test through the detection of antibodies to recombinant HCV polypeptides. However, antibody assays do not distinguish past from current HCV infection. It can detect HCV antibody at an average of 8 weeks after the onset of infection. 2. Qualitative and Quantitative Assays for HCV RNA  Qualitative assays can be used to test for hepatitis C virus (HCV) RNA. HCV RNA can be detected in blood using amplification techniques such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA).  Quantitative assays ascertain HCV RNA quantity in blood, using signal amplification (branched DNA [bDNA] assay) or target amplification techniques (PCR, TMA). RT-PCR is more sensitive than bDNA testing. The HCV RNA level in blood helps predict the likelihood of a response to treatment, and the change in HCV RNA level can also be used to monitor the therapeutic response. 3. HCV Genotyping Hepatitis C virus (HCV) genotyping is helpful for predicting the likelihood of response and duration of treatment. Genotyping can be performed by direct sequence analysis, reverse hybridization to genotype-specific oligonucleotide probes, or restriction fragment length polymorphisms (RFLPs). 4. Other baseline studies include the following:  Complete blood cell (CBC) count with differential  International normalized ratio (INR)  Liver function tests, including levels of ALT and AST, alkaline phosphatase, albumin, and total and direct bilirubin  Calculated glomerular filtration rate (eGFR)  Thyroid function studies  Screening tests for coinfection with human immunodeficiency virus ( HIV) or hepatitis B virus (HBV)  Screening for alcohol abuse, drug abuse, and/or depression  Hepatitis B virus (HBV) testing with hepatitis B surface antigen (HBsAg) (to identify coinfection), as well as hepatitis B surface antibody (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) (for evidence of previous infection)  Serum pregnancy testing in women of childbearing age before initiating a treatment regimen that includes ribavirin or that includes direct-acting antiviral agents (DAAs) without ribavirin

Liver Biopsy Liver biopsy is not considered mandatory before the initiation of treatment for hepatitis C, but it may be helpful for assessing the activity and severity of hepatitis C virus-related liver disease. However, some experts recommend biopsy only in the following situations:  The diagnosis is uncertain  Other coinfections or disease may be present  The patient being considered for treatment has normal liver enzyme levels and no extrahepatic manifestations  The patient is immunocompromised Treatment Hepatitis C has become a curable disease with the use of antiviral agents (>95%). Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). With the exception of pregnant women, the World Health Organization recommends treatment be offered to all individuals aged 12 years or older diagnosed with HCV, regardless of their disease stage. Initiating treatment earlier for patients with lower stage fibrosis may extend the benefits of sustained virologic response (SVR). Treatment of chronic HCV infection has two goals. The first is to achieve sustained eradication of HCV (ie, SVR), which is defined as the persistent absence of HCV RNA in serum 12 weeks after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.

Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria:

 Age older than 18 years  Positive HCV antibody and serum HCV RNA test results  Compensated liver disease (eg, no hepatic encephalopathy or ascites)  Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3, serum creatinine < 1.5 mg/dL)  Willingness to be treated and to adhere to treatment requirements  No contraindications for treatment The endpoint of therapy is an SVR, defined by undetectableHCV RNA in serum or plasma 12 weeks (SVR12) or 24 weeks(SVR24) after the end of therapy, as assessed by a sensitivemolecular method with a lower limit of detection ≤15 IU/ml.Both SVR12 and SVR24 have been accepted as endpoints of ther-apy by regulators in Europe and the United States, given thattheir concordance is >99%. Antivirals approved in Europe in 2018 for treatment CHV- infection are listed below:

IFN-free, ribavirin-free combination treatment regimens available for treatment-naïve patients (defined as patients who havenever been treated for their HCV infection) and treatment-experienced patients (defined as patients who were previously treated withpegylated IFN-aand ribavirin; pegylated IFN-a, ribavirin and sofosbuvir; or sofosbuvir and ribavirin), without cirrhosis or withcompensated (Child-Pugh A) cirrhosis, recommended for each HCV genotype/subtype in 2018 and onwards listed below:

Fig. IFN-free, ribavirin-free combination treatment regimens available for treatment-naïve patients DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r,ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.* Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens.aTreatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis.bTreatment-naïve and treatment-experienced patients without cirrhosis or with compensated (Child- Pugh A) cirrhosis with an HCV RNA level ≤800,000IU/ml (5.9 Log10IU/ml).cTreatment-naïve and treatment- experienced patients without cirrhosis.dTreatment-naïve and treatment-experienced patients with compensated (Child-Pugh A) cirrhosis.eTreatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/ml (5.9 Log10IU/ml).

8. Materials for activating students during a lecture: 1. What is hepatitis B (HBV) (Hep B)? 2. What is acute hepatitis B (HBV) (Hep B)? 3. How is hepatitis B (HBV) (Hep B) transmitted? 4. What is the pathogenesis of hepatitis B (HBV) (Hep B)? 5. What are the signs and symptoms of icteric hepatitis in patients with hepatitis B (HBV) (Hep B)? 6. What are the signs and symptoms of fulminant and subfulminant hepatitis in patients with hepatitis B (HBV) (Hep B)? 7. What is the outcome of infection? 8. What is the role of lab testing in the workup of hepatitis B (HBV) (Hep B)? 9. What is the treatment for acute and chronic hepatitis B (HBV) (Hep B) infection? 10. What is hepatitis C (hep C)? 11. What are symptoms of acute hepatitis C (hep C) infection? 12. Which physical finding are characteristic acute hepatitis C (hep C) infection? 13. What are common extrahepatic manifestations of hepatitis C (hep C) infection? 14. Which baseline studies are performed in patients with suspected hepatitis C (hep C) infection? 15. Which lab tests detect hepatitis C virus (HCV) infection? 16. What are the treatment options for acute and chronic hepatitis C virus (HCV) infection? 17. What is the prognosis of hepatitis C (hep C) infection?

Task 1 The dentist, 29 years old, was successfully vaccinated with the Engeriks-B vaccine a year ago. Ill 5 weeks after another cut on the arm at work. Gradually, there was increasing fatigue, irritability, minor arthralgia, and after 2 weeks - barely noticeable jaundice, minor weakness, and sometimes - nausea without aversion to food. On examination on the 16th day of illness: no complaints. Jaundice is almost invisible, no signs of hemorrhagic syndrome. Not painful, not dense liver, palpated 2 cm below the costal arch. The spleen is not enlarged. Pulse - 60 beats. per minute, T - 36.5 C. In the blood - significant leukopenia with relative lymphomonocytosis, ESR 2 mm / h, significantly dominated by direct bilirubin, ALT - 1650 IU / L, AST - 640 IU / L, thymol test - 4 IU , blood glucose - 6, 4 mmol / l. HCV RNA positive with HCV IgG Ig negative. Formulate the preliminary diagnosis. Prescribe additional diagnostics. Treatment.

Task 2 The 28-year-old anesthesiologist, who was banned from donating HBsAg in his blood two years ago, developed rapidly growing weakness, arthralgia, nausea, anorexia, fever up to 38, 50 C, and after 4 days - bright jaundice, vomiting, insomnia, dizziness. , nosebleeds, minor tachycardia, significant enlargement of the spleen, liver, pain with increased density of its edge. At inspection on the 10th day of an illness: the excited, inadequate, bright jaundice, the painful, pasty liver palpated under a costal arch, tachycardia, arterial hypotension. Ascites has appeared. In the blood - moderate neutrophilic leukocytosis, ESR 20 mm / h, slightly dominated by direct bilirubin, ALT - 4650 IU / L, AST - 5240 IU / L, thymol test - 22 IU, creatinine - 90 μmol / L, urea 1.6 mmol / l, albumin 18 g / l, globulins - 33 g / l, γ - globulins - 34%, prothrombin index -32%. Formulate the preliminary diagnosis. Prescribe additional diagnostics. Treatment.

Test control. 1. Hepatitis B vaccines: A. are not effective in patients with acute hepatitis B B. are live attenuated vaccines C. fewer than 10% of adults fail to respond to hepatitis B vaccines adequately D. are very effective if used for post-exposure prophylaxis E. work best in those aged over 40 years

2. According to the schedule, what is the first vaccination to be administered before a newborn baby leaves the hospital? A. hepatitis B B. MMR C. polio D. diphtheria E. varicella

3. The virus most often causes chronic hepatitis? A. HCV B. HBV C. HAV D. HEV E. HFV

4. What indicator characterizes cytolysis in patients with HCV-infection? A. bilirubin B. KFC C. γGTP D. ALT. E. alkaline phosphatase

5. What type of jaundice is typical for HCV-infection? A. Parenchymatous B. Obturation C. Hemolytic D. Hemolytic and parenchymal. E. All mentioned

6. The antibody - mediated, immune cytolysis of hepatocytes caused by the pathogen is typical for: A. HCV B. HBV C. HAV D. HEV E. HFV

7. Which of the following viral hepatitis is currently most often sexually transmitted: A. HCV B. HBV C. HAV D. HEV E. HFV

8. For which viral hepatitis is not characterized by significant intoxication: A. HCV B. HBV C. HAV D. HEV E. HFV

9. Which pathogen of viral hepatitis most often causes extrahepatic lesions: A. HCV B. HBV C. HAV D. HEV E. HFV

10. Which viral hepatitis is characterized by an acute onset of fever: A. HCV B. HGV C. HBV D. TTV E. All mentioned

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What is HIV and how is it transmitted? 2. What is the pathophysiology of HIV infection? 3. What are the accessory proteins of HIV? 4. What is the pathogenesis of AIDS? 5. How does HIV replicate? 6. How is HIV compartmentalized? 7. What are the three distinct phases of HIV pathogenesis? 8. What are the first cellular targets of HIV? 9. What are the signs and symptoms of HIV infection? 10. What are the signs and symptoms of AIDS? 11. What are risk factors for HIV exposure? 12. Why is screening for HIV infection needed? 13. What are the benefits of early diagnosis of HIV infection? 14. What test should be used for HIV screening? 15. What is antiretroviral therapy for HIV infection? 16. Which pharmacologic drug classes are used in antiretroviral therapy for HIV infection? 17. Which combination antiretroviral therapies (ARTs) are approved as complete daily regimens to treat HIV infection? 18. Which opportunistic infections and conditions are seen in patients with AIDS? 19. What are the signs and symptoms of pulmonary tuberculosis (TB) in HIV-infected persons? 20. What are the signs and symptoms of extrapulmonary tuberculosis (TB)?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Viral hepatitis. HIV infection. Topic HIV infection. AIDS-associated infections and invasions Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. HIV /AIDS is a global public health concern with more than 30 million deaths having been reported. Over 70% of the 35 million people with HIV /AIDS live in sub‐S aharan A frica. The current available antiretroviral treatments are limited because they do not cure but slow the progression of disease. Since the discovery of HIV and its link to AIDS, great strides have been made in understanding its biology and in developing effective treatments. The difficulty in dealing with HIV on a global scale is largely due to the fact that HIV infection is far more common in resource-poor countries. In the developed world, antiretroviral therapy has greatly improved prognosis and increased survival rates. Public education programs have raised awareness such that testing and prevention of infection are more common. Both of these approaches are difficult in countries with undereducated or underfunded populations. Its useful to note, that such views can have extremely harmful effects on people who are exposed to HIV infection unnecessarily or who refuse treatment for their progressing infection. Clinicians should be aware of these issues, should be able and willing to address misinformation, and should direct their patients to reliable sources of information. The introduction of HAART has significantly improved mortality rates. Significant advances in antiretroviral therapy have been made since the introduction of zidovudine (AZT) in 1987. One study of nearly 7000 men with HIV infection found that annual mortality rates decreased from 7% in 1996 to 1.3% in 2004. Opportunistic infections (OIs) were the first clinical manifestations that alerted clinicians to the occurrence of the acquired immunodeficiency syndrome (AIDS). Pneumocystis pneumonia (PCP), toxoplasma encephalitis, cytomegalovirus (CMV) retinitis, cryptococcal meningitis, tuberculosis, disseminated Mycobacterium avium complex (MAC) disease, and pneumococcal respiratory disease, as well as certain cancers such as Kaposi sarcoma and central nervous system lymphoma, have been hallmarks of AIDS. These OIs, and many more, occurred on average 7 to 10 years after infection with HIV. Until effective antiretroviral therapy (ART) was developed, patients generally survived only 1 to 2 years after the initial manifestation of AIDS. Treatment of opportunistic infections is paramount and should be directed at the specific pathogen. Although effective antiretroviral therapy reduces the risk of acquiring an opportunistic infection and reverses the effects of many opportunistic infections (eg, Kaposi sarcoma, cytomegalovirus retinitis), aggressive treatment of life-threatening or otherwise serious infections may necessitate a temporary stay of antiretroviral therapy to avoid drug interactions or cumulative toxicity. 2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the influenza virus, methods for the specific diagnosis of influenza Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. Background of HIV-infection 2. Etiology, pathophysiology of HIV-infection; 3. Clinical presentation of HIV- infection; 4. Diagnosis of HIV-infection. Stages of HIV; 5. The concept of antiretroviral treatment (ART). IRIS. 6. The most common HIV- associated infections.

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: Background. Human immunodeficiency virus (HIV) is a blood-borne virus typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding. HIV disease is caused by infection with HIV-1 or HIV-2, which are retroviruses in the Retroviridae family, Lentivirus genus. The most common route of infection varies from country to country and even among cities, reflecting the population in which HIV was introduced initially and local practices. Co-infection with other viruses that share similar routes of transmission, such as hepatitis B, hepatitis C, and human herpes virus 8 (HHV8; also known as Kaposi sarcoma herpes virus [KSHV]), is common. Two distinct species of HIV (HIV-1 and HIV-2) have been identified, and each is composed of multiple subtypes, or clades. All clades of HIV-1 tend to cause similar disease, but the global distribution of the clades differs. This may have implications on any future vaccine, as the B clade, which is predominant in the developed world (where the large pharmaceutical companies are located), is rarely found in the developing countries that are more severely affected by the disease. HIV-1 probably originated from one or more cross-species transfers from chimpanzees in central Africa. HIV-2 is closely related to viruses that infect sooty mangabeys in western Africa. Genetically, HIV-1 and HIV-2 are superficially similar, but each contains unique genes and its own distinct replication process. HIV-2 carries a slightly lower risk of transmission, and HIV-2 infection tends to progress more slowly to acquired immune deficiency syndrome (AIDS). This may be due to a less-aggressive infection rather than a specific property of the virus itself. Persons infected with HIV-2 tend to have a lower viral load than people with HIV-1, and a greater viral load is associated with more rapid progression to AIDS in HIV-1 infections. HIV-2 is rare in the developed world. Consequently, most of the research and vaccine and drug development has been (perhaps unfairly) focused on HIV-1. Initial description and early spread In the United States, HIV disease was first described in 1981 among 2 groups, one in San Francisco and the other in New York City. Numerous young homosexual men presented with opportunistic infections that, at the time, were typically associated with severe immune deficiency: Pneumocystis pneumonia (PCP) and aggressive Kaposi sarcoma. HIV itself was not identified for another 2 years. During that time, various other causes were considered, including lifestyle factors, chronic drug abuse, and other infectious agents. The HIV epidemic spread rapidly and silently in the absence of testing. However, clear clinical implications arose before society became aware of the disease; for example, prior to the recognition of HIV, only one case of Pneumocystis pneumonia not clearly associated with immune suppression was diagnosed in the United States between January 1976 and June 1980. In 1981 alone, 42 similar diagnoses were made, and by December 1994, 127,626 cases of Pneumocystis pneumonia with HIV infection as the only identified cause of immune suppression had been reported to the Centers for Disease Control and Prevention (CDC). Also, Kaposi sarcoma is up to 30,000 times more likely to develop in persons with HIV infection than in immunocompetent persons. The spread of HIV was retrospectively shown to follow the trucking routes across Africa from logging camps, and the bush-meat trade combined with aggressive logging and improved transportation in the mid-20th century may have allowed what was likely occasional cross-species transmission events to propagate across the country and, eventually, the globe. Pathophysiology HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4+ cells). The loss of CD4+ cells results in the development of opportunistic infections and neoplastic processes. Virology of HIV HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA. HIV contains 3 species-defining retroviral genes: gag, pol, and env. The gag gene encodes group-specific antigen; the inner structural proteins. The pol gene encodes polymerase; it also contains integrase and protease (the viral enzymes) and is produced as a C-terminal extension of the Gag protein). The env gene encodes the viral envelope—the outer structural proteins responsible for cell- type specificity. Glycoprotein 120, the viral-envelope protein, binds to the host CD4+ molecule. HIV-1 has 6 additional accessory genes: tat, rev, nef, vif, vpu, and vpr. HIV-2 does not have vpu but instead has the unique gene vpx. The only other virus known to contain the vpu gene is simian immunodeficiency virus in chimpanzees (SIVcpz), which is the simian equivalent of HIV. Interestingly, chimpanzees with active HIV-1 infection are resistant to disease. The accessory proteins of HIV-1 and HIV-2 are involved in viral replication and may play a role in the disease process. The outer part of the genome consists of long terminal repeats (LTRs) that contain sequences necessary for gene transcription and splicing, viral packaging of genomic RNA, and dimerization sequences to ensure that 2 RNA genomes are packaged. (See the image below.)

Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

The dimerization, packaging, and gene-transcription processes are intimately linked; disruption in one process often subsequently affects another. The LTRs exist only in the proviral DNA genome; the viral RNA genome contains only part of each LTR, and the complete LTRs are re-created during the reverse-transcription process prior to integration into the host DNA. Phases of HIV infection Clinical HIV infection undergoes 3 distinct phases: acute seroconversion, asymptomatic infection, and AIDS. Each is discussed below. (See the image below.)

Timeline of CD4 T-cell and viral-load changes over time in untreated human immunodeficiency virus (HIV) infection. Courtesy of Wikipedia (based on an original from Pantaleo et al (1993)).

Acute seroconversion Animal models show that Langerhans cells are the first cellular targets of HIV, which fuse with CD4+ lymphocytes and spread into deeper tissues. In humans, rapid occurrence of plasma viremia with widespread dissemination of the virus is observed 4-11 days after mucosal entrance of the virus. There is no fixed site of integration, but the virus tends to integrate in areas of active transcription, probably because these areas have more open chromatin and more easily accessible DNA. This greatly complicates eradication of the virus by the host, as latent proviral genomes can persist without being detected by the immune system and cannot be targeted by antivirals. See the image below. During this phase, the infection is established and a proviral reservoir is created. This reservoir consists of persistently infected cells, typically macrophages, and appears to steadily release virus. Some of the viral release replenishes the reservoir, and some goes on to produce more active infection. Seroconversion may take a few weeks, up to several months. Symptoms during this time may include fever, flulike illness, lymphadenopathy, and rash. These manifestations develop in approximately half of all people infected with HIV. Asymptomatic HIV infection At this stage in the infection, persons infected with HIV exhibit few or no signs or symptoms for a few years to a decade or more. Viral replication is clearly ongoing during this time, and the immune response against the virus is effective and vigorous. In some patients, persistent generalized lymphadenopathy is an outward sign of infection. During this time, the viral load, if untreated, tends to persist at a relatively steady state, but the CD4+ T-cell count steadily declines. This rate of decline is related to, but not easily predicted by, the steady-state viral load. Evidence now shows that therapy initiation early in the asymptomatic period is effective. However, very late initiation is known to result in a less effective response to therapy and a lower level of immune reconstitution. AIDS When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. For surveillance purposes in the United States, a CD4+ T-cell count less than 200/µL is also used as a measure to diagnose AIDS, although some opportunistic infections develop when CD4+ T-cell counts are higher than 200/µL, and some people with CD4 counts under 200/µL may remain relatively healthy. Many opportunistic infections and conditions are used to mark when HIV infection has progressed to AIDS. The general frequency of these infections and conditions varies from rare to common, but all are uncommon or mild in immunocompetent persons. When one of these is unusually severe or frequent in a person infected with HIV and no other causes for immune suppression can be found, AIDS can be diagnosed. [10]

Clinical presentation History The history should be carefully taken to elicit possible exposures to human immunodeficiency virus (HIV). Risk factors include the following:  Unprotected sexual intercourse, especially receptive anal intercourse (8-fold higher risk of transmission)  A large number of sexual partners  Prior or current sexually transmitted diseases (STDs): Gonorrhea and chlamydia infections increase the HIV transmission risk 3-fold, raises the transmission risk 7-fold, and herpes genitalis raises the transmission risk up to 25-fold during an outbreak  Sharing of intravenous drug paraphernalia  Receipt of blood products (before 1985 in the United States)  Mucosal contact with infected blood or needle-stick injuries  Maternal HIV infection (for newborns, infants, and children): Steps taken to reduce the risk of transmission at birth include cesarean delivery and prenatal antiretroviral therapy in the mother and antiretroviral therapy in the newborn immediately after birth. The patient may present with signs and symptoms of any of the stages of HIV infection. Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash. The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom. AIDS manifests as recurrent, severe, and occasionally life-threatening infections and/or opportunistic malignancies. The signs and symptoms are those of the presenting illness, meaning that HIV infection should be suspected as an underlying illness when unusual infections present in apparently healthy individuals. HIV infection itself does cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause). Signs and symptoms The patient with HIV may present with signs and symptoms of any of the stages of HIV infection. No physical findings are specific to HIV infection; the physical findings are those of the presenting infection or illness. Manifestations include the following:  Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash  The asymptomatic phase is generally benign  Generalized lymphadenopathy is common and may be a presenting symptom  AIDS manifests as recurrent, severe, and occasionally life-threatening infections or opportunistic malignancies  HIV infection can cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause)

According to the US CDC definition, one has AIDS if he/she is infected with HIV and present with one of the following:  A CD4+ T-cell count below 200 cells/μl (or a CD4+ T-cell percentage of total lymphocytes of less than 14%) OR  he/she has one of the following defining illnesses: o Candidiasis of bronchi, trachea, or lungs o Candidiasis esophageal o Cervical cancer (invasive) o Coccidioidomycosis, disseminated or extrapulmonary o Cryptococcosis, extrapulmonary o Cryptosporidiosis, chronic intestinal for longer than 1 month o Cytomegalovirus disease (other than liver, spleen or lymph nodes) o Encephalopathy (HIV-related) o Herpes simplex: chronic ulcer(s) (for more than 1 month); or bronchitis, pneumonitis, or esophagitis o Histoplasmosis, disseminated or extrapulmonary o Isosporiasis, chronic intestinal (for more than 1 month) o Kaposi's sarcoma o Lymphoma Burkitt's, immunoblastic or primary brain o Mycobacterium avium complex o Mycobacterium, other species, disseminated or extrapulmonary o Pneumocystis carinii pneumonia o Pneumonia (recurrent) o Progressive multifocal leukoencephalopathy o Salmonella sepsis (recurrent) o Toxoplasmosis of the brain o Tuberculosis o Wasting syndrome due to HIV Diagnosis. Screening for human immunodeficiency virus (HIV) infection is paramount, since infected individuals may remain asymptomatic for years while the infection progresses. Serologic tests are the most important studies in the evaluation for HIV infection. A high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) should be used for screening. Most ELISAs can be used to detect HIV-1 types M, N, and O and HIV-2. A positive ELISA result should be followed with confirmatory testing in the form of one or more Western blot assays or similar specific assay. Specific diagnostic criteria vary by test. Results are typically reported as positive, negative, or indeterminate. Secondary testing that may be performed to assist with diagnosis or staging includes the following:  Viral culture  Lymph node biopsy  Proviral DNA polymerase chain reaction (PCR)  Genotyping of viral DNA/RNA In June 2014, the Centers for Disease Control and Prevention (CDC) issued new recommendations for HIV testing in laboratories that are aimed at reducing the time needed to diagnose HIV infection by as much as 3-4 weeks over previous testing approaches. The new testing algorithm is performed as follows:  Diagnosis starts with a fourth-generation test that detects HIV in the blood earlier than antibody tests can; it identifies the viral protein HIV-1 p24 antigen, which appears in the blood before antibodies do  If this test is positive, an immunoassay that differentiates HIV-1 from HIV-2 antibodies should be performed; results from such assays can be obtained faster than they can from the Western blot test  In patients with positive results on the initial antigen test but with negative or indeterminate results on the antibody differentiation assay, HIV-1 nucleic acid testing should be performed to determine whether infection is present

The CD4 T-cell count is a reliable indicator of the current risk of acquiring opportunistic infections. CD4 counts vary, and serial counts are generally a better measure of any significant changes. The reference range for CD4 counts is 500-2000 cells/μL. After seroconversion, CD4 counts tend to decrease (around 700/μL on average) and continue to decline over time. For surveillance purposes, a CD4 count under 200/μL is considered AIDS-defining in the United States owing to the increased risk of opportunistic infections at this level.

Viral load in peripheral blood is used as a surrogate marker of viral replication rate. This is a surrogate because most of the viral replication occurs in the lymph nodes rather than in the peripheral blood.

Baseline Studies Baseline studies for other infections that are important in the initial workup of a patient with newly diagnosed HIV infection include the following:  Purified protein derivative (PPD) skin testing for tuberculosis  Cytomegalovirus (CMV) testing  Syphilis testing  Rapid amplification testing for gonococcal and chlamydial infection  Hepatitis A, B, and C serology  Anti-Toxoplasma antibody  Ophthalmologic examination

The CDC classifies HIV infection into 3 categories, as follows:  Category A: Asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions  Category B: HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection  Category C: HIV infection with AIDS-defining opportunistic infections These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:  > 500/µL: Categories A1, B1, C1  200-400/µL: Categories A2, B2, C2  < 200/µL: Categories A3, B3, C3

Stages of HIV-infection 1. Primary HIV infection  Asymptomatic  Acute retroviral syndrome Clinical stage 1  Asymptomatic  Persistent generalized lymphadenopathy (PGL) Clinical stage 2  Moderate unexplained weight loss (<10% of presumed or measured body weight)  Recurrent respiratory tract infections (RTIs, sinusitis, bronchitis, otitis media, pharyngitis)  Herpes zoster  Angular cheilitis  Recurrent oral ulcerations  Papular pruritic eruptions  Seborrhoeic dermatitis  Fungal nail infections of fingers Clinical stage 3 Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations  Severe weight loss (>10% of presumed or measured body weight)  Unexplained chronic diarrhoea for longer than one month  Unexplained persistent fever (intermittent or constant for longer than one month)  Oral candidiasis  Oral hairy leukoplakia  Pulmonary tuberculosis (TB) diagnosed in last two years  Severe presumed bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia)  Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Conditions where confirmatory diagnostic testing is necessary  Unexplained anaemia (<8 g/dl), and or neutropenia (<500/mm3) and or thrombocytopenia (<50 000/ mm3) for more than one month Clinical stage 4 Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations  HIV wasting syndrome  Pneumocystis pneumonia  Recurrent severe or radiological bacterial pneumonia  Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s duration)  Oesophageal candidiasis  Extrapulmonary TB  Kaposi’s sarcoma  Central nervous system (CNS) toxoplasmosis  HIV encephalopathy Conditions where confirmatory diagnostic testing is necessary:  Extrapulmonary cryptococcosis including meningitis  Disseminated non-tuberculous mycobacteria infection  Progressive multifocal leukoencephalopathy (PML)  Candida of trachea, bronchi or lungs  Cryptosporidiosis  Isosporiasis  Visceral herpes simplex infection  Cytomegalovirus (CMV) infection (retinitis or of an organ other than liver, spleen or lymph nodes)  Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis)  Recurrent non-typhoidal salmonella septicaemia  Lymphoma (cerebral or B cell non-Hodgkin)  Invasive cervical carcinoma  Visceral leishmaniasis

ANTIRETROVIRAL THERAPY (ART) The treatment of human immunodeficiency virus (HIV) disease depends on the stage of the disease and any concomitant opportunistic infections. Highly active antiretroviral therapy (HAART) is the principal method for preventing immune deterioration. In addition, prophylaxis for specific opportunistic infections is indicated in particular cases. Successful long-term HAART results in a gradual recovery of CD4 T-cell numbers and an improvement of immune responses and T-cell repertoire (previously lost antigen responses may be restored). The peripheral T-cell counts initially surge after therapy is initiated, but this represents redistribution of activated T cells from the viral replication centers in the lymph nodes rather than a true increase in total-body CD4 T-cell counts.

Overall Treatment Principles: •recommended that all HIV+ patients initiate combination ART to restore and preserve immune function, reduce morbidity, prolong survival and prevent transmission •patients starting ART should be committed to treatment and understand the importance of adherence; poor compliance can lead to viral resistance; may defer treatment on the basis of clinical and psychosocial factors on case by case basis •consider results of baseline resistance testing and complete ART history before (re-) initiating ART •goal: keep viral load below limit of detection i.e. <40 copies/mL (undetectable); viral load should decrease 10-fold within 4-8 wk, be undetectable by 6 mo, and restore immunological function •strong evidence against intermittent ART or ‘drug holidays’ •ART leads to 96% reduction in risk of transmitting HIV to sexual partners.

While antiretroviral therapy (ART) is recommended for all patients with HIV infection, the following conditions increase the urgency to initiate therapy:  Pregnancy  AIDS-defining conditions  Acute opportunistic infections  Lower CD4 counts (eg, < 200 cells/µL)  Rapidly declining CD4 counts (eg, >100 cells/µL decrease per year)  Higher viral loads (eg, >100,000 copies/mL)  HIV-associated nephropathy (HIVAN)  Acute/early HIV infection  HIV/hepatitis B virus coinfection  HIV/hepatitis C virus coinfection

Since individuals may fail to engage in care between the initial HIV diagnosis (or first clinic visit) and the time ART is prescribed, some groups have proposed rapid ART initiation on the same day of HIV diagnosis as a strategy to increase ART uptake and engagement in care and to accelerate the time to ART-mediated viral suppression. Rapid ART initiation also has the potential to reduce the time during which people with newly diagnosed HIV can transmit HIV. Antiretroviral agents Classes of antiretroviral agents include the following:  Nucleoside reverse transcriptase inhibitors (NRTIs)  Protease inhibitors (PIs)  Nonnucleoside reverse transcriptase inhibitors (NNRTIs)  Entry inhibitors (EI)  Integrase strand transfer inhibitors (INSTI) Current drug regimen recommendations •2NRTIs + 1 INSTI/PI The December 2019 DHHS guideline lists the below regimens as "recommended for most" for treatment-naive patients. INSTI-based regimens are as follows:  Bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) (single-tablet regimen)  Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single-tablet regimen) - Only for patients who are HLA-B*5701–negative  Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine OR tenofovir alafenamide/emtricitabine (two-tablet regimen)  Dolutegravir/lamivudine (DTG/3TC) (single-tablet regimen) - Avoid in patients with an HIV viral load of more than 500,000 copies/mL, patients with HBV co-infection, and patients in whom HIV NRTI resistance testing results are unavailable prior to initiation.  Raltegravir plus tenofovir disoproxil fumarate/emtricitabine OR tenofovir alafenamide/emtricitabine. Protease inhibitor–based regimen  Darunavir (DRV) / ritonavir (RTV) plus tenofovir disoproxil fumarate (TDF) / emtricitabine (FTC) Women who become pregnant while taking antiretroviral agents should contact their physician and register with the Antiretroviral Pregnancy Registry. Regimen selection Antiretrovirals should be prescribed by an infectious disease specialist. Antiretroviral regimen selection is individualized, on the basis of the following:  Virologic efficacy  Toxicity  Pill burden  Dosing frequency  Drug-drug interaction potential  Drug resistance testing results  Comorbid conditions Drug resistance testing typically involves genotyping or phenotyping of resistance in the patient's viral strains. The January 2011 DHHS guidelines recommend genotypic testing to guide the choice of initial therapy in antiretroviral-naïve patients, as well as in patients in whom first or second regimens produce a suboptimal virologic response or virologic failure. Phenotypic testing is generally added to genotypic testing when complex drug resistance mutation patterns, especially to protease inhibitors, are confirmed or suspected. There are several concerns about antiretroviral regimens. The drugs can have serious side effects. Regimens can be complicated, requiring patients to take several pills at various times during the day. If patients miss doses, drug resistance can develop. Single Tablet ART Regimens: Atripla® - efavirenz /tenofovir/ emtricitabine Complera® - rilpivirine /emtricitabine/ tenofovir Odefsey® - rilpivirine /emtricitabine/ tenofovir alafenamide Stribild® - elvitegravir /cobicistat/ emtricitabine/ tenofovir Triumeq® - dolutegravir /abacavir/ lamivudine Genvoya® - tenofovir /emtricitabine/ elvitegravir/ cobici

Treatment Failure •defined primarily by viral load (persistently >200 copies/mL) •ensure that viral load >40 is not just a transient viremia or ‘blip’; confirm medication adherence, assess drug interactions, perform resistance testing. Immune reconstitution inflammatory syndrome (IRIS) Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections. IRIS usually occurs in the first months of treatment but is occasionally delayed. IRIS can complicate virtually any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to brief regimens of corticosteroids. IRIS has two forms:  Paradoxical IRIS, which refers to worsening symptoms due to a previously diagnosed infection  Unmasked IRIS, which refers to the first appearance of symptoms of an infection not previously diagnosed

8. Materials for activating students during a lecture: 1. What is HIV and how is it transmitted? 2. What is the pathophysiology of HIV infection? 3. What are the accessory proteins of HIV? 4. What is the pathogenesis of AIDS? 5. How does HIV replicate? 6. How is HIV compartmentalized? 7. What are the three distinct phases of HIV pathogenesis? 8. What are the first cellular targets of HIV? 9. What are the signs and symptoms of HIV infection? 10. What are the signs and symptoms of AIDS? 11. What are risk factors for HIV exposure? 12. Why is screening for HIV infection needed? 13. What are the benefits of early diagnosis of HIV infection? 14. What test should be used for HIV screening? 15. What is antiretroviral therapy for HIV infection? 16. Which pharmacologic drug classes are used in antiretroviral therapy for HIV infection? 17. Which combination antiretroviral therapies (ARTs) are approved as complete daily regimens to treat HIV infection? 18. Which opportunistic infections and conditions are seen in patients with AIDS? 19. What are the signs and symptoms of pulmonary tuberculosis (TB) in HIV-infected persons? 20. What are the signs and symptoms of extrapulmonary tuberculosis (TB)?

Task 1 A 43-year-old woman presented to the emergency room with confusion, stiff neck, fever, headache, and sore throat that had lasted for over 2 weeks. According to the family, a physician who saw the patient 2 weeks prior to hospital admission prescribed her first cephalexin and later amoxicillin/clavulanic acid. At the emergency room, she had a temperature of 38°C, tender submandibular lymphadenopathy, disorientation, and drowsiness, with intact strength and reflexes. She had no prior relevant medical or surgical history, no medications, and no "sick contacts." A lumbar puncture showed total protein 209 mg/dL, glucose 42 mg/dL, and white blood cells 48 cells/mm3 (99% lymphocytes). A CT of the head showed no acute changes and the chest x-ray was clear. Initially, she was empirically treated with ceftriaxone and acyclovir for presumptive diagnosis of bacterial meningitis and herpes simplex encephalitis. She markedly improved by day 5 when acyclovir was stopped. 1. Formulate the preliminary diagnosis. 2. Prescribe additional diagnostics. 3. Treatment. Test control. 1. A person with HIV is considered to have progressed to AIDS when: the number of their CD4 cells falls below: A. 1,000 per cubic milliliter B. 500 per cubic milliliter C. 200 per cubic milliliter D. 350 per cubic milliliter E. 50 per cubic milliliter

2. Which drugs (of the following) are inhibitors of the process of reverse transcription in the production of HIV? A. Lamivudine B. Acyclovir, C. ritonavir, D. Ribavirin, E. Peg-interferon

3. What is the function of the enzyme protease of HIV? A. Provides post-translational processing of internal HIV proteins. B. Provides post-translational processing of HIV glycoproteins. C. Provides straight cytolytic effect on T-cells D. Provides integration of DNA provirus with the genome of the cell. E. All mentioned

4. What drugs (listed) are HIV protease inhibitors? A. Ritonavir, B. Azidothymidine, C. Zalcitabine, D. Stavudine, E. Amantadine

5. Which protein attaches HIV-1 to the surface of a sensitive cell? A. gp120 B. gp41 C. r24 D. r18 E. all mentioned

6. Which HIV protein provides penetration of the virus sensitive cell? A. gp41 B. gp120 C. р24 D. р18 E. all mentioned

7. What receptors in a sensitive cell HIV adsorbs at? A. On CD4 receptors B. On sialic acid residues, which are glycoproteins and gangliosides. C. On CD21 receptors. D. On CD8 receptors E. All mentioned

8. At what clinical stage of HIV infection does a person become a source of infection for other people? A. Stage of acute HIV infection. B. Stage of asymptomatic infection. C. Stage of persistent generalized lymphadenopathy. D. Terminal stage of HIV infection. E. Any stage of HIV infection.

9. What is the main goal of HAART: A. Reduce the virus load 2. B. Restore the number of T cells to improve the functions of the immune system C. Reduce the risk of HIV transmission from mother to child D. Increase the life expectancy and increase the quality of life of HIV-infected people E. All mentioned

10. Define the obligatory minimum requirements for the procedure of counseling and testing for HIV: A. Voluntariness B. Confidentiality C. Anonymity D. Accessibility E. All mentoned

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What are key features of fever of unknown origin (FUO)? 2. How are the conditions of the differential diagnosis of fever of unknown origin (FUO) categorized? 3. What are noninfectious inflammatory causes of fever of unknown origin (FUO)? 4. What are common infectious inflammatory causes of fever of unknown origin (FUO)? 5. What are less common infectious causes of fever of unknown origin (FUO)? 6. What are malignant and neoplastic causes of fever of unknown origin (FUO)? 7. Which symptoms suggest a malignant cause of fever of unknown origin (FUO)? 8. What should be the focus of history for fever of unknown origin (FUO)? 9. What is the basis for selection of diagnostic tests in fever of unknown origin (FUO)? 10. What is the role of lab studies in the workup of fever of unknown origin (FUO)? 11. What are the treatment options for fever of unknown origin (FUO)?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Vector-borne infectious diseases. Fever syndrome. Sepsis. Topic Differential diagnosis of fever syndrome in infectology Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic.

Fever is defined as a rectal temperature that exceeds 38°C (100.4°F). Direct the initial evaluation of these patients toward identifying or ruling out serious bacterial infections (SBI), most commonly urinary tract infections. The following questions are important to consider:

 What laboratory studies are indicated for various age ranges?  Which patients need in-depth evaluation and treatment?  Which patients need treatment with antibiotics?  Which patients should be hospitalized?  Which patients can be sent home safely and what follow-up is appropriate for them?  Are the diagnosis and treatment modalities for each patient cost-effective?  What is the potential morbidity associated with testing and treatment?  What are the parental (and patient) preferences for testing and treatment?

Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:  Unexplained are worrisome to patients and clinicians, but most persistent fevers are diagnosed, and often within one week of hospital evaluation or 3 outpatient visits.  Most fevers that persist beyond this period are caused by common conditions presenting uncommonly.  Hundreds of conditions may cause FUO. While infections remain a significant cause, most FUOs in the developed world are caused by noninfectious inflammatory disorders, with malignancy a much smaller percentage. Infection is likely to evolve with increased global travel and use of immunomodulating drugs.  The differential diagnoses of FUO depend on and continue to evolve based on regional factors, exposures, and available diagnostic tools.  A significant percentage of FUO cases are caused by miscellaneous conditions, and there is no standard algorithm for evaluating FUO. The approach to diagnostic study is best guided by ongoing assessment for historical, physical, and basic laboratory clues. Following clues and beginning with the least invasive evaluation avoids unnecessary harm and cost to the patient.  Physical examination in FUO should pay special attention to skin, eyes, lymph nodes, liver, and spleen.  It is reassuring that most cases of FUO that remain undiagnosed despite intensive evaluations have a good long-term prognosis and resolve within a year.

2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Anatomy The structure of the oropharynx, nose, larynx, trachea, bronchi, lungs, heart, nervous system Histology The structure of the mucous membrane of the nose, larynx, oropharynx, trachea Microbiology Properties of the influenza virus, methods for the specific diagnosis of influenza Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, l / u, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. internal diseases Symptoms and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of chloramphenicol, Pharmacology ciprofloxacin, pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan: 1. The basic concepts of fever 2. Pathophysiology of fever 3. Etiology of fever 4. Diagnostical algorithm for fever 5. Treatment of fever 6. The concept of fever of unknown origin (FUO) 1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: Fever is elevated body temperature (> 37.8° C orally or > 38.2° C rectally) or an elevation above a person’s known normal daily value. Fever occurs when the body's thermostat (located in the hypothalamus) resets at a higher temperature, primarily in response to an infection. Elevated body temperature that is not caused by a resetting of the temperature set point is called hyperthermia. Many patients use “fever” very loosely, often meaning that they feel too warm, too cold, or sweaty, but they have not actually measured their temperature. Symptoms are due mainly to the condition causing the fever, although fever itself can cause chills, sweats, and discomfort and make patients feel flushed and warm. Pathophysiology During a 24-hour period, temperature varies from lowest levels in the early morning to highest in late afternoon. Maximum variation is about 0.6° C. Body temperature is determined by the balance between heat production by tissues, particularly the liver and muscles, and heat loss from the periphery. Normally, the hypothalamic thermoregulatory center maintains the internal temperature between 37° and 38° C. Fever results when something raises the hypothalamic set point, triggering vasoconstriction and shunting of blood from the periphery to decrease heat loss; sometimes shivering, which increases heat production, is induced. These processes continue until the temperature of the blood bathing the hypothalamus reaches the new set point. Resetting the hypothalamic set point downward (eg, with antipyretic drugs) initiates heat loss through sweating and vasodilation. The capacity to generate a fever is reduced in certain patients (eg, alcoholics, the very old, the very young). Pyrogens are substances that cause fever. Exogenous pyrogens are usually microbes or their products. The best studied are the lipopolysaccharides of gram-negative bacteria (commonly called endotoxins) and Staphylococcus aureus toxin, which causes toxic shock syndrome. Fever is the result of exogenous pyrogens that induce release of endogenous pyrogens, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and IL-6 and other cytokines, which then trigger cytokine receptors, or of exogenous pyrogens that directly trigger Toll-like receptors. Prostaglandin E2 synthesis appears to play a critical role. Consequences of fever Although many patients worry that fever itself can cause harm, the modest transient core temperature elevations (ie, 38 to 40° C) caused by most acute infections are well tolerated by healthy adults. However, extreme temperature elevation (typically > 41° C) may be damaging. Such elevation is more typical of severe environmental hyperthermia but sometimes results from exposure to illicit drugs (eg, cocaine, phencyclidine), anesthetics, or antipsychotic drugs. At this temperature, protein denaturation occurs, and inflammatory cytokines that activate the inflammatory cascade are released. As a result, cellular dysfunction occurs, leading to malfunction and ultimately failure of most organs; the coagulation cascade is also activated, leading to disseminated intravascular coagulation (DIC). Because fever can increase the basal metabolic rate by about 10 to 12% for every 1° C increase over 37° C, fever may physiologically stress adults with preexisting cardiac or pulmonary insufficiency. Fever can also worsen mental status in patients with dementia. Fever in healthy children can cause febrile seizures. Etiology Many disorders can cause fever. They are broadly categorized as  Infectious (most common)  Neoplastic  Inflammatory (including rheumatic, nonrheumatic, and drug-related) The cause of an acute (ie, duration ≤ 4 days) fever in adults is highly likely to be infectious. When patients present with fever due to a noninfectious cause, the fever is almost always chronic or recurrent. Also, an isolated, acute febrile event in patients with a known inflammatory or neoplastic disorder is still most likely to be infectious. In healthy people, an acute febrile event is unlikely to be the initial manifestation of a chronic illness. Infectious causes Virtually all infectious illnesses can cause fever. But overall, the most likely causes are  Upper and lower respiratory tract infections  Gastrointestinal infections  Urinary tract infections  Skin infections Most acute respiratory tract and gastrointestinal infections are viral. Specific patient and external factors also influence which causes are most likely. Patient factors include health status, age, occupation, and risk factors (eg, hospitalization, recent invasive procedures, presence of IV or urinary catheters, use of mechanical ventilation). External factors are those that expose patients to specific diseases—eg, through infected contacts, local outbreaks, disease vectors (eg, mosquitoes, ticks), a common vehicle (eg, food, water), or geographic location (eg, residence in or recent travel to an endemic area). Table 1. Some Causes of Acute Fever Predisposing Factor Cause None (healthy) Upper or lower respiratory tract infection Gastrointestinal infection Urinary tract infection Skin infection Hospitalization IV catheter infection Urinary tract infection (particularly in patients with an indwelling catheter) Pneumonia (particularly in patients using a ventilator) Atelectasis Surgical site infection (postoperatively) Deep venous thrombosis or pulmonary embolism Diarrhea (Clostridioides difficile–induced) Drugs Hematoma Transfusion reaction Decubitus ulcers Travel to endemic Coccidioidomycosis areas (less common) Diarrheal disorders Hantavirus Histoplasmosis Legionnaires' disease Rickettsial infections (eg, African tick typhus, Mediterranean spotted fever) Multidrug resistant bacteria Plague Tularemia Typhoid fever Viral hepatitis Zika virus infection, chikungunya, Ebola, Japanese encephalitis, rabies, measles, and Vector exposure (in Ticks: Rickettsiosis, ehrlichiosis, anaplasmosis, Lyme US) disease, babesiosis, tularemia Mosquitoes: Arboviral encephalitis Wild animals: Tularemia, rabies, hantavirus infection Fleas: Plague Domestic animals: Brucellosis, cat-scratch disease, Q fever, toxoplasmosis Birds: Psittacosis Reptiles: Salmonella infection Bats: Rabies, histoplasmosis Immunocompromise Viruses:Varicella-zoster virus or cytomegalovirus infection Bacteria: Infection due to encapsulated organisms (eg, pneumococci, meningococci), Staphylococcus aureus, gram- negative bacteria (eg, Pseudomonas aeruginosa), Nocardia species, or Mycobacteria species Fungi: Infection due to Candida, Aspergillus, Histoplasma, or Coccidioides species; microsporidia, Pneumocystis jirovecii; or fungi that cause mucormycosis Parasites: Infection due to Toxoplasma gondii, Strongyloides stercoralis, Cryptosporidium species, or Cystoisospora (previously Isospora belli) Drugs that can increase Amphetamines heat production Cocaine Methylenedioxymethamphetamine (MDMA, or Ecstasy) Antipsychotics Anesthetics Drugs that can trigger Beta-lactam antibiotics fever Sulfa drugs Phenytoin Carbamazepine Procainamide Quinidine Amphotericin B Interferons

Evaluation Two general issues are important in the initial evaluation of acute fever:  Identifying any localizing symptoms (eg, headache, cough): These symptoms help narrow the range of possible causes. The localizing symptom may be part of the patient’s chief complaint or identified only by specific questioning.  Determining whether the patient is seriously or chronically ill (particularly if such illness is unrecognized): Many causes of fever in healthy people are self-limited, and many of the possible viral infections are difficult to diagnose specifically. Limiting testing to the seriously or chronically ill can help avoid many expensive, unnecessary, and often fruitless searches. History History of present illness should cover magnitude and duration of fever and method used to take the temperature. True rigors (severe, shaking, teeth-chattering chills—not simply feeling cold) suggest fever due to infection but are not otherwise specific. Pain is an important clue to the possible source; the patient should be asked about pain in the ears, head, neck, teeth, throat, chest, abdomen, flank, rectum, muscles, and joints. Other localizing symptoms include nasal congestion and/or discharge, cough, diarrhea, and urinary symptoms (frequency, urgency, dysuria). Presence of rash (including nature, location, and time of onset in relation to other symptoms) and lymphadenopathy may help. Infected contacts and their diagnosis should be identified. should identify symptoms of chronic illness, including recurrent fevers, night sweats, and weight loss. Past medical history should particularly cover the following:  Recent surgery  Known conditions that predispose to infection (eg, HIV infection, diabetes, cancer, organ transplantation, sickle cell disease, valvular heart disorders—particularly if an artificial valve is present)  Other known disorders that predispose to fever (eg, rheumatologic disorders, systemic lupus erythematosus, gout, sarcoidosis, hyperthyroidism, cancer) Questions to ask about recent travel include location, time since return, locale (eg, in back country, only in cities), vaccinations received before travel, and any use of prophylactic antimalarial drugs (if required). All patients should be asked about possible exposures. Examples include unsafe food (eg, unpasteurized milk and milk products, raw or undercooked meat, fish, shellfish) or water, insect bites (eg, history of tick, mosquito, or other arthropod vector exposure), animal contact, unprotected sex, and occupational or recreational exposures (eg, hunting, hiking, water sports). Vaccination history, particularly against hepatitis A and B and against organisms that cause meningitis, influenza, or pneumococcal infection, should be noted. Drug history should include specific questions about the following:  Drugs known to cause fever  Drugs that predispose to increased risk of infection (eg, corticosteroids, anti-tumor necrosis factor drugs, chemotherapeutic and antirejection drugs, other immunosuppressants)  Illicit use of injection drugs (predisposing to endocarditis, hepatitis, septic pulmonary emboli, and skin and soft-tissue infections) Physical examination Physical examination begins with confirmation of fever. Fever is most accurately diagnosed by measuring rectal temperature. Oral temperatures are normally about 0.6° C lower and may be falsely even lower for many reasons, such as recent ingestion of a cold drink, mouth breathing, hyperventilation, and inadequate measurement time (up to several minutes are required with mercury thermometers). Measurement of tympanic membrane temperature by infrared sensor is less accurate than rectal temperature. Monitoring skin temperature using temperature-sensitive crystals incorporated into plastic strips placed on the forehead is insensitive for detecting elevations in the core temperature. During the COVID-19 pandemic, use of infrared devices to measure skin temperature (eg, of the forehead) to screen people for fever prior to entry in public places has become common. Other vital signs are reviewed for presence of tachypnea, tachycardia, or hypotension. For patients with localizing symptoms, examination proceeds as discussed elsewhere in THE MANUAL. For febrile patients without localizing symptoms, a complete examination is necessary because clues to the diagnosis may be in any organ system. The patient’s general appearance, including any weakness, lethargy, confusion, cachexia, and distress, should be noted. All of the skin should be inspected for rash, particularly petechial or hemorrhagic rash and any lesions (eg, eschar) or areas of erythema or blistering suggesting skin or soft-tissue infection. Neck, axillae, and epitrochlear and inguinal areas should be examined for adenopathy. In hospitalized patients, presence of any IVs, nasogastric tubes, urinary catheters, and any other tubes or lines inserted into the body should be noted. If patients have had recent surgery, surgical sites should be thoroughly inspected. For the head and neck examination, the following should be done:  Tympanic membranes: Examined for infection  Sinuses (frontal and maxillary): Percussed  Temporal arteries: Palpated for tenderness  Nose: Inspected for congestion and discharge (clear or purulent)  Eyes: Inspected for conjunctivitis or icterus  Fundi: Inspected for Roth spots (suggesting endocarditis)  Oropharynx and gingiva: Inspected for inflammation or ulceration (including any lesions of candidiasis, which suggests immunocompromise)  Neck: Flexed to detect discomfort, stiffness, or both, indicating meningismus, and palpated for adenopathy The lungs are examined for crackles or signs of consolidation, and the heart is auscultated for murmurs (suggesting possible endocarditis). The abdomen is palpated for hepatosplenomegaly and tenderness (suggesting infection). The flanks are percussed for tenderness over the kidneys (suggesting pyelonephritis). A pelvic examination is done in women to check for cervical motion or adnexal tenderness; a genital examination is done in men to check for urethral discharge and local tenderness. The rectum is examined for tenderness and swelling, suggesting perirectal abscess (which may be occult in immunosuppressed patients). All major joints are examined for swelling, erythema, and tenderness (suggesting a joint infection or rheumatologic disorder). The hands and feet are inspected for signs of endocarditis, including splinter hemorrhages under the nails, painful erythematous subcutaneous nodules on the tips of digits (Osler nodes), and nontender hemorrhagic macules on the palms or soles (Janeway lesions). The spine is percussed for focal tenderness. Neurologic examination is done to detect focal deficits. Red flags The following findings are of particular concern:  Altered mental status  Headache, stiff neck, or both  Petechial rash  Hypotension  Dyspnea  Significant tachycardia or tachypnea  Temperature > 40° C or < 35° C  Recent travel to an area where serious diseases (eg, malaria) are endemic  Recent use of immunosuppressants Interpretation of findings The degree of elevation in temperature usually does not predict the likelihood or cause of infection. Fever pattern, once thought to be significant, rarely is helpful with the possible exceptions of tertian and quartan malaria and relapsing episodes (eg, brucellosis). Likelihood of serious illness is considered. If serious illness is suspected, immediate and aggressive testing and often hospital admission are needed. Red flag findings strongly suggest a serious disorder, as in the following:  Headache, stiff neck, and petechial or purpuric rash suggest meningitis.  Tachycardia (beyond the modest elevation normally present with fever) and tachypnea, with or without hypotension or mental status changes, suggest sepsis.  Malaria should be suspected in patients who have recently traveled to an endemic area. Immunocompromise, whether caused by a known disorder or use of immunosuppressants or suggested by examination findings (eg, weight loss, oral candidiasis), is also of concern, as are other known chronic illnesses, injection drug use, and heart murmur. Older adults, particularly those in nursing homes, are at particular risk of serious bacterial or viral (eg, COVID-19) infection Localizing findings identified by history or physical examination are evaluated and interpreted (see elsewhere in THE MANUAL). Other suggestive findings include generalized adenopathy and rash. Generalized adenopathy may occur in older children and younger adults who have acute mononucleosis; it is usually accompanied by significant pharyngitis, malaise, and hepatosplenomegaly. Primary HIV infection or secondary syphilis should be suspected in patients with generalized adenopathy, sometimes accompanied by arthralgias, rash, or both. HIV infection develops 2 to 6 weeks after exposure (although patients may not always report unprotected sexual contact or other risk factors). Secondary syphilis is usually preceded by a chancre, with systemic symptoms developing 4 to 10 weeks later. However, patients may not notice a chancre because it is painless and may be located out of sight in the rectum, vagina, or oral cavity. Fever and rash have many infectious and drug causes. Petechial or purpuric rash is of particular concern; it suggests possible meningococcemia, Rocky Mountain spotted fever (particularly if the palms or soles are involved), or, less commonly, some viral infections (eg, dengue fever, hemorrhagic fevers). Other suggestive skin lesions include the classic erythema migrans rash of Lyme disease, target lesions of Stevens-Johnson syndrome, and the painful, tender erythema of cellulitis and other bacterial soft-tissue infections. The possibility of delayed drug hypersensitivity (even after long periods of use) should be kept in mind. If no localizing findings are present, healthy people with acute fever and only nonspecific findings (eg, malaise, generalized aches) most likely have a self-limited viral illness, unless a history of exposure to infected contacts (including a new, unprotected sexual contact), to disease vectors, or in an endemic area (including recent travel) suggests otherwise. Patients with significant underlying disorders are more likely to have an occult bacterial or parasitic infection. Injection drug users and patients with a prosthetic heart valve may have endocarditis. Immunocompromised patients are predisposed to infection caused by certain microorganisms. Drug fever (with or without rash) is a diagnosis of exclusion, often requiring a trial of stopping the drug. One difficulty is that if antibiotics are the cause, the illness being treated may also cause fever. Sometimes a clue is that the fever and rash begin after clinical improvement from the initial infection and without worsening or reappearance of the original symptoms (eg, in a patient being treated for pneumonia, fever reappears without cough, dyspnea, or hypoxia). Testing Testing depends on whether localized findings are present. If localizing findings are present, testing is guided by clinical suspicion and findings, as for the following:  Mononucleosis or HIV infection: Serologic testing  Bacterial or fungal infection: Blood cultures to detect possible  Meningitis: Immediate lumbar puncture and IV dexamethasone and antibiotics (head CT should be done before lumbar puncture if patients are at risk of brain herniation; IV dexamethasone and antibiotics must be given immediately after blood cultures are obtained and before head CT is done)  Specific disorders based on exposure (eg, to contacts, to vectors, or in endemic areas): Testing for those disorders, particularly a peripheral blood smear for malaria  Respiratory infection: Rapid molecular tests for common viral and bacterial community- acquired respiratory tract infections If no localizing findings are present in otherwise healthy patients and serious illness is not suspected, patients can usually be observed at home without testing. In most, symptoms resolve quickly; the few who develop worrisome or localizing symptoms should be reevaluated and tested based on the new findings. If serious illness is suspected in patients who have no localizing findings, testing is needed. Patients with red flag findings suggesting sepsis require cultures (urine and blood), chest x-ray, and evaluation for metabolic abnormalities with measurement of serum electrolytes, glucose, blood urea nitrogen, creatinine, lactate, and liver enzymes. Complete blood count is typically done, but sensitivity and specificity for diagnosing serious bacterial infection are low. However, white blood cell (WBC) count is important prognostically for patients who may be immunosuppressed (ie, a low WBC count may be associated with a poor prognosis). C-reactive protein elevation is a sensitive but nonspecific indicator of sepsis. An elevated level is indicative of a bacterial process but lacks sufficient sensitivity to warrant routine use. Patients with certain underlying disorders may need testing even if they have no localizing findings and do not appear seriously ill. Because of the risk and devastating consequences of endocarditis, febrile injection drug users are usually admitted to the hospital for serial blood cultures and often echocardiography. Patients taking immunosuppressants require complete blood count; if neutropenia is present, testing is initiated and chest x-ray is done, as are cultures of blood, sputum, urine, stool, and any suspicious skin lesions. Because bacteremia and sepsis are frequent causes of fever in patients with neutropenia, empiric broad-spectrum IV antibiotics should be given promptly, without waiting for culture results. Treatment Specific causes of fever are treated with anti-infective therapy; empiric anti-infective therapy that is based on the most likely anatomic site and the pathogens involved is required when suspicion of serious infection is high. Whether fever due to infection should be treated with antipyretics is controversial. Experimental evidence, but not clinical studies, suggests that fever enhances host defenses. Fever should probably be treated in certain patients at particular risk, including adults with cardiac or pulmonary insufficiency or with dementia. Drugs that inhibit brain cyclooxygenase effectively reduce fever:  Acetaminophen 650 to 1000 mg orally every 6 hours  Ibuprofen 400 to 600 mg orally every 6 hours The daily dose of acetaminophen should not exceed 4 g to avoid toxicity; patients should be warned not to simultaneously take nonprescription cold or flu remedies that contain acetaminophen. Other nonsteroidal anti-inflammatory drugs (eg, aspirin, naproxen) are also effective antipyretics. Salicylates should not be used to treat fever in children with viral illnesses because use has been associated with Reye syndrome. If temperature is ≥ 41° C, other cooling measures (eg, evaporative cooling with tepid water mist, cooling blankets) should also be started.

Fever of unknown origin The syndrome of fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following:  a temperature greater than 38.3°C (101°F) on several occasions,  more than 3 weeks' duration of illness,  failure to reach a diagnosis despite one week of inpatient investigation. FUO is currently classified into 4 distinct categories:

 Classic FUO: Fever for > 3 weeks with no identified cause after 3 days of hospital evaluation or ≥ 3 outpatient visits  Health care–associated FUO: Fever in hospitalized patients receiving acute care and with no infection present or incubating at admission if the diagnosis remains uncertain after 3 days of appropriate evaluation  Immune-deficient FUO: Fever in patients with neutropenia and other immunodeficiency if the diagnosis remains uncertain after 3 days of appropriate evaluation, including negative cultures after 48 hours  HIV-related FUO: Fever for > 3 weeks in outpatients with confirmed HIV infection or > 3 days in inpatients with confirmed HIV infection if the diagnosis remains uncertain after appropriate evaluation

Etiology. Causes of FUO are usually divided into 4 categories:

 Infections (25 to 50%)  Connective tissue disorders (10 to 20%)  Neoplasms (5 to 35%)  Miscellaneous (15 to 25%)

Infections are the most common cause of FUO. In patients with HIV infection, opportunistic infections (eg, tuberculosis; infection by atypical mycobacteria, disseminated fungi, or cytomegalovirus) should be sought. Common connective tissue disorders include systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, vasculitis, and juvenile rheumatoid arthritis of adults (adult Still disease). The most common neoplastic causes are lymphoma, leukemia, renal cell carcinoma, hepatocellular carcinoma, and metastatic carcinomas. However, the incidence of neoplastic causes of FUO has been decreasing, probably because they are being detected by ultrasonography and CT, which are now widely used during initial evaluation. Important miscellaneous causes include drug reactions, deep venous thrombosis, recurrent pulmonary emboli, sarcoidosis, inflammatory bowel disease, and factitious fever. No cause of FUO is identified in about 10% of adults.

The 5%-15% of patients whose FUO remains undiagnosed, even after extensive evaluations, usually have a benign long-term course, but close follow-up and systematic reevaluation studies are essential to avoid missing potential etiologies.

8. Materials for activating students during a lecture: 1. What is the term fever means? 2. Which are the consequences of fever? 3. Which main groups etiological factors of fever divided into? 4. What is the role of history taking in the workup of fever? 5. What is the role of physical examination in the workup of fever? 6. What is the role of lab studies in the workup of fever? 7. What are the treatment options for fever? 8. What are key features of fever of unknown origin (FUO)? 9. How are the conditions of the differential diagnosis of fever of unknown origin (FUO) categorized? 10. What are noninfectious inflammatory causes of fever of unknown origin (FUO)? 11. What are common infectious inflammatory causes of fever of unknown origin (FUO)? 12. What are less common infectious causes of fever of unknown origin (FUO)? 13. What is the role of lab studies in the workup of fever of unknown origin (FUO)? 14. What are the treatment options for fever of unknown origin (FUO)?

Task 1 Task A 28-year-old woman is transferred from an outside hospital with a chief complaint of fever of unknown origin for the past 3 months. Her fever has been as high as 102.2°F (39°C) and has had no noticeable pattern. The patient has a history of bronchial asthma and chronic bronchitis that has not responded to multiple courses of antimicrobial treatment including amoxicillin/clavulanic acid, cefotaxime, and levofloxacin. She has a 5-year history of asthma managed with inhaled bronchodilators and an occasional need for aminophylline. She also has a history of allergic rhinitis that precedes her history of asthma. Severe upper-back pain that limits movement and is associated with numbness of the sole of her right foot developed 2 weeks after the fever. She has noted difficulty holding heavy objects with either her right or left hand and difficulty with other upper-extremity tasks, such as combing her hair. She has a productive cough (yellowish sputum) that is not related to posture and has no diurnal variation. She reports significant weight loss. Although she is unable to quantify how much weight she has lost, she notes that her clothes no longer fit her. She does not smoke or take other medications, has not traveled, and does not have pets. On examination, the patient is very uncomfortable and restless. Besides the high fever, she has a pulse of 110 beats/min, blood pressure of 110/70 mm Hg, and a respiratory rate of 25 breaths/min. The patient weighs about 187 lb (85 kg; this likely represents a nearly 44-lb [20-kg] weight loss over the preceding 5 to 6 months). Examination of the chest reveals crepitations and wheezes throughout both lung fields, but normal heart sounds without evidence of cardiac murmur or friction rub are found. Examination of the back reveals severe tenderness of the midline cervical spine, which broadens to involve both shoulders down the spine to the 2nd lumbar vertebra. Proximal weakness of both upper limbs is noted, but the sensory examination of the upper extremities is normal. Lower extremity sensory motor examination is normal and symmetric. The laboratory investigations include a complete blood cell count (CBC) with a hemoglobin of 12.9 gm/dL, a platelet count of 350,000/mm3, and a white blood cell count of 25,000/mm3, with 12% eosinophils. The erythrocyte sedimentation rate (ESR) is elevated at 65 in the 1st hour. Liver enzyme findings are unremarkable, with an AST of 35 IU, ALT of 25 IU, and a serum bilirubin of 0.7 mg/dL. The creatinine is normal at 0.5 mg, with a blood urea nitrogen (BUN) of 35 mg/dL. The rheumatoid factor finding is positive. A urine analysis shows no evidence of infection or proteinuria. A plain chest radiograph is performed, which reveals multiple scattered infiltrates in both lungs. A high-resolution CT scan shows interstitial lung fibrosis. What is the diagnosis? Correct answer: Churg-Strauss syndrome (CSS). has long been known as a cause of fever of unknown originThis case presented with a history and physical examination consistent with CSS, including allergic rhinitis and asthma, myalgias, elevated ESR, eosinophilia, transient interstitial lung fibrosis, positive rheumatoid factor, and mononeuritis. In this patient, antineutrophil cytoplasmic antibodies (c-ANCA and p-ANCA) were negative, as is found in approximately 50% of CSS patients. Test control. 1. What is criterion of FUO? A. presence of the pathogen in the blood B. dissemination of infection throughout the body from the primary source C. three or more foci of infection linked together D. more than 3 weeks' duration of illness E. All answers are correct

2. Which of following are FUO categories: A. classical, B. hospital-acquired, C. neutropenic D. HIV-related E. all mentioned

3. Noninfectious Inflammatory Causes of FUO are: A. Abdominopelvic abscesses B. Cat scratch disease (CSD) C. Systemic lupus erythematosus (SLE) D. Lymphoma, renal cell carcinoma E. Thyroiditis

4. What FUO therapy should be focused on? A. Treatment should be directed toward the underlying cause B. Compulsory administration of high doses of antipyretics C. High doses of corticosteroids in priority D. Broad spectrum antibiotics prescription empirically E. Immunomodulators have shown high efficiency

5. The main role in pathogenesis of hepatolienal syndrome during acute brucellosis plays: A. intoxication, B. high fever, C. parenchymal diffusion and tropism of brucellosis to cells of the reticuloendothelial system D. granulomatous hepatitis, E. toxic hepatitis

6. In the pathogenesis of hepatolienal syndrome in chronic brucellosis the main are: A. hepatitis, B. intoxication syndrome, C. dysbacteriosis, D. long-term drug therapy, E. decrease in enzymatic activity of digestive organs

7. What types of fever are typical for brucellosis: A. continuous B. remitting C. subfebrile D. Wunderlich E. subnormal

8. Lymphadenopathy development in brucellosis is based on: A. reaction of the autonomic nervous system B. circulation of endotoxin in the blood C. proliferative reaction of the reticuloendothelial system in response to the penetration of brucellosis D. generalization of infection E. formation of metastatic foci

9. Choose the most effective antibacterial treatment for acute brucellosis: A. penicillin + cefatoxime, B. ampicillin + gentamicin, C. doxacycline + rifampicin, D. tetracycline + ofloxacin, E. ampicillin + norfloxacin

10. The main clinical criteria for acute brucellosis are: A. lymphadenopathy, B. hepatolienal syndrome, C. dysfunction of CCC and emergency, D. severe sweating E. lacunar sore throat

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture

1. What does the term International Health Regulations means? 2. Which are the criteria of public health emergencies of international concern (PHEIC)? 3. What is plague? 4. How is plague transmitted? 5. What are the signs and symptoms of plague? 6. Which lab studies are performed to screen for and diagnosis plague? 7. Which studies are used to determine the severity of organ complications caused by plague? 8. What are the treatment options for plague? 9. What is hemorrhagic fever (HF)? 10. What is yellow fever? 11. How is yellow fever transmitted? 12. What are the signs and symptoms of yellow fever? 13. Which studies are performed to screen for and diagnosis yellow fever? 14. What are the treatment options for yellow fever? 15. What is the etiology of Marburg and Ebola fevers? 16. How are Marburg and Ebola fevers transmitted? 17. What are the signs and symptoms of acute toxoplasmosis? 18. What are the signs and symptoms of Marburg and Ebola fevers? 19. How is the diagnosis of Marburg and Ebola fevers confirmed? 20. What are the treatment options for Marburg and Ebola fevers?

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Infectious diseases with contact and multiple transmission. Topic Infectious diseases controlled by the International Health Regulations. Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. The International Health Regulations, or IHR (2005), represent an agreement between 196 countries including all WHO Member States to work together for global health security. Through IHR, countries have agreed to build their capacities to detect, assess and report public health events. WHO plays the coordinating role in IHR and, together with its partners, helps countries to build capacities. IHR also includes specific measures at ports, airports and ground crossings to limit the spread of health risks to neighboring countries, and to prevent unwarranted travel and trade restrictions so that traffic and trade disruption is kept to a minimum. Plague was first described in the Old Testament and has persisted into the modern era. Plague has caused large-scale epidemics, thereby changing the course of history in many nations. The first pandemic was believed to have started in Africa and killed 100 million people over a span of 60 years. In the Middle Ages, plague killed approximately one fourth of Europe's population. The pandemic that began in China in the 1860s spread to Hong Kong in the 1890s and was subsequently spread by rats transported on ships to Africa, Asia, California, and port cities of South America. In the early twentieth century, plague epidemics accounted for about 10 million deaths in India. Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates that 200,000 cases of disease and 30,000 deaths a year occur, but the number of officially reported cases is far lower. The largest Ebola outbreak to date occurred in West Africa from 2014 to 2016. This outbreak primarily occurred in Guinea, Sierra Leone, and Liberia, with >28,000 cases and >11,000 deaths. As a result of this outbreak, several sporadic cases of imported Ebola virus disease also occurred in industrialized nations, including the United States, the United Kingdom, Spain, and Italy. Lassa fever high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year.

2. The educational goals of the lecture. To analyze the characteristics of infectious diseases, the patterns of the course of the infectious and epidemiological process of various infectious diseases, the principles of their diagnosis, treatment and prevention; types of infectious diseases hospitals, requirements for the territory of infectious diseases hospitals; structural subdivisions, purposes and tasks of the sanitary inspection room, the purpose and components of the boxes and semi-boxes, auxiliary sections, the principles of disinfection in an infectious diseases hospital; principles of preventing nosocomial infection, infection of medical personnel; rules for maintaining medical documentation in the infectious diseases ward; rules for discharge of patients from the infectious diseases hospital; features of infectious diseases, phases of the infectious process, factors that affect its course, the role of immunity in infectious diseases; principles for classifying infectious diseases ; general characteristics of different groups of infectious diseases - intestinal, respiratory, blood, wound infections, infectious diseases with multiple transmission mechanisms. Explain the etiology of infectious diseases, pathogenicity factors of the pathogen; epidemiology; pathogenesis, clinical manifestations; the period of occurrence and clinical manifestations of diseases complications; diagnosis; principles of treatment and prevention; indications for antibacterial treatment. Analyze the rules for staying in an infectious diseases hospital and, in particular, at the patient’s bedside; collect an epidemiological history, separate the possible ways and factors of infection transmission; decide on the necessity and place of hospitalization; draw up and submit the appropriate documentation to the sanitary and epidemiological service (SES); adhere to the rules for discharge of the patient with infection department. Explain the basic working rules at the patient’s bedside; to collect a medical history with an assessment of epidemiological data; examine the patient and detect the main symptoms and syndromes, substantiate the clinical diagnosis, determine the need for hospitalization; conduct differential diagnosis of disease; on the basis of a clinical examination, to identify possible complications, urgent conditions in time, draw up medical documentation on the fact of the establishment of a previous diagnosis of (emergency report to the district epidemiological department); make a plan for laboratory and additional examination of the patient; interpret the results of a laboratory examination; to draw up an individual treatment plan taking into account the syndromes of the disease, the presence of complications, the severity of the condition, allergic history, concomitant pathology; provide emergency care at the prehospital stage; draw up a plan of anti- epidemic and preventive measures in the focus of infection; give recommendations regarding the regimen, diet, examination, supervision, during the period of convalescence.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Microbiology Properties of bacteria and viruses, methods for the specific diagnosis. Physiology The parameters of the physiological norm of human organs and systems; laboratory examination parameters are normal (total blood, urine, blood biochemistry, parameters of WWTP, electrolytes, etc.). Pathophysiology The mechanism of violation of the functions of organs and systems in pathological conditions of different genesis. Pathological anatomy Changes in the structure of the mucous membrane of the oropharynx, tonsils, nose, renal tubule epithelium, the structure of the central and peripheral NS, myocardium. Pharmacology Groups of drugs that are used to treat the disease, dosing (single and daily), their side effects, contraindications and so on Propaedeutics of Methods and main stages of a clinical examination of a patient. Symptoms internal diseases and syndromes of the disease. Clinical Famakokinetics and pharmacodynamics, side effects of antimicrobials, Pharmacology pathogenetic therapy. Neurology Pathogenesis, clinical signs of toxic brain edema, arachnoiditis, syndrome, Hyena-Barre, polyneuritis, Reye's syndrome 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan:

The concept of infectious process and infectious diseases. The etiology of infectious diarrhea. Pathophysiology of infectious diarrhea. Clinical presentation of acute diarrhea. Management of acute diarrhea.

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: INTERNATIONAL HEALTH REGULATIONS (IHR) With the signing of the revised International Health Regulations (IHR) in 2005, the international community agreed to improve the detection and reporting of potential public health emergencies worldwide. IHR (2005) better addresses today’s global health security concerns and are a critical part of protecting global health. The regulations require that all countries have the ability to detect, assess, report and respond to public health events.

With trade and travel expanding on a global level, the opportunity for greater disease transmission also increases. The public health and economic impact due to infectious diseases can cause great harm to humans and severely damage a country’s resources. IHR (2005) is coordinated by the World Health Organization (WHO) and aims to keep the world informed about public health risks and events. As an international treaty, the IHR (2005) is legally binding; all countries must report events of international public health importance. Countries reference IHR (2005) to determine how to prevent and control global health threats while keeping international travel and trade as open as possible.

IHR (2005) requires that all countries have the ability to do the following:

 Detect: Make sure surveillance systems and laboratories can detect potential threats  Assess: Work together with other countries to make decisions in public health emergencies  Report: Report specific diseases, plus any potential international public health emergencies, through participation in a network of National Focal Points  Respond: Respond to public health events

IHR (2005) also includes specific measures countries can take at ports, airports and ground crossings to limit the spread of health risks to neighboring countries, and to prevent unwarranted travel and trade restrictions.

In 2003, severe acute respiratory syndrome (SARS) threatened global health, showing us how easily an outbreak can spread. Recently, the Ebola epidemic in West Africa and outbreaks of MERS- CoV have shown that we are only as safe as the most fragile state. All countries have a responsibility to one another to build healthcare systems that are strong and that work to identify and contain public health events before they spread.

While previous regulations required countries to report incidents of cholera, plague, and yellow fever, IHR (2005) is more flexible and future-oriented, requiring countries to consider the possible impact of all hazards, whether they occur naturally, accidentally, or intentionally In spite of broader global agreement to the importance of IHR (2005), only about 1/3 of the countries in the world currently have the ability to assess, detect, and respond to public health emergencies. These gaps in global preparedness leave Americans and the rest of the world vulnerable. One of the most important aspects of IHR (2005) is the requirement that countries detect and report events that may constitute a potential public health emergency of international concern (PHEIC).

Under IHR (2005), a public health emergencies of international concern (PHEIC) is declared by the World Health Organization if the situation meets 2 of 4 criteria:

 Is the public health impact of the event serious?  Is the event unusual or unexpected?  Is there a significant risk of international spread?  Is there a significant risk of international travel or trade restrictions?

Once a WHO member country identifies an event of concern, the country must assess the public health risks of the event within 48 hours. If the event is determined to be notifiable under the IHR, the country must report the information to WHO within 24 hours.

Some diseases always require reporting under the IHR, no matter when or where they occur, while others become notifiable when they represent an unusual risk or situation.

Always Notifiable:

 Smallpox  Poliomyelitis due to wild-type poliovirus  Human influenza caused by a new subtype  Severe acute respiratory syndrome (SARS)

Other Potentially Notifiable Events:

 May include cholera, pneumonic plague, yellow fever, viral hemorrhagic fever, and West Nile fever, as well as any others that meet the criteria laid out by the IHR.  Other biological, radiological, or chemical events that meet IHR criteria

Since IHR (2005) was put into place, four PHEICs have been declared by WHO:

 H1N1 influenza (2009)  Polio (2014)  Ebola (2014)  Zika virus (2016) When a PHEIC is declared, WHO helps coordinate an immediate response with the affected country and with other countries around the world.

PLAGUE

Plague is an acute, contagious, febrile illness transmitted to humans by the bite of an infected rat flea. Human-to-human transmission is rare except during epidemics of pneumonic plague. The disease is caused by the plague bacillus, rod-shaped bacteria referred to as Yersinia pestis. Plague is worldwide in distribution, with most of the human cases reported from developing countries. Plague is a zoonotic disease that primarily affects rodents; humans are incidental hosts. Dog- to-human transmission was reported in a 2014 outbreak in Colorado. Survival of the bacillus in nature depends on flea-rodent interaction, and human infection does not contribute to the bacteria's persistence in nature. Of the 1500 flea species identified, only 30 of them have been shown to act as vectors of plague. The most prominent of these vectors is Xenopsylla cheopis (oriental rat flea); however, Oropsylla montana has been incriminated as the primary vector for this disease in North America.

Pathophysiology

Y pestis is a nonmotile, pleomorphic, gram-negative coccobacillus that is nonsporulating. The bacteria elaborate a lipopolysaccharide endotoxin, coagulase, and a fibrinolysin, which are the principal factors in the pathogenesis of plague. The pathophysiology of plague basically involves two phases—a cycle within the fleas and a cycle within humans.

The key to the organism’s virulence is the phenomenon of "blockage," which aids the transmission of bacteria by fleas. After ingestion of infected blood, the bacteria survive in the midgut of the flea owing to a plasmid-encoded phospholipase D that protects them from digestive juices. The bacteria multiply uninhibited in the midgut to form a mass that extends from the stomach proximally into the esophagus through a sphincterlike structure with sharp teeth called the proventriculus.

It has been shown that this property requires the presence of hemin-producing genes, which are needed for the formation of a biofilm that permits colonization of the proventriculus. In fact, as described by Jarrett et al (2004), this mutation in hemin genes allows colonization in the midgut without extension to the proventriculus. Consequently, the "blockage phenomenon" does not occur, thereby leading to failure of transmission. This blockage causes the flea to die of starvation and dehydration.

As a desperate measure, the flea then repeatedly tries to obtain a meal by biting a host, managing only to regurgitate the infected mass into host's bloodstream. However, the concept that the flea must be engorged before becoming infectious loses support when trying to explain the rapid rate of spread of disease during a plague epidemic. Studies of vectors such as O montana clearly indicate the redundancy of the aforementioned hypothesis, since this vector does not die of blockage and remains infectious for a long period, unlike its counterpart.

Once the flea bites a susceptible host, the bacilli migrate to the regional lymph nodes, are phagocytosed by polymorphonuclear and mononuclear phagocytes, and multiply intracellularly. Survival and replication within macrophages is probably of greatest importance in early stages of the disease. Involved lymph nodes show dense concentrations of plague bacilli, destruction of the normal architecture, and medullary necrosis. With subsequent lysis of the phagocytes, bacteremia can occur and may lead to invasion of distant organs in the absence of specific therapy.

The following are the modes of plague transmission in humans:

1. Bites by fleas 2. Exposure to humans with pneumonic plague 3. Handling of infected carcasses 4. Scratches or bites from infected domestic cats 5. Exposure to aerosols containing plague-causing bacilli

Another potential cause of plague transmission in humans is contact with an infected dog. In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924.

Clinical presentation

History

Travel to endemic areas within and outside the United States, history of a flea bite, close contact with a potential host, or exposure to dead rodents or rabbits should raise suspicion for plague.

Form Clinical presentation Bubonic  This is the most common presentation of plague. The incubation plague period varies but usually ranges 2-6 days. There is a sudden onset of high fever, chills, and headache.  Patients with this type experience body aches, extreme exhaustion, weakness, abdominal pain, and/or diarrhea.  Painful, swollen lymph glands (buboes) arise, usually in the groin (most common site), axilla, or neck.  Axillary, cervical, and epitrochlear buboes are almost always seen in cat-associated plague. Physically:

 Vesicles may be observed at the site of the infected flea bite. With advanced disease, papules, pustules, carbuncles, or an eschar may be observed in areas of the skin drained by the involved lymph nodes. A generalized papular rash of the hands and feet may be observed.  Buboes are unilateral, oval, extremely tender lymph nodes and can vary from 2-10 cm in size. Femoral lymph nodes are most commonly involved. Patients with an inguinal bubo walk with a limp, and the affected limb may be in a position of flexion, abduction, and external rotation. Patients resist any attempt to examine the involved lymph nodes. Enlargement of the buboes leads to rupture and discharge of malodorous pus.  Hepatomegaly and splenomegaly often occur and may be tender. Without intervention, this stage may lead to secondary pneumonic plague or meningitis or may disseminate and manifest as a sepsis picture. Pneumonic  Pneumonic plague is highly contagious and transmitted by aerosol plague droplets.  This is often secondary to bubonic or septicemic plague. However, primary pneumonic plague may be seen in laboratory workers, individuals exposed to an infected person, or those who have been exposed to a cat with pneumonic plague.  There is an abrupt onset of fever and chills, accompanied by cough, chest pain, dyspnea, purulent sputum, or hemoptysis.  Buboes may or may not be associated with pneumonic plague.  The ability for plague to be spread by aerosols makes Y pestis a potential agent of bioterrorism. Septicemic  Septicemic plague is observed in elderly patients and causes a rapid plague onset of symptoms.  Patients experience nausea, vomiting, abdominal pain, and diarrhea. (Diarrhea may be the predominant symptom.)  Patients exhibit a toxic appearance and soon become moribund.  Buboes are uncommon in septicemic plague, making the diagnosis elusive.  Because of an overwhelming infection with the plague bacillus, patients with septicemic plague have a toxic appearance and may present with tachycardia, tachypnea, and hypotension. Hypothermia is common.  Generalized purpura may be observed and can progress to necrosis and gangrene of the distal extremities.  Septicemic plague carries a high mortality rate and is associated with disseminated intravascular coagulation (DIC), multiorgan failure, and profound hypotension. Meningeal  This is characterized by fever, headache, and nuchal rigidity. plague  Buboes are common in meningeal plague.  Axillary buboes are associated with an increased incidence of meningeal plague. Pharyngeal  Pharyngeal plague results from ingestion of the plague bacilli. plague  Patients experience sore throat with pharyngeal erythema, fever, and painful cervical lymph nodes.  Asymptomatic pharyngeal carrier state of Y pestis infection was described an in patients with bubonic plague. Genitourinary  This was reported as the sole presentation of Y pestis infection in 4 /gastrointestin of 27 patients in a case series published in 1992. al plague Cutaneous  Manifests as purpura plague

Workup

Laboratory Studies

The possibility of plague should be strongly considered in febrile patients from endemic areas who have history of exposure to rodents. Rapid recognition of the classic symptoms of this disease and laboratory confirmation are essential to instituting lifesaving therapy. Expertise in testing for plague bacilli is limited to reference laboratories in plague-endemic states and the CDC.

 Leukocytosis with a predominance of neutrophils is observed, and the degree of leukocytosis is proportional to the severity of illness.  Peripheral blood smear shows toxic granulations and Dohle bodies.  Thrombocytopenia is common, and fibrin degradation product levels may be elevated.  Serum transaminases and bilirubin levels may be elevated.  Proteinuria may be present, and abnormalities in renal function have been associated.  Hypoglycemia may be observed.  Twenty-seven percent to 96% of blood cultures are positive for Y pestis in patients with bubonic plague and septicemic plague. Microbiology staff should be informed of the possibility of Y pestis agents in samples so that they can take adequate precautions when handling specimens.  Y pestis may be observed on a peripheral blood smear. Smear stained with Wright-Giemsa reveals rod-shaped bacteria. A Wayson stain demonstrates the typical "safety pin" appearance  Lymph node aspirates often demonstrate Y pestis. In patients with pharyngeal plague, Y pestis is cultured from throat swabs.  Cerebrospinal fluid (CSF) analysis in meningeal plague may show pleocytosis with a predominance of polymorphonuclear leukocytes. Gram stain of CSF may show plague bacilli. Limulus test of CSF demonstrates the presence of endotoxin.  Gram stain of sputum often reveals Y pestis. Imaging Studies

 Chest radiography reveals patchy infiltrates, consolidation, or a persistent cavity in patients with pneumonic plague.  ECG reveals sinus tachycardia and ST-T changes.  Nuclear imaging may help localize areas of lymphadenitis and meningeal inflammation. Treatment. All patients with suspected plague and signs of pneumonia should be placed in strict respiratory isolation for 48-72 hours after antibiotic therapy is initiated and kept there until pneumonia has been ruled out or until sputum culture have shown negative findings. Report patients thought to have plague to the local health department and to the WHO.

Alert laboratory personnel to the possibility of the diagnosis of plague. All fluid specimens must be handled with care to prevent aerosolization of the infected fluids. Gowns, gloves, and masks should be worn at all times, and strict infection control is of utmost importance.

Antibiotic treatment. Untreated plague can progress to a fulminant illness with a high risk of mortality. Thus, early and appropriate antibiotic treatment is essential.

 Historically, streptomycin (15 mg/kg, up to 1 g intramuscularly every 12 h) has been the drug of choice.  Gentamicin (5 mg/kg intravenously or intramuscularly once daily) is comparable to or superior than streptomycin. Gentamicin has been used successfully in the treatment of human plague is inexpensive, and can be dosed once daily.  Doxycycline (200 mg PO/IV every 12 hours for 72 hours) is a recommended alternative in patients who cannot take aminoglycosides or in the event of a mass casualty scenario, making parenteral therapy unachievable.  Because chloramphenicol attains high CSF concentrations, it has been used to treat meningeal plague, although no studies have been conducted for substantiation.  Studies in murine models have shown that fluoroquinolones demonstrate efficacy similar to that of the aminoglycosides. Fluoroquinolones are a reasonable alternative therapy. However, no clinical trials of fluoroquinolone therapy in human plague have been conducted. The FDA has approved levofloxacin and moxifloxacin for the treatment of plague. These have also been approved for use as prophylaxis following exposure to Yersinia pestis.  Beta-lactam antibiotics and macrolides should not be used.  Patients with advanced plague have a presentation of typical gram-negative sepsis and need antibiotic treatment for 10-14 days, along with other supportive measures. Supportive therapy

 Hemodynamic monitoring and ventilatory support are performed as appropriate.  Management of sepsis associated with plague requires aggressive intravenous hydration. Norepinephrine and other vasopressors may be required to manage hypotension and to improve hemodynamic status.  Enlarging or fluctuant buboes require incision and drainage. Postexposure prophylaxis

 Presumptive therapy consists of a 7-day course of oral doxycycline and ciprofloxacin.  Chloramphenicol may be used as an alternative.  Levofloxacin may be prescribed as a 10-14 day regimen for either treatment or postexposure prophylaxis. In a community experiencing a pneumonic plague epidemic, individuals with a temperature of 38.5°C or higher or newly onset cough should promptly receive parenteral antimicrobial therapy.

HEMORRHAGIC FEVERS

Hemorrhagic fevers are viral infections; important examples are Ebola and Marburg hemorrhagic fevers, Crimean–Congo hemorrhagic fever (CCHF), Rift Valley fever (RVF), Lassa fever, Hantavirus diseases, dengue and yellow fever.

YELLOW FEVER

Yellow fever is one of many causes of viral hemorrhagic fever. It is a member of the flavivirus family (group B arbovirus). The Flavivirus genus is composed of more than 70 viruses, most of which are arthropod-borne, with 30 that are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, West Nile, Zika, and tick-borne encephalitis. Transmission. As an arthropod-borne virus (ie, arbovirus), yellow fever is transferred from host to host by contaminated mouthparts of mosquitoes. Different species of the Aedes and Haemagogus genus breed in unique habitats (peridomestically versus within the forest canopy). Consequently, these vectors transmit the virus in 3 ways: (1) between monkeys, (2) from monkeys to humans, and (3) from person to person. This variability has led to 3 types of transmission cycles: sylvatic (jungle), intermediate (savannah), and urban.

 Sylvatic (or jungle) yellow fever: In tropical rainforests, monkeys, which are the primary reservoir of yellow fever, are bitten by wild mosquitoes of the Aedes and Haemogogus species, which pass the virus on to other monkeys. Occasionally humans working or travelling in the forest are bitten by infected mosquitoes and develop yellow fever.  Intermediate yellow fever: In this type of transmission, semi-domestic mosquitoes (those that breed both in the wild and around households) infect both monkeys and people. Increased contact between people and infected mosquitoes leads to increased transmission and many separate villages in an area can develop outbreaks at the same time. This is the most common type of outbreak in Africa.  Urban yellow fever: Large epidemics occur when infected people introduce the virus into heavily populated areas with high density of Aedes aegypti mosquitoes and where most people

have little or no immunity, due to lack of vaccination or prior exposure to yellow fever. In these conditions, infected mosquitoes transmit the virus from person to person.

Fig. Transmission cycles of yellow fever in Africa and South America. Adapted from Annu Rev Entomol. 2007.

Pathophysiology. The E protein (virulence factor) interacts with the cellular receptor, and virions are endocytosed into the dendritic cells. Subsequently, epidermal dendritic cells and lymph channels disseminate virions. After invasion in the host, Kupffer cells (fixed liver macrophages) are infected within 24 hours. Yellow fever is primarily viscerotropic, with the liver being the most affected organ. The infection quickly disseminates to the kidneys, lymph nodes, spleen, and bone marrow. Renal failure occurs as renal tubules undergo fatty change and eosinophilic degeneration, likely due to direct viral effect, hypotension, and hepatic involvement. The liver is the most important organ affected in yellow fever. The disease was labeled "yellow" based on the profound jaundice observed in affected individuals. Hepatocellular damage is characterized by lobular steatosis and necrosis, with recent data indicating apoptosis as the primary mechanism of cell death in the liver, corresponding with subsequent formation of Councilman bodies (degenerative eosinophilic hepatocytes). The kidneys also undergo significant pathologic changes. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever; consequently, acute tubular necrosis develops in advanced disease. Hemorrhage and erosion of the gastric mucosa lead to hematemesis, popularly known as black vomit. Fatty infiltration of the myocardium, including the conduction system, can lead to myocarditis and arrhythmias. Central nervous system (CNS) findings can be attributed to cerebral edema and hemorrhages compounded on metabolic disturbances. The bleeding diathesis of this disease is secondary to reduced hepatic synthesis of clotting factors, thrombocytopenia, and platelet dysfunction. The terminal event of shock can be attributed to a combination of direct parenchymal damage and a systemic inflammatory response. This cytokine storm has been characterized by increased levels of interleukin (IL)-6, IL-1 receptor antagonist, interferon-inducible protein-10, and tumor necrosis factor (TNF)–alpha. Viral antigens are found diffusely in kidneys, myocardium, and hepatocytes. In individuals who survive yellow fever, the recovery is complete, with no residual fibrosis. Signs and symptoms. Once contracted, the yellow fever virus incubates in the body for 3 to 6 days. Many people do not experience symptoms, but when these do occur, the most common are fever, muscle pain with prominent backache, headache, loss of appetite, and nausea or vomiting. In most cases, symptoms disappear after 3 to 4 days. A small percentage of patients, however, enter a second, more toxic phase within 24 hours of recovering from initial symptoms. High fever returns and several body systems are affected, usually the liver and the kidneys. In this phase people are likely to develop jaundice (yellowing of the skin and eyes, hence the name ‘yellow fever’), dark urine and abdominal pain with vomiting. Bleeding can occur from the mouth, nose, eyes or stomach. Half of the patients who enter the toxic phase die within 7 - 10 days. Diagnosis. Yellow fever is difficult to diagnose, especially during the early stages. A more severe case can be confused with severe malaria, leptospirosis, viral hepatitis (especially fulminant forms), other haemorrhagic fevers, infection with other flaviviruses (such as dengue haemorrhagic fever), and poisoning. Polymerase chain reaction (PCR) testing in blood and urine can sometimes detect the virus in early stages of the disease. In later stages, testing to identify antibodies is needed (ELISA and PRNT). Treatment Good and early supportive treatment in hospitals improves survival rates. There is currently no specific anti-viral drug for yellow fever but specific care to treat dehydration, liver and kidney failure, and fever improves outcomes. Associated bacterial infections can be treated with antibiotics. In 2001, an expert panel recommended the following common-sense recommendations (although these have never been validated in clinical studies):

 Maintenance of nutrition and prevention of hypoglycemia  Nasogastric suction to prevent gastric distension and aspiration  Gastric acid suppression to prevent gastric bleeding  Treatment of hypotension with fluid resuscitation and vasoactive drugs (dopamine)  Administration of oxygen  Correction of metabolic acidosis  Treatment of bleeding with fresh frozen plasma  Dialysis if indicated by renal failure  Treatment of secondary bacterial infections with indicated antimicrobials Prevention 1. Vaccination is the most important means of preventing yellow fever. The yellow fever vaccine is safe, affordable and a single dose provides life-long protection against yellow fever disease. A booster dose of yellow fever vaccine is not needed. Several vaccination strategies are used to prevent yellow fever disease and transmission: routine infant immunization; mass vaccination campaigns designed to increase coverage in countries at risk; and vaccination of travellers going to yellow fever endemic areas. In accordance with the International Health Regulations (IHR), countries have the right to require travellers to provide a certificate of yellow fever vaccination. If there are medical grounds for not getting vaccinated, this must be certified by the appropriate authorities. The IHR are a legally binding framework to stop the spread of infectious diseases and other health threats. Requiring the certificate of vaccination from travellers is at the discretion of each State Party, and it is not currently required by all countries. 2. Vector control. The risk of yellow fever transmission in urban areas can be reduced by eliminating potential mosquito breeding sites, including by applying larvicides to water storage containers and other places where standing water collects. Personal preventive measures such as clothing minimizing skin exposure and repellents are recommended to avoid mosquito bites. The use of insecticide-treated bed nets is limited by the fact that Aedes mosquitos bite during the daytime. EBOLA AND MARBURG HEMORRHAGIC FEVER Etiology. The genus name of the filoviruses reflects their unique filamentous structure (the Latin word filum means thread). The two species, Marburg and Ebola, are identical in morphology. Virions are always 80 nm in diameter, but vary considerably in length. The genome consists of a single 19-kilobase strand of negative-sense RNA containing 7 genes. Transcription and genome replication are performed by a complex of the RNA-dependent RNA polymerase and three other virus- encoded proteins. Marburg and Ebola virus replicate in identical fashion, except that the primary product of the glycoprotein gene of all Ebola species is a C-terminally truncated protein (“sGP”) that is secreted from infected cells. Production of full-length membrane-bound GP requires the post-transcriptional addition of a nucleotide to its messenger RNA during transcription. The release of sGP may contribute in some way to viral persistence in the filoviral maintenance host, but no role in the pathogenesis of Ebola hemorrhagic fever in humans has been identified. Epidemiology. The filoviruses are the only agents of viral hemorrhagic fever for which no natural reservoir has been identified. As described below, virus has been recovered from a variety of wild primates, but because these animals die quickly from infection, they cannot serve as a natural reservoir for Ebola virus. A number of studies have provided evidence that fruit bats, widely distributed in central Africa, may be the reservoir host of both Ebola and Marburg virus. A number of captured bats have demonstrated anti-Ebola or -Marburg antibodies in serum and the presence of viral sequences in liver and spleen tissues by RT-PCR, but live virus has yet to be isolated from any of these animals. Ebola or Marburg hemorrhagic fever of humans has occurred in 4 ways:  exposure to an infected nonhuman primate, either in the wild or in captivity;  presumed exposure to the unidentified reservoir host in Africa;  contamination by virus-containing body fluids of patients;  result of a laboratory accident. Marburg virus was discovered when infected monkeys were inadvertently imported from Uganda to vaccine production facilities in Marburg, Germany and Belgrade, Yugoslavia in 1967, causing outbreaks of hemorrhagic fever that killed 7 of 31 infected persons. Since the first outbreak, Marburg hemorrhagic fever has only occurred in Africa. Up until 2000, only 6 additional cases were identified, but in that year a large epidemic came to light in Watsa, in northeastern Democratic Republic of Congo (DRC, the former Zaire). More than 150 cases were eventually confirmed, with a fatality rate of greater than 80%. Genetic analysis of viral isolates showed that the epidemic had resulted from multiple independent introductions of virus into the local community of gold miners, and that little secondary spread of infection had taken place. In 2005, Marburg virus appeared unexpectedly in Angola, far from any previous site of human infection, causing some 250 cases of illness with a mortality that approached 90%. The spread of infection in a hospital pediatrics ward played a major role in amplifying the epidemic. In contrast to Watsa, only a single strain of virus was isolated. Ebola virus first came to the attention of the world scientific community in 1976, when two large epidemics occurred almost simultaneously in Zaire and Sudan. The former was centered at a mission hospital, where virus was inadvertently transmitted by contaminated syringes to nearly 100 patients, all of whom developed fatal disease. Many of the doctors, nurses and family members who cared for the first wave of patients also became infected; the final death toll was 280 out of 318 cases. The source of the initial infection was never identified. Another large hospital-based outbreak caused by the Zaire species occurred in Kikwit, DRC in 1995, with a case fatality rate exceeding 80% among more than 300 patients. In that and other large filoviral hemorrhagic fever epidemics since that time, teams of international medical workers helped to bring the outbreak to an end through case identification, contact tracing and the establishment of an isolation ward. The 1976 Sudan outbreak also involved extensive secondary transmission of virus in the hospital setting. In contrast to epidemics caused by Ebola Zaire virus, the case fatality rate for that epidemic and for two more in 1979 and in 2000 were all approximately 50%. The 2000 outbreak, which occurred in Gulu, Uganda, was the largest yet recorded, with 425 patients. Beginning in 1996, a new epidemiologic pattern was observed, in which humans became infected with Ebola Zaire virus through contact with sick or dead chimps or gorillas. In the first known outbreak of this type, 19 Gabonese villagers who butchered and ate a chimp found dead in the forest developed fulminant hemorrhagic fever, and most of them died. The virus is now spreading among populations of great apes in Gabon and neighboring Republic of Congo, causing both a massive die- off of these animals and a repeated epidemics among local residents. A third species of Ebola virus was identified in the Ivory Coast, where it infected a researcher who performed a necropsy on a dead chimpanzee. No other human cases have been recognized. The fourth species of Ebola virus, the enigmatic Reston agent, made its world debut in 1989, when it caused an outbreak among captive primates recently imported from the Philipines to a monkey quarantine facility in suburban Virginia. The origin of the virus and its relationship to the 3 African Ebola species still have not been determined. None of the animal caretakers who were exposed to sick animals became ill, prompting some researchers to propose that Ebola Reston virus is avirulent for humans. Pathogenesis Infection of a laboratory primate with a few particles of Ebola or Marburg virus by injection, inhalation or placement in the mouth or eye initiates an inexorable “chain reaction,” in which replication in monocytes, macrophages and dendritic cells releases large numbers of new virions that spread rapidly to the same cell types in lymph nodes, liver and spleen and other tissues throughout the body. From those cells, infection then spreads further to infect hepatocytes and other parenchymal cells; only lymphocytes and neurons are known to remain free of infection. Infected cells undergo death through necrosis, causing massive tissue damage. At the same time, cytokines and chemokines released from infected macrophages cause vasodilatation and increased permeability, and cell-surface tissue factor triggers disseminated intravascular coagulation. The host immune response is markedly impaired by the destruction of virus-infected dendritic cells and a massive loss of lymphocytes through apoptosis. Clinical Presentation The fulminant illess caused by Ebola or Marburg virus displays all of the classic features of the hemorrhagic fever syndrome. Exposure to the agent is usually followed within 3-7 days by the abrupt onset of high fever, malaise and a variety of nonspecific signs and symptoms produced by high levels of circulating cytokines and chemokines. These early changes are soon followed by the development of a “vascular leak” (see below) that results in a fall in blood pressure, leading in almost all cases to intractable shock and death during the second week of illness. All patients show evidence of coagulation abnormalities, with hemorrhages in the conjunctiva and easy bruising. Bleeding from the gastrointestinal and genitourinary tracts is frequently seen during the terminal phase of illness, but is rarely the cause of death. Survival appears to require the rapid mobilization of a specific immune response: those patients who develop anti-Ebola IgM or IgG antibodies during the second week of illness are likely to recover, while the persistence of high levels of circulating virus in the absence of a detectable antibody response is predictive of death. Laboratory Diagnosis Because the clinical features of an isolated case of Ebola or Marburg hemorrhagic fever do not differ from those of other types of VHF or a number of other infectious diseases present in central Africa, specific diagnosis requires the detection of viral antigen by ELISA or viral RNA by RT-PCR. Saliva from sick persons is usually positive by both tests, but serum is a much more reliable sample early in the course of illness. Confirmatory testing of Ebola or Marburg hemorrhagic fever can be performed in Africa, at laboratories in Libreville, Gabon or in South Africa, or in the USA, at the CDC or USAMRIID. The same tests can also be performed in small mobile containment labs set up by international teams during outbreaks. Antiviral Therapy There is currently no approved therapy for filoviral hemorrhagic fever; treatment is supportive, based on maintenance of an adequate circulating blood volume until the immune system clears the infection. Experimental approaches that show promise for human use are described above. Prevention and control Good outbreak control relies on applying a package of interventions, including case management, surveillance and contact tracing, a good laboratory service, safe burials and social mobilisation. Community engagement is key to successfully controlling outbreaks. Raising awareness of risk factors for Ebola infection and protective measures (including vaccination) that individuals can take is an effective way to reduce human transmission. Risk reduction messaging should focus on several factors:

 Reducing the risk of wildlife-to-human transmission from contact with infected fruit bats, monkeys, apes, forest antelope or porcupines and the consumption of their raw meat. Animals should be handled with gloves and other appropriate protective clothing. Animal products (blood and meat) should be thoroughly cooked before consumption.

 Reducing the risk of human-to-human transmission from direct or close contact with people with Ebola symptoms, particularly with their bodily fluids. Gloves and appropriate personal protective equipment should be worn when taking care of ill patients. Regular hand washing is required after visiting patients in hospital, as well as after taking care of patients at home.

 Outbreak containment measures, including safe and dignified burial of the dead, identifying people who may have been in contact with someone infected with Ebola and monitoring their health for 21 days, the importance of separating the healthy from the sick to prevent further spread, and the importance of good hygiene and maintaining a clean environment.

 Reducing the risk of possible sexual transmission, WHO recommends that male survivors of EVD practice safer sex and hygiene for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus. Contact with body fluids should be avoided and washing with soap and water is recommended. WHO does not recommend isolation of male or female convalescent patients whose blood has been tested negative for Ebola virus.  Reducing the risk of transmission from pregnancy related fluids and tissue, Pregnant women who have survived Ebola disease need community support to enable them to attend frequent antenatal care (ANC) visits, to handle any pregnancy complications and meet their need for sexual and reproductive care and delivery in a safe way. This should be planned together with the Ebola and Obstetric health care expertise. Pregnant women should always be respected in the sexual and reproductive health choices they make.

LASSA FEVER Etiology. The arenaviruses are spherical, lipid-enveloped viruses that frequently entrap host ribosomes during their formation, giving them a “sandy” appearance on electron microscopy (the Latin word arena means “sand”). The genome consists of two ambisense RNA molecules, in which proteins are encoded in both directions on the same strand. The large (L) segment encodes the RNA- dependent RNA polymerase and a Z protein that is thought to link the nucleocapsid to the lipid membrane. The small (S) strand encodes a nucleoprotein, that encapsidates the genomic RNA, and two surface glycoproteins, G1 and G2. Epidemiology. The arenaviruses that cause hemorrhagic fever are divided into two groups: an “Old World” agent, Lassa virus, found in west Africa, and a number of “New World” viruses that cause severe disease in South America and the southwestern United States. Each agent is named after the location where it was first isolated. All of them are maintained in rodents, among which they spread through direct contact or excretions; none is transmitted by an arthropod vector. Humans become infected when they handle, butcher or eat the maintenance host or are exposed to its aerosolized urine or feces. Lassa is by far the most common type of arenavirus hemorrhagic fever. Serosurveys have suggested that as many as 100,000 people become infected each year in west Africa, principally in the three coastal countries of Liberia, Guinea and Sierra Leone, where the causative agent is maintained in multimammate rats. The high incidence of human infection reflects frequent contact with these animals, which infest living areas and are a source of food. Pathogenesis. As in other types of VHF, viral replication in Lassa fever is centered in monocytes, macrophages and dendritic cells, with the development of high levels of circulating virus in the bloodstream and spread to the liver and other body tissues, including the central nervous system. The prognosis at the time of hospital admission is strongly determined by the level of virus in the blood; patients with the highest levels are at greatest risk of death. The severity of hepatic involvement, as indicated by the serum aspartate aminotransferase level, also correlates with a fatal outcome. In contrast to Ebola and Marburg hemorrhagic fever, in which evidence of an adaptive immune response to the infecting pathogen is rarely detectable, a majority of Lassa fever patients have IgM antibodies to Lassa virus in their plasma at the time of hospital admission, and about half have IgG. Antibody and virus may co-circulate throughout the course of the illness, with no evident relationship to the eventual outcome. The induction of cell-mediated immunity appears to be a more important factor than the humoral response in controlling and eliminating viral replication. Clinical Manifestations. Outbreaks of the disease have occurred in west African hospitals when the lack of proper infection control measures has resulted in widespread contact with body fluids of patients or the re-use of contaminated syringes. Lassa fever has occasionally been diagnosed in travelers who have entered the United States or Europe, but no secondary transmission has occurred. Most cases of Lassa fever are asymptomatic or mild, but among patients sick enough to require hospitalization, the case fatality rate may be 15-20% or higher. In contrast to other types of VHF, Lassa fever usually develops gradually, after a 1-3 week incubation period. The syndrome includes fever, sore throat, headache and myalgias, which may progress to severe illness characterized by neurologic dysfunction and shock. Although hemorrhage may occur in severe cases, it is not a prominent part of the syndrome. Patients occasionally show signs of meningitis, and virus has been isolated from the cerebrospinal fluid. For unknown reasons, permanent deafness is a major complication of the disease. Laboratory Diagnosis Virus may be isolated from the blood throughout the course of Lassa fever, and it is also present in urine, pharyngeal secretions and other body fluids. Specific testing is based either on ELISA for viral antigens or RT-PCR. Antiviral Therapy Ribavirin has been accepted as an effective treatment of Lassa fever ever since a large study in Sierra Leone showed that patients treated with either the intravenous or the oral drug had a significantly better prognosis than an earlier series of patients with similar severity of illness who received no specific therapy. The fatality rate of cases with high viremia or significant liver involvement was reduced from roughly 50 to less than 20%. Treatment was most effective if begun within 6 days after the onset of illness. Vaccines. A number of experimental Lassa fever vaccines have been effective in laboratory rodents and nonhuman primates, but none has yet advanced to human clinical trials. Prevention. Control measures therefore focus on reducing exposure to the virus by eliminating the viral reservoir host, the multimammate mouse, from areas of human habitation.

8. Materials for activating students during a lecture:

1. What does the term International Health Regulations means? 2. Which are the criteria of public health emergencies of international concern (PHEIC)? 3. What is plague? 4. How is plague transmitted? 5. What are the signs and symptoms of plague? 6. Which lab studies are performed to screen for and diagnosis plague? 7. Which studies are used to determine the severity of organ complications caused by plague? 8. What are the treatment options for plague? 9. What is hemorrhagic fever (HF)? 10. What is yellow fever? 11. How is yellow fever transmitted? 12. What are the signs and symptoms of yellow fever? 13. Which studies are performed to screen for and diagnosis yellow fever? 14. What are the treatment options for yellow fever? 15. What is the etiology of Marburg and Ebola fevers? 16. How are Marburg and Ebola fevers transmitted? 17. What are the signs and symptoms of acute toxoplasmosis? 18. What are the signs and symptoms of Marburg and Ebola fevers? 19. How is the diagnosis of Marburg and Ebola fevers confirmed? 20. What are the treatment options for Marburg and Ebola fevers?

Task 1 The 55-year-old woman was admitted to the hospital on the 4th day of the illness, which began with high fever and headache. Consciousness is disturbed - sopor, skin and sclera jaundice. Numerous hemorrhages on the face, torso, extremities. Massive gastric and uterine bleeding. Body temperature 37.5 C. Breathing over the lungs is vesicular, isolated wet rales, BH 20 min. Heart tones are muted, heart rate 108 minutes, blood pressure 80/40 mm Hg. Abdomen mild, moderate hepatolienal syndrome. Oliguria. Relatives indicate that the patient returned from vacation 5 days before the illness. Traveled to the countries of equatorial Africa. In the blood sample: Erythrocytes - 3.1 x 10 12 / l, HB - 80 g / l, leukocytes - 2.3 x 109 / l, ESR - 24 mm / h, platelets - 80 thousand. protein - 125 g / l, ALT - 640, AST - 725, urea - 11.2 mmol / l, creatinine - 145 mmol / l. FDI - 52% 1. Preliminary diagnosis 2. Survey plan 3. Treatment Task 2 Patient K., 32 years old, doctor, hospitalized in the infectious department on the first day of illness with complaints of fever up to 40C, chills, headache, sharp chest pain with deep breathing, shortness of breath, cough with a large amount of foamy sputum . In the afternoon he returned from India, where he worked in a hospital during a business trip. Objective: the condition is extremely serious. Body temperature 41.4C, blood pressure 60/40 mm Hg. Art., Ps 130 per minute, BH 38 per minute. Breathing is shallow, rhythmic. Inhibited, does not answer questions. There is no rash on the skin, the face is hyperemic, scleritis. The cough is intense with a large amount of bloody sputum. Heart tones are sharply muffled. In the lungs breathing is weakened, many numerous wet rales over both lungs. Does not respond to palpation of the abdomen. Liver, spleen without features. Meningeal signs are absent. In the blood sample: L-20109 / l, Hb-98g / l, ESR-40 mm / h. 1. Preliminary diagnosis 2. Survey plan 3. Treatment

Test control. 1. The causative agent of plague is: A. Borellia reccurens. B. Yersenia pestis. C. Salmonella typhi. D. Leptospira interrorgans. E. Yersenia pseudotuberculosis.

2. Plague belongs to: A. Zoonoses. B. Anthroponoses. C. Sapronoses. D. Anthropozoonoses E. -

3. Etiotropic therapy for GH is carried out: A. metronidazole B. delagil C. albendazole D. ribavirin E. acyclovir

4. Plague buboes morphologically are: A. Regional lymph node with serous - hemorrhagic inflammation. B. Abscess at the site of primary affect. C. Unchanged lymph node. D. Purulent-necrotic inflammation E. Infectious and allergic inflammation

5. Clinical forms of plague: A. Bubonic B. Primary - pulmonary. C. Skin. D. Meningeal. E. Intestinal

6. The causative agent of yellow fever: A. flavivirus B. herpesvirus C. arbovirus D. rickettsia E. VG virus

7. Signs of internal bleeding complicated hemorrhagic fever (HF): A. bradycardia is replaced by tachycardia B. signs of encephalopathy are found C. falls blood pressure D. there are attacks of heart pain E. cyanosis progresses

8. The nature of the rash typical for yellow fever: A. vesicular B. hemorrhagic C. petechial D. papular E. pustular

9. The nature of the rash in Marburg fever, which appears at the end of the 1st week. diseases: A. papular B. vesicular C. roseolase D. pustular E. purpura

10. Pecularities of Ebola fever are following: A. gradual onset B. acute, sudden onset C. the hemorrhagic syndrome is expressed from the first days D. spotty-papular rash from the first day E. pancytopenia

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. Definition of vaccination. The mechanisms of the formation of post- vaccination immunity. 2. Characterization of vaccine preparations, their classification. 3. Calendar of vaccinations. Routine vaccinations by age. 4. Vaccination against tuberculosis. 5. Hepatitis B vaccination. 6. Vaccination against poliomyelitis. 7. Vaccination against diphtheria. 8. Measles vaccination. 9. Vaccination against whooping cough. 10. Rubella vaccination. 11. Mumps vaccination. 12. Hemophilus influenza vaccination.

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Clinical epidemiology and Immunoprophylaxis Topic Vaccine prophylaxis Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. There’s no question that immunization is one of the greatest success stories in global health, saving millions of lives every year from vaccine-preventable diseases. Every year more than 116 million, or 86% of all infants born are vaccinated – a number than has been holding firm for a decade.

Immunization is a global health and development success story, saving millions of lives every year. Vaccines reduce risks of getting a disease by working with your body’s natural defences to build protection. When you get a vaccine, your immune system responds.

We now have vaccines to prevent more than 20 life-threatening diseases, helping people of all ages live longer, healthier lives. Immunization currently prevents 2-3 million deaths every year from diseases like diphtheria, tetanus, pertussis, influenza and measles.

Immunization is a key component of primary health care and an indisputable human right. It’s also one of the best health investments money can buy. Vaccines are also critical to the prevention and control of infectious-disease outbreaks. They underpin global health security and will be a vital tool in the battle against antimicrobial resistance.

Yet despite tremendous progress, far too many people around the world – including nearly 20 million infants each year – have insufficient access to vaccines. In some countries, progress has stalled or even reversed, and there is a real risk that complacency will undermine past achievements.

Global vaccination coverage – the proportion of the world’s children who receive recommended vaccines – has remained the same over the past few years.

2. The educational goals of the lecture. Treat basic ideas about the specific prevention of infectious diseases. Classify drugs for the planned prevention of infectious diseases, means of application and methods of introducing immune preparations. Explain the vaccination technique. Draw up a vaccination plan for the vaccination calendar, provide emergency assistance in case of complications for vaccination.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies Autonomy and No. Competence Awareness Skill Communication responsibility methods of of communication communication communicative to ensure effective method. behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation Autonomy and No. Competence Awareness Skill Communication responsibility 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; Autonomy and No. Competence Awareness Skill Communication responsibility knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program Autonomy and No. Competence Awareness Skill Communication responsibility 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines Microbiology Types of immunity, vaccine strains of pathogens, their characteristics, the concept of vaccines and serums Infectious diseases Clinical manifestations of infectious diseases. Directions of the fight against infectious diseases, specific prevention. 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of See items 1 i 2 5% the relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan:

1. Definition of vaccination. The mechanisms of the formation of post- vaccination immunity. 2. Characterization of vaccine preparations, their classification. 3. Calendar of vaccinations. Routine vaccinations by age.

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture:

Measures to increase non-susceptibility of population. Non-susceptibility of population is increased by improving general non-specific resistance of population by improving the living and labour conditions, nutrition, physical training, health envigorating measures and by creating specific immunity through preventive vaccination. The ancients noted that people who had sustained many infectious diseases became non-susceptible to repeated infection with the same disease. In the Orient (China, India) they believed that if a person could sustain a mild form of an infection, it could protect him from dangerous diseases during epidemic outbursts. They protected themselves from smallpox by rubbing the content of smallpox lesions into the skin or ingested crusts (variolation), or put contaminated underwear of smallpox patients on healthy children, etc. In Europe, first attempts to create artificial non-susceptibility to infectious diseases were made in the 18th century. Variolation was practiced in England, Germany, Italy, France, Russia and some other countries. Samoilovich, for example, suggested that population could be immunized by the bubonic contents of plague patients. The discovery of the English physician Edward Jenner has become a turn point in the teaching of artificial immunity. In 1796, Jenner developed a process of producing immunity to smallpox by inoculation with cowpox vaccine. Louis Pasteur produced a live vaccine against anthrax by attenuating the causative agents at high temperature. His principle was used successfully by other investigators who also manufactured live vaccines. Virulence of tuberculosis bacteria has thus been decreased by multiple cultivation of the starting culture on bile-potato media. Most effective proved the method of controlled variability of microbes and selection of low-virulence and highly immunogenic strains. Artificial active immunity is now induced by vaccines (from Latin vacca, cow and vaccina, cowpox); the method is known as vaccination. The following preparations are used to prevent infectious diseases: live vaccines prepared from attenuated non-pathogenic microorganisms or viruses; inactivated vaccines prepared from inactive cultures of pathogenic microorganisms causing infectious diseases; chemical vaccines (antigens), isolated from microorganisms by various chemical methods; toxoids, prepared by treating toxins (the poisons produced by microorganisms causing infectious diseases) with formaldehyde. Vaccines can produce immunity against a given infectious disease or can be polyvalent, i. e., effective against several infectious diseases. Adsorbed vaccines are popular. Aluminium hydroxide is used as an adsorbent. Adsorbed vaccines induce active durable immunity in the vaccinated macroorganism by creating a depot at the site of administration of the antigen, which is slowly absorbed. Kinds of immunopreparates Live vaccines are used to create specific immunity against poliomyelitis, measles, influenza, tuberculosis, brucellosis, plague, tularaemia, anthrax, Q fever, skin leishmaniasis, epidemic parotitis, and some other diseases. Live vaccines prepared from attenuated vaccine strains of microorganisms are more effective than inactivated chemical vaccines. Immunity induced by live vaccines is about the same as produced by normal infection. Live vaccines are given in a single dose intracutaneously, subcutaneously, per os, into the nose or by scarification. The disadvantage of live vaccines is that they should be stored and transported at a temperature not exceeding 4-8 °C. Inactivated vaccines are prepared from highly virulent strains with adequate antigen properties. They are used to prevent typhoid fever, paratyphoid, cholera, influenza, pertussis, tick- borne encephalitis, and some other diseases. Depending on the microorganism species, various methods are used to inactivate them. The microorganisms can be treated with formaldehyde, acetone, alcohol, merthiolate, or at high temperature. Efficacy of inactivated vaccines is lower than that of live vaccines although there are some highly effective inactivated vaccines as well. Inactivated vaccines are injected subcutaneously. Adsorbed vaccines are given intramuscularly. Inactivated vaccines are more stable in storage. They can be kept at temperatures from 2 to 10 °C. Chemical vaccines are more active immunologically. These are specific antigens extracted chemically from microbial cells. Adsorbed chemical vaccines are used for active immunization against typhoid fever, paratyphoid and other diseases. Toxoids are formaldehyde-treated exotoxins of the microorganisms causing diphtheria, tetanus, cholera, botulism, and other diseases. Diphtheria and tetanus toxoid is used in the adsorbed form. Toxoids are highly efficacious. When administered into a macroorganism, the vaccine induces an active immunity against a particular infection. Live vaccines produce an immunity that lasts from 6 months to 5 years. Duration of immunity produced by inactivated vaccines is from a few months to a year. Immune sera and their active fractions (mainly immunoglobulins) induce passive immunity. Immune sera and immunoglobulins are prepared from blood of hyperimmune animals and from people who have sustained a particular disease or have been immunized otherwise. Passive immunization is used for urgent prophylaxis of people who are infected or supposed to be infected, and also for treatment of the corresponding infectious disease. The effect of immune sera and immunoglobulins lasts from 3 to 4 weeks. They are given intramuscularly. Bacteriophages are used to prevent and treat some infectious diseases. Bacteriophages are strictly specific toward separate species and even types of bacteria. The preparations can be given parenterally (percutaneously, intracutaneously, subcutaneously, intramuscularly, intravenously) or enterally (per os), intranasally or by inhalation (aerosols). When giving vaccines parenterally, it is necessary to observe sterile conditions and to adhere to the rules specified for injection of a particular vaccine. Jet injections are widely used now: the preparations are administered into the skin, subcutaneously and intramuscularly using various syringes. When given in the liquid state or in tablets, the vaccine should be taken together with water. Live vaccines are usually given in a single dose, while inactivated vaccines are given in two or three doses at intervals from 7 to 10 or from 30 to 45 days. Revaccination is used to maintain immunity induced by previous vaccination. The terms of revaccination depend on a particular disease and vary from several months to 5 years. Efficacy of immunization depends largely on regularity of revaccination performed in due time with adequate doses. Quality of the vaccine, and the condition of its storage and transportation are also important. When selecting persons for immunization, contraindications should be considered. Individual contraindications depend on the route of vaccination, the presence of concurrent diseases, the stage of recovery, previous vaccinations, and the like. Vaccination should be performed by a physician or secondary medical personnel after thorough examination of persons to be vaccinated in order to reveal possible contraindications, the presence of allergic reactions to medicines, food, etc. The main contraindications to prophylactic vaccination are as follows: (1) acute fever; concurrent diseases attended by fever; (2) recently sustained infections; (3) chronic diseases such as tuberculosis, heart diseases, severe diseases of the kidneys, liver, stomach or other internal organs; (4) second half of pregnancy; (5) first nursing period; (6) allergic diseases and states (bronchial asthma, hypersensitivity to some foods, and the like). Complication of immunization. Vaccination can induce various reactions. These can be malaise, fever, nausea, vomiting, headache and other general symptoms; a local reaction can develop: inflammation at the site of injection (hyperaemia, oedema, infiltration, regional lymphadenitis). Pathology can also develop in response to vaccination; such pathologies are regarded as postvaccination complications. They are divided into the following groups: (1) complications developing secondary to vaccination; (2) complications due to aseptic conditions of vaccination; (3) exacerbation of a pre-existing disease. Prevention of postvaccination complications includes: strict observation of aseptic vaccination conditions, adherence to the schedule of vaccination, timely treatment of pathological states (anaemia, rickets, skin diseases, etc.), timely revealing of contraindications to vaccination, and screening out the sick or asthenic persons. All cases with severe reactions to vaccination should be reported to higher authorities. If vaccination is performed by scarification, the results are not always positive, and the vaccine must therefore be tested. The results of vaccination should be assessed at various terms, depending on a particular disease against which a person is vaccinated. The result of vaccination against, e. g. anthrax, should be assessed in 2-3 days. Vaccination should be performed according to a predetermined plan, or for special epidemiologic indications. Planned vaccination is performed against tuberculosis, diphtheria, tetanus, pertussis, poliomyelitis, measles, epidemic parotitis, and against some other infections within the confinement of separate districts or population groups, regardless of the presence or absence of a given disease. Vaccination for special epidemiologic indications are performed in the presence of direct danger of spreading of a particular infection. Vaccination reports must be compiled and special entries made in histories. The results of vaccination (efficacy of vaccination) are assessed by comparing morbidity rates among the vaccinated and non-vaccinated groups of population. The number of the diseased and severity of cases must be assessed (agglutination test, complement fixation test, test for allergy). Sanitary and epidemiologic posts and stations must supervise the work of vaccination posts. Each country has its own calendar of vaccinations, which are caused by the spread of infectious diseases and the availability of specific prophylaxis. Table 1: Summary of WHO Position Papers - Recommended Routine Immunizations for all Children

In order to assist programme managers develop optimal immunization schedules WHO has compiled key information on its current routine immunization recommendations intо table (Table 1). Table 2. Routine Immunizations in Ukraine *

At the first 18 months 2-18 years Infectious 1 3-5 1 2 4 6 12 18 6 7 14 16 adults disease day day month month month month month month years years years years Hepatitis B 1d 2d 3d Tuberculosis 1d R Measles, mumps, 1d 2d rubella Every Diphtheria, 1d 2d 3d 1R 2R 3R 10 tetanus years Pertussis 1d 2d 3d 1R Polio 1d 2d 3d 1R 2R 3R HiB 1d 2d 1R *- Order MPH of Ukraine № 2070 from 11.10.2019. 1d-the first dose of vaccine; 2d- second dose of vaccine; 3 – third dose of vaccine; R- revaccination; 1R- the first revaccination, 2R-second revaccination.

Hepatitis B Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease. It is a major global health problem, and the most serious type of viral hepatitis. It is estimated that about 780,000 people die each year due to consequences of hepatitis B, such as liver cirrhosis and liver cancer. The virus is highly contagious and is transmitted through contact with the blood or other body fluids of an infected person. Hepatitis B virus can survive outside the body for at least 7 days, and is an important occupational hazard for health workers. Hepatitis B is preventable with currently available safe and effective vaccines. WHO recommends that all infants should receive their first dose of vaccine as soon as possible after birth, preferably within 24 hours. Delivery of hepatitis B vaccine within 24 hours of birth should be a performance indicator for all immunization programmes. The birth dose should be followed by 2 or 3 doses to complete the primary series. There is no evidence to support the need for a booster dose of hepatitis B vaccine. Protection lasts at least 20 years, and is possibly life-long.

Tuberculosis Tuberculosis (TB) is a disease that is caused by a bacterium, which resulted in estimated 10.4 million new cases in 2016 and 1.7 million deaths. Over 90% of TB cases occur in low and middle income countries that have fragile healthcare infrastructures and constrained resources available, and therefore struggle to tackle one of the world’s deadliest communicable diseases. The bacterium responsible for TB, called Mycobacterium tuberculosis (Mtb), is transmitted by people infected with pulmonary (lung) TB who release Mtb into the air through coughing, sneezing or spitting. Approximately 1/3 of the world’s population carry the disease but don’t have any symptoms (known as latent infection), however approximately 10% of these people will likely develop active disease during their lifetime and become capable of transmitting the bacterium. The TB epidemic continues in spite of an available, cost-effective and broadly implemented vaccine for infants – Bacille Calmette-Guerin (BCG) – and the carefully managed use of drugs for those who do become infected through directly observed therapy (DOTs). This is because BCG vaccination is only partially effective: it provides some protection against severe forms of pediatric non-pulmonary TB, such as TB meningitis, but is unreliable against adult pulmonary TB, which accounts for most of the TB disease burden (and transmission) worldwide. In addition, infection with Human Immunodeficiency Virus (HIV) infection can increase the likelihood of TB acquisition by up to 25-fold, and resistance to previously effective TB drug regimens is increasing. WHO continues to recommend the vaccination of neonates with BCG, due to its protective effect in infants and young children. However, children infected with HIV through vertical transmission from their HIV-infected mother are at risk of developing severe vaccine-related disease. Therefore, children known to be HIV infected should not be vaccinated with BCG.

Diphtheria Diphtheria is an infectious disease caused by the bacterium Corynebacterium diphtheria, which primarily infects the throat and upper airways, and produces a toxin affecting other organs. The illness has an acute onset and the main characteristics are sore throat, low fever and swollen glands in the neck, and the toxin may, in severe cases, cause myocarditis or peripheral neuropathy. The diphtheria toxin causes a membrane of dead tissue to build up over the throat and tonsils, making breathing and swallowing difficult. The disease is spread through direct physical contact or from breathing in the aerosolized secretions from coughs or sneezes of infected individuals. Vaccination against diphtheria has reduced the mortality and morbidity of diphtheria dramatically, however diphtheria is still a significant child health problem in countries with poor EPI coverage. In countries endemic for diphtheria, the disease occurs mostly as sporadic cases or in small outbreaks. Diphtheria is fatal in 5 - 10% of cases, with a higher mortality rate in young children. Treatment involves administering diphtheria antitoxin to neutralize the effects of the toxin, as well as antibiotics to kill the bacteria. Diphtheria vaccine is a bacterial toxoid, ie. a toxin whose toxicity has been inactivated. The vaccine is normally given in combination with other vaccines as DTwP/DTaP vaccine or pentavalent vaccine. For adolescents and adults the diphtheria toxoid is frequently combined with tetanus toxoid in lower concentration (Td vaccine). WHO recommends a 3-dose primary vaccination series with diphtheria containing vaccine followed by 3 booster doses. The primary series should begin as early as 6-week of age with subsequent doses given with a minimum interval of 4 weeks between doses. The 3 booster doses should preferably be given during the second year of life (12-23 months), at 4-7 years and at 9-15 years of age. Ideally, there should be at least 4 years between booster doses.  To further promote immunity against diphtheria, combined diphtheria and tetanus toxoid vaccine (Td or TD) should be used rather than tetanus toxoid alone. This can be used in pregnancy as well as following injuries.

Tetanus Tetanus can be prevented through immunization with tetanus-toxoid-containing vaccines (TTCV), which are included in routine immunization programmes globally and administered during antenatal care contacts. To be protected throughout life, WHO recommends that an individual receives 6 doses (3 primary plus 3 booster doses) of TTCV. The 3-dose primary series should begin as early as 6 weeks of age, with subsequent doses given with a minimum interval of 4 weeks between doses. The 3 booster doses should preferably be given during the second year of life (12–23 months), at 4–7 years of age, and at 9–15 years of age. Ideally, there should be at least 4 years between booster doses. There are many kinds of vaccines used to protect against tetanus:  Diphtheria and tetanus (DT) vaccines

 Diphtheria, tetanus, and pertussis (whooping cough) (DTaP) vaccines

 Tetanus and diphtheria (Td) vaccines

 Tetanus, diphtheria, and pertussis (Tdap) vaccines Neonatal tetanus can be prevented by immunizing women of reproductive age with TTCV, either during pregnancy or outside of pregnancy. Additionally, robust medical practices can also prevent tetanus disease including clean delivery and cord care during childbirth, and proper wound care for surgical and dental procedures.

Poliomyelitis Polio (poliomyelitis) is a highly infectious . The poliovirus invades the nervous system and can cause irreversible paralysis in a matter of hours. Polio is spread through person- to-person contact. When a child is infected with wild poliovirus, the virus enters the body through the mouth and multiplies in the intestine. It is then shed into the environment through the faeces where it can spread rapidly through a community, especially in situations of poor hygiene and sanitation. If a sufficient number of children are fully immunized against polio, the virus is unable to find susceptible children to infect, and dies out. Most infected people (90%) have no symptoms or very mild symptoms and usually go unrecognized. In others, initial symptoms include fever, fatigue, headache, vomiting, stiffness in the neck and pain in the limbs. There is no cure for polio, only treatment to alleviate the symptoms. Heat and physical therapy is used to stimulate the muscles and antispasmodic drugs are given to relax the muscles. While this can improve mobility, it cannot reverse permanent polio paralysis. There are 3 types of wild poliovirus (WPV) - types 1, 2 and 3. In September 2015, WPV type 2 was officially declared eradicated. Since WPV type 3 has not been detected since November 2012, WPV type 1 is probably the only wild poliovirus type that remains in circulation. Polio can be prevented through immunization. Polio vaccine, given multiple times, almost always protects a child for life. The development of effective vaccines to prevent paralytic polio was one of the major medical breakthroughs of the 20th century. There are six different vaccines to stop polio transmission:  Inactivated polio vaccine (IPV) – protects against poliovirus types 1, 2, and 3

 Trivalent oral polio vaccine (tOPV) – protects against poliovirus types 1, 2, and 3 - following the "OPV Switch" in April 2016, tOPV is no longer in use

 Bivalent oral polio vaccine (bOPV) – protects against poliovirus types 1, and 3

 Monovalent oral polio vaccines (mOPV1, mOPV2 and mOPV3) – protect against each individual type of poliovirus, respectively If enough people in a community are immunized, the virus will be deprived of susceptible hosts and will die out. High levels of vaccination coverage must be maintained to stop transmission and prevent outbreaks occurring.

Pertussis Pertussis, also known as whooping cough, is a highly contagious respiratory infection caused by the bacterium Bordetella pertussis. In 2018, there were more than 151 000 cases of pertussis globally. Pertussis spreads easily from person to person mainly through droplets produced by coughing or sneezing. The disease is most dangerous in infants, and is a significant cause of disease and death in this age group. The first symptoms generally appear 7 to 10 days after infection. They include a mild fever, runny nose and cough, which in typical cases gradually develops into a hacking cough followed by whooping (hence the common name of whooping cough). Pneumonia is a relatively common complication, and seizures and brain disease occur rarely. People with pertussis are most contagious up to about 3 weeks after the cough begins, and many children who contract the infection have coughing spells that last 4 to 8 weeks. Antibiotics are used to treat the infection.

Haemophilus influenzae type b (Hib) Haemophilus influenza type b (Hib) is a bacteria responsible for severe pneumonia, meningitis and other invasive diseases almost exclusively in children aged less than 5 years. It is transmitted through the respiratory tract from infected to susceptible individuals. Hib also causes potentially severe inflammatory infections of the face, mouth, blood, epiglottis, joints, heart, bones, peritoneum, and trachea. Although this problem occurs worldwide the burden of Hib disease was considerably higher in resource-poor countries, prior to the introduction of the vaccine into their national immunization programmes. Vaccines are the only public health tool capable of preventing the majority of serious Hib disease. Hib vaccines are safe and efficacious even when administered in early infancy. In view of their demonstrated safety and efficacy, WHO recommends that Hib conjugate vaccines to be included in all routine infant immunization programmes.

Measles Measles is a highly contagious viral disease. It remains an important cause of death among young children globally, despite the availability of a safe and effective vaccine. Under the Global Vaccine Action Plan, measles and rubella are targeted for elimination in five WHO Regions by 2020. WHO is the lead technical agency responsible for coordination of immunization and surveillance activities supporting all countries to achieve this goal. Measles is transmitted via droplets from the nose, mouth or throat of infected persons. Initial symptoms, which usually appear 10–12 days after infection, include high fever, a runny nose, bloodshot eyes, and tiny white spots on the inside of the mouth. Several days later, a rash develops, starting on the face and upper neck and gradually spreading downwards. Severe measles is more likely among poorly nourished young children, especially those with insufficient vitamin A, or whose immune systems have been weakened by HIV/AIDS or other diseases. The most serious complications include blindness, encephalitis (an infection that causes brain swelling), severe diarrhoea and related dehydration, and severe respiratory infections such as pneumonia. Routine measles vaccination for children, combined with mass immunization campaigns in countries with low routine coverage, are key public health strategies to reduce global measles deaths. While vaccination has drastically reduced global measles deaths — a 73% drop between 2000-2018 worldwide — measles is still common in many developing countries, particularly in parts of Africa and Asia. More than 140,000 people died from measles in 2018. The overwhelming majority (more than 95%) of measles deaths occur in countries with low per capita incomes and weak health infrastructures. The measles vaccine has been in use since the 1960s. It is safe, effective and inexpensive. WHO recommends immunization for all susceptible children and adults for whom measles vaccination is not contraindicated. Reaching all children with 2 doses of measles vaccine, either alone, or in a measles-rubella (MR), measles-mumps-rubella (MMR), or measles-mumps-rubella- varicella (MMRV) combination, should be the standard for all national immunization programmes.

Rubella Under the Global Vaccine Action Plan, measles and rubella are targeted for elimination in 5 WHO Regions by 2020. WHO is the lead technical agency responsible for coordination of immunization and surveillance activities supporting all countries to achieve this goal. Transmitted in airborne droplets when infected people sneeze or cough, rubella is an acute, usually mild viral disease traditionally affecting susceptible children and young adults worldwide. Rubella infection just before conception and in early pregnancy may result in miscarriage, foetal death or congenital defects known as congenital rubella syndrome (CRS). The highest risk of CRS is found in countries with high rates of susceptibility to rubella among women of childbearing age. In 1996, an estimated 22 000 babies were born with CRS in Africa, an estimated 46 000 in South-East Asia and close to 13 000 in the Western Pacific. Very few countries in these regions had introduced rubella-containing vaccine by the year 2008, and therefore the current burden of CRS in these settings is thought to be similar to that estimated for 1996. Rubella vaccines are available either in monovalent formulation or in combinations with other vaccine viruses, as rubella-containing vaccines (RCVs). Commonly used RCVs are combinations with vaccines against measles (MR), measles and mumps (MMR), or measles, mumps and varicella (MMRV). Large-scale rubella vaccination during the last decade has drastically reduced or practically eliminated rubella and CRS in many developed and in some developing countries. Indeed, the western hemisphere and several European countries have eliminated rubella and CRS. WHO recommends that countries take the opportunity of accelerated measles control and elimination activities to introduce rubella-containing vaccines. All countries that have not yet introduced rubella vaccine, and are providing two doses of measles vaccine using routine immunization and/or supplementary immunization activities should consider the inclusion of RCV in their immunization programme.

Mumps Mumps is an infection caused by a virus and spread human-to-human via direct contact or by airborne droplets. It is sometimes called infectious parotitis, and it primarily affects the salivary glands. Initial symptoms are typically non-specific, such as headache, malaise and fever, followed within a day by the characteristic swelling of the parotid (salivary) glands. Mumps is generally a mild childhood disease, most often affecting children between five and nine years old. However, the mumps virus can infect adults as well and when it does, possible complications are more likely to be serious. Complications of mumps can include meningitis (in up to 15% of cases), orchitis and deafness. Very rarely, mumps can cause encephalitis and permanent neurological damage. Safe and effective vaccines against mumps have been available since the 1960s. The vaccine is most often incorporated into national immunization programmes in a combined measles-mumps-rubella (MMR) vaccine. In countries where large-scale immunization against mumps has been implemented, the incidence of the disease has dropped dramatically. WHO recommends integrating strategies to control mumps with existing high priority goals of measles and rubella control or elimination. Once the decision has been made to include mumps vaccine, the use of combined MMR vaccine is strongly encouraged. Pneumococcal disease Streptococcus pneumoniae is a bacterium that is the cause of a number of common diseases, ranging from serious diseases such as meningitis, septicaemia and pneumonia to milder but commoner infections such as sinusitis and otitis media. Pneumococcal diseases are a common cause of morbidity and mortality worldwide, though rates of disease and death are higher in developing countries than in industrialized country settings, with the majority of deaths occurring in sub-Saharan Africa and Asia. Disease is most common at the extremes of age, i.e, in young children and among the elderly. The organism is transmitted mainly through respiratory droplets and colonizes the back of the nose (nasopharynx). Infection of other parts of the body, resulting in disease, occur through direct spread or through invasion of the blood stream. Out of over 90 serotypes, only a small minority cause most disease. There are 2 available pneumococcal conjugate vaccines (PCV) that target either 10 or 13 of the most prevalent serotypes. Currently available PCVs are safe and efficacious. WHO recommends the inclusion of PCVs in childhood immunization programmes worldwide. In particular, countries with high childhood mortality (i.e. under 5 mortality rate of >50 deaths/1000 births) should make the introduction of these multicomponent PCVs a high priority. In many countries, the routine use of pneumococcal conjugate vaccines has dramatically reduced the incidence of serious diseases due to the organism with virtual disappearance of disease due to serotypes of the organism in the vaccines used. Rotavirus Rotaviruses are the most common cause of severe diarrhoeal disease in young children throughout the world. According to WHO estimates in 2013 about 215 000 children aged under 5 years die each year from vaccine-preventable rotavirus infections; the vast majority of these children live in low-income countries. Four oral, live, attenuated rotavirus vaccines, Rotarix™ (derived from a single common strain of human rotavirus); RotaTeq™ (a reassorted bovine-human rotavirus); Rotavac™ (naturally occurring bovine-human reassortant neonatal G9P, also called 116E); and RotaSiil™ (bovine-human reassortant with human G1, G2, G3 and G4 bovine UK G6P[5] backbone) are available internationally and WHO prequalified. All four vaccines are considered highly effective in preventing severe gastrointestinal disease. In low income countries, vaccine efficacy can be lower than in industrialized settings, similar to other live oral vaccines. Even with this lower efficacy, a greater reduction in absolute numbers of severe gastroenteritis and death was seen, due to the higher background rotavirus disease incidence. WHO recommends that rotavirus vaccines should be included in all national immunization programmes and considered a priority particularly in countries in South and Southeast Asia and sub-Saharan Africa. WHO continues to recommend that the first dose of rotavirus vaccine be administered as soon as possible after 6 weeks of age, along with DTP vaccination. Apart from a low risk of intussusception (up to 6 per 100 000 infants vaccinated)1 the current rotavirus vaccines are considered safe and well tolerated. Human papillomavirus (HPV) Human papillomavirus (HPV) causes cervical cancer, which is the fourth most common cancer in women, with an estimated 266,000 deaths and 528,000 new cases in 2012. A large majority (around 85%) of the global burden occurs in the less developed regions, where it accounts for almost 12% of all female cancers. Although most infections with HPV cause no symptoms, persistent genital HPV infection can cause cervical cancer in women. Virtually all cervical cancer cases (99%) are linked to genital infection with HPV and it is the most common viral infection of the reproductive tract. HPV can also cause other types of anogenital cancer, head and neck cancers, and genital warts in both men and women. HPV infections are transmitted through sexual contact. Three HPV vaccines are now being marketed in many countries throughout the world - a bivalent, a quadrivalent, and a nonavalent vaccine. All three vaccines are highly efficacious in preventing infection with virus types 16 and 18, which are together responsible for approximately 70% of cervical cancer cases globally. The vaccines are also highly efficacious in preventing precancerous cervical lesions caused by these virus types. The quadrivalent vaccine is also highly efficacious in preventing anogenital warts, a common genital disease which is virtually always caused by infection with HPV types 6 and 11. The nonavalent provides additional protection against HPV types 31, 33, 45, 52 and 58. Data from clinical trials and initial post-marketing surveillance conducted in several continents show all three vaccines to be safe. The primary target group in most of the countries recommending HPV vaccination is young adolescent girls, aged 9-14. For all three vaccines, the vaccination schedule depends on the age of the vaccine recipient.

 Females <15 years="" at="" the="" time="" of="" first=""> a 2-dose schedule (0, 6 months) is recommended.

o If the interval between doses is shorter than 5 months, then a third dose should be given at least 6 months after the first dose.

 Females ≥15 years at the time of first dose: a 3-dose schedule (0, 2, 6 months) is recommended. NB: A 3-dose schedule remains necessary for those known to be immunocompromised and/or HIV-infected. .

Given the possible development of anaphylactic shock (usually in the first 15 minutes), after vaccination provide observation for 30 minutes. Vaccination sites should be provided with anti- shock therapy. The main criterion when deciding on contraindications for the introduction of a specific vaccine is a list of contraindications, as defined in the instructions for its use. Routine vaccinations with the vaccine, toxoid are postponed until the end of the acute manifestations of the disease and exacerbation of chronic diseases and are carried out after recovery or in the period of remission of the chronic disease.

8. Materials for activating students during a lecture: 4. Definition of vaccination. The mechanisms of the formation of post- vaccination immunity. 5. Characterization of vaccine preparations, their classification. 6. Calendar of vaccinations. Routine vaccinations by age. 7. Vaccination against tuberculosis. 8. Hepatitis B vaccination. 9. Vaccination against poliomyelitis. 10. Vaccination against diphtheria. 11. Measles vaccination. 12. Vaccination against whooping cough. 13. Rubella vaccination. 14. Mumps vaccination. 15. Hemophilus influenza vaccination.

Task 1 A mother with an 8-year-old child came to the doctor's office for an appointment. During a clinical examination, the child was diagnosed with measles. The child is isolated at home during the illness, treatment is prescribed. In addition, it was revealed that the child had not been revaccinated against tuberculosis. What is the doctor’s tactics regarding BCG revaccination and its timing? Answer: 4 weeks after the measles disease, a Mantoux test is necessary. If the test result is negative, carry out BCG revaccination (3 days after the test, but no later than 2 weeks). Task 2 How to solve the issue of vaccinating a child 5 months. If the child 1 month. and therefore moved to the outpatient service area and does not have any vaccination documents? On the child’s left shoulder there is a scar after BCG vaccination 0.5 cm in d. According to my mother, BCG vaccination was carried out in the hospital, she does not know about other vaccinations. Answer: The child needs vaccination with DTP and polio vaccine in full (three times with an interval of 1 month). Test control. 1. Vaccination is the creation of an immunological layer among the population using: A. live, inactivated, chemical vaccines, toxoids and immunoglobulins; B. live, inactivated and chemical vaccines and toxoids; C. toxoids; D. live and inactivated vaccines; E. immunoglobulins. 2. A possible way to gain active natural immunity: A. vaccine administration; B. administration of immunoglobulin; C. after the illness; D. administration of toxoid; E. all answers are correct. 3. Passive artificial immunity is formed after the introduction of: A. toxoids; B. serums; C. live vaccines; D. inactivated vaccines; E. recombinant vaccines. 4. Live vaccines consist of: A. microorganisms with preserved virulence. B. inactivated microorganisms; C. inactivated toxins of microorganisms; D. pathogens with impaired reproduction function; E. microorganisms with no virulence. 5. Recombinant vaccines include: A. hepatitis B vaccine; B. tuberculosis vaccine; C. polio vaccine; D. measles vaccine; E. mumps vaccine. 6. Live vaccines include: A. hepatitis B vaccine; B. tetanus vaccine; C. tuberculosis vaccine; D. diphtheria vaccine; E. pertussis vaccine. 7. To toxins belongs: A. tuberculosis vaccine; B. hepatitis B vaccine; C. pertussis vaccine; D. diphtheria vaccine; E. measles vaccine. 8. Anatoxins are: A. antibodies to exotoxins of microorganisms; B. toxins of microorganisms deprived of their toxigenicity; C. inactivated microorganisms; D. recombinant vaccines; E. all answers are correct. 9. Who needs routine measles vaccination if children have not previously had measles and are not vaccinated against measles? A. 1 year old child vaccinated from month therefore, DTP vaccine; B. a child of 1 year 2 months. who was ill with otitis media; C. a child 1 year 2 months., who had been ill with chickenpox in 2 months. . 10. Which of the listed individuals with a negative Mantoux reaction can be revaccinated against tuberculosis? A. adolescent 15 years after viral hepatitis B 3 months. B. a teenager of 15 years who had been ill with chickenpox for 2 months. C. child 7 years old from a cell of scarlet fever; D. a 7-year-old child revaccinated with ADS-M toxoid at 2 months; E. 7-year-old child revaccinated with polio vaccine in 3 months.

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture 1. What does the term Health care–associated infections (HAIs) mean? 2. Which elements does transmission of infection within a health care setting require? 3. Which common routes of transmission microorganisms are spread to others through? 4. Disinfection: types and methods. 5. The main disinfectants approved for use in medical facilities of the dental profile. 6. Pre-sterilization treatment: types and methods. Storage requirements for sterile material. 7. The basics of sterilization: types and methods of sterilization. Operating modes of sterilizers. 8. Quality control of pre-sterilization treatment. Methods of placing samples on the remnants of detergents and hidden blood. 9. Quality control of sterilization.

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval

Ministry of Public Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the department Infection diseases and epidemiology «28» August 2019 protocol № 1 from «28» August 2019 the Head of the Department ______Koval T.I.

Methodical Instruction for lectures

Study discipline Infectious diseases Module № Clinical epidemiology and Immunoprophylaxis Topic Health Care–Associated Infections. Infection control system Course 5 Faculty Foreign students (Medical) Number of teaching hours: 2

Poltava -2019

1. Scientific and methodological substantiation of the topic. The occurrence and undesirable complications from health care–associated infections (HAIs) have been well recognized in the literature for the last several decades. The occurrence of HAIs continues to escalate at an alarming rate. HAIs originally referred to those infections associated with admission in an acute-care hospital (formerly called a nosocomial infection), but the term now applies to infections acquired in the continuum of settings where persons receive health care (e.g., long-term care, home care, ambulatory care). These unanticipated infections develop during the course of health care treatment and result in significant patient illnesses and deaths (morbidity and mortality); prolong the duration of hospital stays; and necessitate additional diagnostic and therapeutic interventions, which generate added costs to those already incurred by the patient’s underlying disease. HAIs are considered an undesirable outcome, and as some are preventable, they are considered an indicator of the quality of patient care, an adverse event, and a patient safety issue.

Health care-associated infections (HAIs) are infections people get while they're receiving health care for another condition. HAIs can happen in any health care facility, including hospitals, ambulatory surgical centers, end-stage renal disease facilities, and long-term care facilities. Bacteria, fungi, viruses, or other, less common pathogens can cause HAIs.

HAIs are a significant cause of illness and death — and they can have serious emotional, financial, and medical consequences. At any given time, about 1 in 25 inpatients have an infection related to hospital care. These infections lead to tens of thousands of deaths and cost the U.S. health care system billions of dollars each year.

2. The educational goals of the lecture. To analyze the idea of disinfection, pre-sterilization cleaning and sterilization of medical instruments. To classify the main disinfectants that are approved for use in medical institutions, the treatment regimen for medical instruments: types and methods of disinfection, quality control of sterilization processing and sterilization. Explain the organization and conduct of disinfection and sterilization of medical instruments, preparation of disinfectants, master the methods of conducting azopyramic and phenolphthalein samples, determination of the indication of contamination of medical instruments.

3. The goals of the personality development of the future specialist (educational goals), relevant aspects: deontological, environmental, legal, professional responsibility, psychological, ethical, patriotic, etc.

4. Learning outcomes: Autonomy and No. Competence Awareness Skill Communication responsibility Integral Competency 1. Ability to solve typical and complex specialized tasks and practical problems in professional activities in the field of healthcare or in the learning process, which involves research and / or innovation and is characterized by the complexity and uncertainty of conditions and requirements. General competencies 1. Ability for abstract To know the To be able to To establish To be responsible thinking, analysis and methods of analyze appropriate for the timely synthesis. analysis, synthesis information, make links to achieve acquisition of and further informed goals. modern knowledge. modern learning decisions, be able to acquire modern knowledge 2. Ability to learn and master To know current To be able to To establish To be responsible modern knowledge. industry trends analyze appropriate for the timely and analyze them professional links to achieve acquisition of information, make goals. modern knowledge. informed decisions, acquire modern knowledge 3. Ability to apply knowledge To have To be able to solve Clear and Responsible for in practical situations specialized complex issues and unambiguous decision making in conceptual problems arising in reporting of difficult conditions knowledge professional their own acquired in the activities. conclusions, learning process. knowledge and explanations that substantiate them, to specialists and non-specialists. 4. Knowledge and To have deep To be able to carry The ability to To be responsible understanding of the knowledge of the out professional effectively for development, subject area and structure of activities that formulate a the ability to further understanding of professional require updating communication professional professional activities activity. and integration of strategy in training with a high knowledge. professional level of autonomy. activities 5. Ability to adapt and act in a To know the types To be able to use To establish To be responsible new situation. and methods of means of self- appropriate for the timely use of adaptation, the regulation, to be relationships to self-regulation principles of able to adapt to achieve results. methods. action in a new new situations situation (circumstances) of life and activity. 6. Ability to make informed To know the To be able to make To use To be responsible decisions tactics and an informed communication for the choice and communication decision, choose strategies and tactics of the strategy, laws and ways and strategies interpersonal communication methods of of communication skills method. communicative to ensure effective behavior teamwork Autonomy and No. Competence Awareness Skill Communication responsibility

7. Able to work in a team To know the To be able to make To use To be responsible environment tactics and an informed communication for the choice and communication decision, choose strategies tactics of the strategy, laws and ways and strategies communication methods of of communication method. communicative to ensure effective behavior teamwork 8. Interpersonal To know the laws To be able to To use To be responsible communication skills and methods of choose methods interpersonal for the choice and interpersonal and strategies for communication tactics of the communication interpersonal skills communication communication method. 9. Ability to communicate in To have perfect To be able to apply To use the To be responsible the state language both knowledge of the knowledge of the official for fluency in the orally and in writing. state language state language, language in state language, for both orally and in professional and the development of writing business professional communication knowledge. and in the preparation of documents. 10. Ability to communicate in To have basic To be able to To use a foreign To be responsible a foreign language knowledge of a communicate in a language in for the foreign language foreign language. professional development of activities professional knowledge using a foreign language. 11. Skills to exploit To have in-depth To be able to use To use To be responsible information and knowledge in the information and information and for the communication technology field of communication communication development of information and technologies in the technologies in professional communication professional professional knowledge and technologies used industry, which activities skills. in professional requires updating activities and integration of knowledge. 12. Certainty and perseverance To know the To be able to To establish Responsible for the regarding tasks and responsibilities determine goals interpersonal quality responsibilities and ways to and objectives, to relationships to performance of accomplish tasks be persistent and effectively assigned tasks conscientious in complete tasks the performance of and duties responsibilities 13. Ability to act responsibly To know your To form your civic Ability to Responsible for and consciously in the social and civil consciousness, to convey your civic position and social dimension rights and be able to act in social and social activities responsibilities accordance with it position 14. The pursuit of To know the To be able to To submit To be responsible environmental problems of formulate proposals to for the conservation. environmental requirements for relevant implementation of conservation and yourself and others authorities and environmental how to preserve regarding the issue institutions on protection environment of environmental measures to measures within conservation preserve and own competence. Autonomy and No. Competence Awareness Skill Communication responsibility protect the environment 15. Ability to plan and manage To know the To be able to To establish To be responsible time principles of consistently carry appropriate for the appropriate planning, to know out the actions in relationships to procedure and the requirements accordance with achieve results. timing of actions for the timing of the requirements an action for the timing of their implementation 16. Ability to act ethically To know the To be able to apply Ability to To be responsible basics of ethics ethical and convey their for the and deontology deontological professional implementation of norms and position to ethical and principles in patients, deontological professional members of norms and activities their families, principles in colleagues professional activities Special (professional) competencies 1. Skills of interrogation1 and To have To be able to To form a To be responsible . clinical examination of the specialized conduct a communication for the quality patient knowledge about conversation with strategy when collection of the human body, the patient; communicating information its organs and physical with the patient received on the systems, to know examination, effectively. To basis of an the standard palpation, enter interview, survey, patterns of percussion, information examination and questioning and auscultation based about the state for a timely physical on algorithms and of human health assessment of the examination of standards. in medical patient’s general the patient. records health

2. Ability to 2determine the To have To be able to To formulate To be responsible . necessary list of laboratory specialized analyze the results and convey to for making and instrumental studies knowledge about of laboratory and the patient and decisions regarding and evaluate their results the human body, instrumental specialists the evaluation of its organs and studies and on conclusions laboratory and systems, standard their basis to regarding the instrumental methods for evaluate necessary studies. conducting information about list of laboratory and the patient's laboratory and instrumental condition instrumental studies defined by studies. the program. 3. Ability to 3conduct To have To be able to To formulate Responsible for . differential diagnosis knowledge of the conduct and convey to timely and correct clinical differential the patient and diagnosis. manifestations of diagnosis between specialists the various diseases infectious and results of other diseases differential diagnosis 4. Ability to 4establish a To have To be able to Based on Following ethical . diagnosis of the disease specialized conduct a physical regulatory and legal standards, knowledge about examination of the documents, to to be responsible Autonomy and No. Competence Awareness Skill Communication responsibility the human body, patient; be able to keep medical for making its organs and make an informed records of the informed decisions systems, standard decision regarding patient and actions examination the definition of a (inpatient card, regarding the techniques; leading clinical etc.). correctness of the disease diagnosis symptom or established algorithms; syndrome; be able diagnosis of the algorithms for to prescribe a disease determining laboratory and leading symptoms instrumental and syndromes; examination of the laboratory and patient by using instrumental standard methods examination methods; knowledge regarding the assessment of human condition. 5. Ability to 5prescribe To have To be able to To formulate To be responsible . treatment specialized choose the and convey to for the timeliness knowledge necessary complex the patient and and correctness of regarding of therapeutic specialists the the choice of algorithms and measures, appropriate treatment program treatment depending on the complex of for the patient schemes for clinical form of the treatment for infectious disease the patient. To diseases be able to record prescribtions in medical records 6. Ability to 6diagnose of To have To be able, in Under any To be responsible . emergency conditions specialized conditions of lack circumstances, for the timeliness knowledge about of information, adhering to the and effectiveness of the human body, using standard relevant ethical medical measures its organs and methods, by and legal regarding the systems, to know making an standards, to diagnosis of the standard informed decision make an emergency techniques for to assess a informed conditions physical person’s condition decision examination of and the need for regarding the the patient. emergency care assessment of the condition of a person and the organization of necessary medical measures, depending on the condition of the person 7. Skills of emergency7 To have To be able to To explain the To be responsible . medical care specialized provide emergency need and for the timeliness knowledge about medical care in procedure for and quality of the human body, case of emergency conducting emergency medical its organs and emergency care Autonomy and No. Competence Awareness Skill Communication responsibility systems, the medical algorithm for treatment providing measures emergency medical care in case of emergency 8. Skills of medical8 To have To be able to To formulate To be responsible . manipulation specialized perform medical and convey for the quality of knowledge about manipulations conclusions to medical procedures the human body, provided by the the patient and its organs and program specialists about systems; the need for knowledge of medical medical procedures manipulation algorithms provided by the program 9. Ability to 9keep medical To know the To be able to To otain the To be responsible . records system of official determine the necessary for the workflow in the source and location information completeness and professional work of the necessary from a specific quality of the of medical information source and, analysis of personnel, depending on its based on its information and including modern type; be able to analysis, to conclusions based computer process form relevant on its analysis. information information and conclusions technologies analyze the information received 10. Ability to 1conduct To know the To have skills in To know the To be responsible 0. sanitary-hygienic and system of organizing the principles of for the timely and preventive measures sanitary-hygienic sanitary-hygienic presenting high-quality and preventive and medical- information implementation of measures when protective regime about the measures to ensure working with of the main units sanitary- the sanitary- patients with of medical hygienic hygienic and infectious institutions. To be condition of the medical-protective diseases. able to organize premises and regime of the main To know the the promotion of a compliance units of medical principles and healthy lifestyle. with the institutions, methods of hospital-wide promoting a promoting a and medical- healthy lifestyle; healthy lifestyle protective regimes; to use lectures and interviews. 5. Interdisciplinary integration. Names of previous Acquired skills disciplines 1. Microbiology Know the general microbiological and immunological characteristics of pathogens of infectious diseases; be able to analyze the results of microbiological studies, summarize them. 2. Social Know the epidemiological research methods; be able to analyze infectious diseases. medicine 3. Infectious Know the clinical manifestations, features of the course, laboratory diagnosis and prevention of infectious diseases. To be able to isolate the diseases sources of infection, to prescribe primary anti-epidemic measures in the foci. 6. Plan and organizational structure of the lecture

№ The main stages of the lecture and Type of lecture. Time distribution their content Means of activating students. Materials of methodological support Time distribution 1. Preparatory stage. Determination of the See items 1 i 2 5% relevance of the topic, educational objectives of the lecture and motivation 2. Main stage Thematic lecture. 85 %-90% The presentation of the lecture material according to the plan:

1. The concept of care–associated infections (HAIs). 2. Patient Risk Factors for Health Care–Associated Infections 3. Prevention and control of infectious diseases 4. Disinfection measures

1. Final stage Educational literature. 5 % 2. General lecture summary and Tasks, questions. conclusions. 3. Answers to possible questions. Self-study assignments students 7. The content of the lecture: Health care–associated infections (HAIs) were defined as those that develop during hospitalization but are neither present nor incubating upon the patient’s admission to the hospital; generally for those infections that occur more than 48 to 72 hours after admission and within 10 days after hospital discharge. Some hospitals use these definitions exactly as written; other hospitals may use some but not all of the CDC definitions; and other health care facilities may need to modify or develop their own definitions. Whatever definition is used, it should be consistent within the institution and be the same or similar to those developed by CDC or those used by other investigators. Having standard definitions is useful if the health care facility wants to compare surveillance results or performance measures within its various medical/surgical specialties, against those of other health care institutions, or with national published data. Patient Risk Factors for Health Care–Associated Infections Transmission of infection within a health care setting requires three elements: a source of infecting microorganisms, a susceptible host, and a means of transmission for the microorganism to the host. Source of Microorganisms During the delivery of health care, patients can be exposed to a variety of exogenous microorganisms (bacteria, viruses, fungi, and protozoa) from other patients, health care personnel, or visitors. Other reservoirs include the patient’s endogenous flora (e.g., residual bacteria residing on the patient’s skin, mucous membranes, gastrointestinal tract, or respiratory tract) which may be difficult to suppress and inanimate environmental surfaces or objects that have become contaminated (e.g., patient room touch surfaces, equipment, medications). Host Susceptibility Patients have varying susceptibility to develop an infection after exposure to a pathogenic organism. Some people have innate protective mechanisms and will never develop symptomatic disease because they can resist increasing microbial growth or have immunity to specific microbial virulence properties. Others exposed to the same microorganism may establish a commensal relationship and retain the organisms as an asymptomatic carrier (colonization) or develop an active disease process. Intrinsic risk factors predispose patients to HAIs. The higher likelihood of infection is reflected in vulnerable patients who are immunocompromised because of age (neonate, elderly), underlying diseases, severity of illness, immunosuppressive medications, or medical/surgical treatments. Patients with alterations in cellular immune function, cellular phagocytosis, or humoral immune response are at increased risk of infection and the ability to combat infection. A person with a primary immunodeficiency (e.g., anemia or autoimmune disease) is likely to have frequently recurring infections or more severe infections, such as recurrent pneumonia.21 Secondary immunodeficiencies (e.g., chemotherapy, corticosteroids, diabetes, leukemia) increase patient susceptibility to infection from common, less virulent , opportunistic fungi, and viruses. Considering the severity of a patient’s illness in combination with multiple risk factors, it is not unexpected that the highest infection rates are in ICU patients. HAI rates in adult and pediatric ICUs are approximately three times higher than elsewhere in hospitals.22 Extrinsic risk factors include surgical or other invasive procedures, diagnostic or therapeutic interventions (e.g., invasive devices, implanted foreign bodies, organ transplantations, immunosuppressive medications), and personnel exposures. According to one review article, at least 90 percent of infections were associated with invasive devices.23 Invasive medical devices bypass the normal defense mechanism of the skin or mucous membranes and provide foci where pathogens can flourish, internally shielded from the patient’s immune defenses. In addition to providing a portal of entry for microbial colonization or infection, these devices also facilitate transfer of pathogens from one part of the patient’s body to another, from health care worker to patient, or from patient to health care worker to patient. Infection risk associated with these extrinsic factors can be decreased with the knowledge and application of evidence-based infection control practices. Prolonged hospitalization, due to a higher acuity of illness, contributes to host susceptibility as there is more opportunity to utilize invasive devices and more time for exposure to exogenous microorganisms. These patients are also more susceptible to rapid microbial colonization as a consequence of the severity of the underlying disease, depending on the function of host defenses and the presence of risk factors (e.g., age, extrinsic devices, extended length of stay). Exposure to these colonizing microorganisms is from such sources as (1) endemic pathogens from an endogenous source, (2) hospital flora in the health care environment, and (3) hands of health care workers. A study related to length of hospitalization examining adverse events in medical care indicated that the likelihood of experiencing an adverse event increased approximately 6 percent for each day of hospital stay. The highest proportion of adverse events (29.3 percent) was not related to surgical procedures but linked instead to the subsequent monitoring and daily care lacking proper antisepsis steps.24 Means of Transmission Among patients and health care personnel, microorganisms are spread to others through four common routes of transmission: contact (direct and indirect), respiratory droplets, airborne spread, and common vehicle. Contact transmission This is the most important and frequent mode of transmission in the health care setting. Organisms are transferred through direct contact between an infected or colonized patient and a susceptible health care worker or another person. Patient organisms can be transiently transferred to the intact skin of a health care worker (not causing infection) and then transferred to a susceptible patient who develops an infection from that organism—this demonstrates an indirect contact route of transmission from one patient to another. An infected patient touching and contaminating a doorknob, which is subsequently touched by a health care worker and carried to another patient, is another example of indirect contact. Microorganisms that can be spread by contact include those associated with impetigo, abscess, diarrheal diseases, scabies, and antibiotic-resistant organisms (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]). Respiratory droplets Droplet-size body fluids containing microorganisms can be generated during coughing, sneezing, talking, suctioning, and bronchoscopy. They are propelled a short distance before settling quickly onto a surface. They can cause infection by being deposited directly onto a susceptible person’s mucosal surface (e.g., conjunctivae, mouth, or nose) or onto nearby environmental surfaces, which can then be touched by a susceptible person who autoinoculates their own mucosal surface. Examples of diseases where microorganisms can be spread by droplet transmission are pharyngitis, meningitis, and pneumonia. Airborne spread When small-particle-size microorganisms (e.g., tubercle bacilli, varicella, and rubeola virus) remain suspended in the air for long periods of time, they can spread to other people. The CDC has described an approach to reduce transmission of microorganisms through airborne spread in its Guideline for Isolation Precautions in Hospitals.25 Proper use of personal protective equipment (e.g., gloves, masks, gowns), aseptic technique, hand hygiene, and environmental infection control measures are primary methods to protect the patient from transmission of microorganisms from another patient and from the health care worker. Personal protective equipment also protects the health care worker from exposure to microorganisms in the health care setting. Common Vehicle Common vehicle (common source) transmission applies when multiple people are exposed to and become ill from a common inanimate vehicle of contaminated food, water, medications, solutions, devices, or equipment. Bacteria can multiply in a common vehicle but viral replication can not occur. Examples include improperly processed food items that become contaminated with bacteria, waterborne shigellosis, bacteremia resulting from use of intravenous fluids contaminated with a gram- negative organism, contaminated multi-dose medication vials, or contaminated bronchoscopes. Common vehicle transmission is likely associated with a unique outbreak setting and will not be discussed further in this document.

The IPC global unit will lead WHO’s work on IPC and will work collaboratively with related units in SDS, in particular the Patient Safety & Quality unit and the newly created unit dealing with Quality Universal Health Coverage, as well as with other related departments and units at the three levels of WHO. Given that unsafe health care practices related to injections include the re-use of injection equipment, the over-use of injections for certain health conditions, accidental needle-stick injuries in health workers, and unsafe management of sharps waste, WHO is committed to promoting safe injection practices. This work supports a key recommendation to Member States to switch to the exclusive use of reuse-prevention syringes (RUPs) for all injections by 2020. WHO also recommends syringes with sharp injury protection (SIPs) features. The IPC global unit will deliver its work based on five main functions:  Leadership, connecting and coordinating  Campaigns and advocacy  Technical guidance and implementation  Capacity-building  Measuring and learning.  Prevention and control of infectious diseases include the following: (1) mass-scale measures aimed at improvement of public health, prevention and spread of infectious diseases; (2) medical measures aimed at reduction of infectious morbidity and eradication of some diseases; (3) health education and involvement of population in prevention or restriction of the spread of infectious diseases; (4) prevention of import of infectious diseases from other countries. Improvement of peoples' well-being, adequate housing, medical aid, and health education should be adequately planned and carried out. Preventive sanitary supervision is also necessary. Industrial objects, residential houses, children's and medical institutions should be constructed with strict adherence to the special sanitary require-ments that are intended to improve labour and living conditions, prevention of onset and spread of infectious diseases. Preventive measures aimed to control infectious diseases taken by medical personnel are divided into preventive and anti- epidemic. Preventive measures are carried out regardless of the presence or absence of infectious diseases at a given time and locality. These measures are aimed at prevention of infectious diseases. Anti-epidemic measures are necessary when an infectious disease develops. It has already been said that the following three basic factors are necessary for development of an epidemic: the source of infection, transmission mechanism, and susceptibility of population. Exclusion of any of these factors terminates the spread of an epidemic process. Prophylactic and antiepidemic measures are therefore aimed at control of the source of infection, disruption of the route by which infection spreads, and strengthening of non-susceptibility of population. DISINFECTION MEASURES The subject matter of disinfection are methods and means of control (or eradication) of the causative agents of infection in various objects and substrates of the environment, and also means of accomplishment of these means and measures. Disinfection measures includes three concepts: (1) disinfection proper; (2) disinsection (control of the arthropods transmitting infections); (3) deratization (rodent control). Depending on the mechanism of infection transmission, it may be necessary to perform disinfection alone (respiratory infections); disinfection and disinsection (intestinal infections); disinsection (louse-borne fever, malaria); disinfection, disinsection and rodent control (plague). Besides, sterilization is also used. Sterilization implies complete eradication of pathogenic and non-pathogenic microorganisms (spores included) in the environment. Sterilization is used for treatment of surgical, gynaecological, stomatological and other fools, apparatuses, dressing materials, linen, needles, syringes, etc. Nutrient media, laboratory ware, tools and instruments are sterilized in microbiology. Before sterilization, all objects are first disinfected and cleaned with detergents, hydrogen peroxide and similar solutions. Several disinfection methods are known. Glass, metal, thermally stable polymers and rubber articles can be sterilized by boiling for 30 minutes, by treatment in special sterilizers at a temperature of 110 + 2°C and elevated pressure of steam. Special sterilization units must be provided for regular sterilization of tools, instruments and other materials. DISINFECTION Disinfection describes a process that eliminates many or all pathogenic microorganisms, except bacterial spores, on inanimate objects. In health-care settings, objects usually are disinfected by liquid chemicals or wet pasteurization. Each of the various factors that affect the efficacy of disinfection can nullify or limit the efficacy of the process. Disinfection includes focal and preventive disinfection. Focal disinfection is necessary if infection develops in a family, children’s institution, or any other public institution. It implies current and final disinfection. Current disinfection includes regular disinfection measures taken during the entire period of presence of a patient or a carrier in a given enclosure. The object of current disinfection is to prevent the spread of the infection. If, for some reason, the patient is not hospitalized, he must be isolated in a separate room or his bed screened from the other family. Only indispensable objects may be left in the room where the patient remains. The patient must use a separate towel, dishes, bed-pan and the like. In intestinal infections, excrements of the patient (urine, faeces, vomitus) must be mixed with l/5th volume of dry lime chloride, or the excrements should be poured over with two volumes of a 10-20 per cent lime chloride solution or a 5 per cent chloramines or chlor solution. The room must be cleaned 2 or 3 times a day using a moist cloth and aired properly. A 2 per cent soap-soda or 0.2 per cent chloramines solution should be used for the purpose. The concentration of chloramines solution depends on the sensitivity of the pathogenic microbes to disinfectants. Glass ware and dishes used by the patient should be boiled for 15 minutes. Disinfection should be done by a person who takes care of the patient (after being properly instructed) or medical personnel. Final disinfection is carried out in the focus of those infections whose causative agents are stable in the environment (typhoid fever, viral hepatitis, cholera, diphtheria, poliomyelitis, plague, etc.). Final disinfection in the focus of paratyphoid and quarantine infection should be performed simultaneously with evacuation of the patient. In the focus of other infection, disinfection should be done not later than in 6 hours (in towns and cities) or 12 hours (in rural areas) after evacuation of the patient. In addition to disinfection, disinsection should also be carried out in foci of intestinal infections (flies should be destroyed). This measure should be taken after hospitalization of the patient, after his recovery or death (if the patient remained at home). Final disinfection is also necessary after discharge of the patient from the hospital, after removal of the diseased from children’s or other institution. Final disinfection should be performed by representatives of a sanitary-epidemiologic post or station. As soon as the disinfection brigade has arrived at the site of disinfection, the scope of work must be determined and a solution of required concentration prepared. If flies are found in the enclosure, disinsection should be performed after the windows and the doors are closed tightly. After disinsection has been performed, the window can be opened, and the patient’s belongings (linen, clothes, carpets, toys) are put into special bags for disinfection in special chambers. Disinfection should be done in the following order: objects that were used for care of the patient, and his excrements are disinfected first, then follows disinfection of remaining food, linen, toys, pieces of furniture. After decontamination of all objects in the room, the floor and the walls are sprayed with the disinfectant in the room of the patient and the adjacent premises. In 30-50 minutes, the rooms are treated with a disinfect ant solution. Depending on pathogenicity of the causative agent, disinfection can be done by the family themselves after being properly instructed by the medical personnel. Preventive disinfection is necessary in all cases regardless of the presence or absence of infectious diseases in a given district or area. Examples of preventive disinfection are daily cleaning at medical institutions, hospitals, schools and other children’s institutions, public establishments using a 0.5 per cent chloramines solution. Pasteurization of milk, chlorination of water, washing hands before meals, and the like are also preventive disinfection measures.

Methods of desinfection Thorough cleaning and drying will remove most organisms from a surface and should always precede disinfection and sterilisation procedures. Cleaning is normally accomplished by the use of water, mechanical action and detergents. It may be manual or mechanical, using ultrasonic cleaners or washer/disinfectors that may facilitate cleaning and decontamination of some items and reduce the need for handling. A. Manual Cleaning All items requiring disinfection or sterilisation should be dismantled before cleaning. Cold water is preferred for cleaning as it will remove most of the protein materials (blood, sputum, etc.) that would be coagulated by heat or disinfectants and would subsequently be difficult to remove. The most simple, cost effective method is to thoroughly brush the item, keeping the brush below the surface of the water to prevent the release of aerosols. The brush should be decontaminated after use and dried. Rinse items finally in clean, warm water and dry. Items are then ready for use or disinfection or sterilisation. Personnel handling contaminated items should wear good quality gloves for personal protection. Additional recommendations have recently been published: Association for the Advancement of Medical Instrumentation (AAMI) suggests initial rinse in cold water followed by warm water/detergent solution and final rinse. JHPIEGO, an agency that is usually involved in very resource-poor settings, suggests soaking instruments and other soiled materials in cold water with bleach to 0.5% to decontaminate, followed by cold water wash and rinse. B. Environmental cleaning Floors, surfaces, sinks and drains should be cleaned with water and detergent. Routine use of disinfectants is unnecessary. If there is spillage, e.g. blood, sputum, although cleaning is preferred, disinfection before cleaning is sometimes recommended. Clean/wipe wearing gloves using 0.5-1% sodium hypochlorite (5,000-10,000 ppm of Cl2 ) (household bleach) or a disinfectant with appropriate activity. Gloves should be worn. Release of chlorine gas from disinfection of large spillage can be hazardous to staff. If spillage is immediately removed, general disinfection of the room is not necessary; thorough cleaning will suffice. C. Disinfection Disinfection can be carried out by either thermal or chemical processes. Thermal disinfection is preferred whenever possible. It is generally more reliable than chemical processes, leaves no residues, is more easily controlled and is non-toxic. Organic matter (serum, blood, pus or faecal material) interferes with the antimicrobial efficiency of either method. The larger the numbers of microbes present the longer it takes to disinfect. Thus scrupulous cleaning before disinfection is of the greatest importance.

Thermal and physical methods Although not necessary for disinfection, autoclaving or steam sterilization (or a pressure cooker) may be preferred if available for the decontamination of certain items, e.g. vaginal speculae. Moist heat at 70-100°C 1. Boiling (100°C) for at least 5 minutes (holding time) is a simple and very reliable method for the inactivation of microorganisms including hepatitis B virus, human immunodeficiency virus and mycobacteria. Provided it is carefully carried out, it is a high-level disinfection procedure. The items should be thoroughly cleaned, placed in a container and covered with water. The water is heated until it reaches boiling point. Disinfection should be timed (at least 5 min) from when boiling commences. Addition of a 2% solution of sodium bicarbonate helps to prevent corrosion of the instruments and utensils. If cheatle forceps are used these should be boiled (or autoclaved) with the holder at least daily and stored dry. The boiler should be emptied and dried daily. 2. Disinfection at lower temperatures is possible (e.g. 80°C for 5 min) for items damaged by boiling, if suitable temperature controlling equipment is available. 3.Disinfection by hot water can also be performed in specially constructed washing machines e.g. for linen, bedpans, dishes and cutlery, respiratory circuits, laboratory glassware and used surgical instruments before autoclaving. In these machines the process of cleaning, hot water disinfection and drying are combined in a very effective procedure, providing some items ready for use, e.g. respiratory circuits, or safe to handle e.g. surgical instruments. The thorough initial rinsing and washing removes most of the microorganisms and shorter disinfection times may be appropriate, e.g. 70°C for 3 min, 80°C for 1 minute. If machines are used they should be regularly maintained and checked for efficacy. Low to high level disinfection is achieved depending on type of machine and complexity of the items. 4.U-V lamps are used to disinfect air in enclosures (in hospitals, children's institutions, in food industry, etc.). If people are present in the enclosure, the radiation must be directed only into the upper or lower layers of air. Direct sun rays kill many pathogenic microbes. This simple method must be utilized as much as possible.

Chemical Methods Before deciding to use a disinfectant, consider whether a more appropriate method is available. The main use of chemical disinfection is for heat-labile equipment where single use is not cost effective. Some of these items (e.g. bronchoscopes) require high-level disinfection. A limited number of disinfectants (e.g. glutaraldehyde 2%, 6% hydrogen peroxide, 0.2-0.3% peracetic acid) can be used for this purpose. If a sporicidal action is required, immersion in 2% glutaraldehyde for at least 3 hours is required. Chemical disinfectants must be made up freshly to the correct concentrations according to the manufactures' instructions and discarded after the correct period of time or number of uses. They should be stored in clean bottles with plastic stoppers. When the bottle is empty it should be thoroughly cleaned before re-filling. Partially empty bottles should not be topped up since this will encourage contamination with and multiplication of disinfectant resistant organisms. The object must be thoroughly rinsed with sterile water after disinfection. If sterile water is not available, freshly boiled water can be used. After rinsing, items must be kept dry and well protected from being recontaminated. Disinfection of surfaces Soiled surfaces may be cleaned of visible soilage and disinfected with a chemical agent suitable for the task. On a clean surface alcohol is rapidly bactericidal and rinsing is not required.

STERILISATION Sterilization describes a process that destroys or eliminates all forms of microbial life and is carried out in health-care facilities by physical or chemical methods. Steam under pressure, dry heat, EtO gas, hydrogen peroxide gas plasma, and liquid chemicals are the principal sterilizing agents used in health-care facilities. Sterilization is intended to convey an absolute meaning; unfortunately, however, some health professionals and the technical and commercial literature refer to “disinfection” as “sterilization” and items as “partially sterile.” When chemicals are used to destroy all forms of microbiologic life, they can be called chemical sterilants. These same germicides used for shorter exposure periods also can be part of the disinfection process (i.e., high-level disinfection). Sterilization is accomplished principally by steam under pressure (autoclaving), dry heat, by ethylene oxide gas or low temperature steam and formaldehyde. 1. Steam Sterilization is the most common and preferred method employed for sterilisation of all items that penetrate the skin and mucosa, providing they are not damaged by heat and moisture. Steam sterilisation is dependable, non toxic, inexpensive, sporicidal, with rapid heating and good penetration of fabrics. Method: The steam must be applied for a specified time so that the items reach a specified temperature: a)120°C for 20 min for unwrapped items, 30 minutes for packaged items at 1.036 Bar (15.03psi) above atmospheric pressure. b)132°C for 40 min for unwrapped items in a gravity sterilizer or wrapped items in a vacuum assisted steriliser at 2.026 Bar (29.41 psi) above atmospheric pressure. As a possible alternative for unwrapped instruments or utensils, a domestic pressure cooker may be used. Holding time at least 30 min. 2. Dry heat is preferred for reusable glass syringes, and ointments, powders, oils etc. Method A hot air oven equipped with fan or conveyor, which will ensure even distribution of heat. The recommended temperature and time for sterilisation of medical equipment is as follows: a)160°C for 2 hours b)180°C for 1 hour Sterile items should be protected against recontamination. 3.Ethylene oxide gas is used for low temperature sterilisation of selected items in hospitals. Ethylene oxide gas is toxic so the manufacturers' instructions for installation and use should be followed. There are four parameters that must be maintained to ensure EO sterilisation: gas concentration, temperature, humidity, and exposure time. Gas concentration should be 450 to 1200 mg/L, temperature ranges 29° to 65° C, humidity from 45% to 85%, and exposure times from two to five hours. The process has a long cycle as aeration of the items is required. Microbiological control of the process is recommended.

Organisation of Physical Facilities in a Sterile Service Department The service should be managed by a suitably qualified individual. All staff should be trained and undergo continuous professional development. Written protocols for all procedures should be maintained and there should be an audited programme of quality assurance. The central processing areas should consist of decontamination, packaging, sterilisation and storage areas. Decontamination Receive materials, sort, clean and preferably disinfect. Wear appropriate gloves and plastic aprons. Gown sleeves that are fluid-resistant are desirable as are surgical face masks and eye protection. Packaging Assembling. i.e. oiling (milking) and packaging clean but unsterile materials prior to sterilisation. Label accurately with contents, date of processing and expire date Sterilization Process Autoclaving is preferred. Any sterilisation procedure should be monitored routinely by physical (mechanical), chemical and biological techniques. Mechanical techniques include the daily assessment of cycle time, temperature and pressure gauge. A log book should be kept. Change of colour of chemical indicators placed on the outside of each pack shows that the pack has been exposed to the sterilisation process. Similarly, chemical indicators should be used inside the pack to verify steam penetration efficiency in addition to physical measurements. The Bowie/Dick test in 134° C vacuum-assisted autoclaving is recommended daily before the sterilizer is used. Biological indicators (BI) of Geobacillus stearothermophilus spores are used to monitor steam and dry heat sterilisation processes in some countries, while Bacillus atrophaeus spores are used for monitoring ethylene oxide. Biological indicators should be placed in a process control device or test pack that is representative of the load to be sterilized. AAMI recommends that steam autoclaves be tested with BI at least weekly and with every load of implantable devices and that implantables be quarantined until the BI is read. AAMI recommends that every ethylene oxide load be monitored with BI. AAMI also recommends BIs used when sterilizers are installed, after major repairs, malfunctions or sterilizer failures. Storage Ensure stock rotation and store dry. Sterile items should be protected against recontamination.

8. Materials for activating students during a lecture: 1. What does the term Health care–associated infections (HAIs) mean? 2. Which elements does transmission of infection within a health care setting require? 3. Which common routes of transmission microorganisms are spread to others through? 4. Disinfection: types and methods. 5. The main disinfectants approved for use in medical facilities of the dental profile. 6. Pre-sterilization treatment: types and methods. Storage requirements for sterile material. 7. The basics of sterilization: types and methods of sterilization. Operating modes of sterilizers. 8. Quality control of pre-sterilization treatment. Methods of placing samples on the remnants of detergents and hidden blood. 9. Quality control of sterilization.

Task 1 The hot air sterilization was condacted. Syringes packed in kraft bags are sterilized. Sterilization mode: 180 degrees - 60 minutes. Acetic acid is used as a control. Did the nurse make mistakes at work? Sample answer. Yes. Sucrose, IS 180, etc. are used to control the sterilization mode in a dry heat oven. Task 2 The nurse conducts sterilization of dental instruments in a dry-heat cabinet in an open container. Sterilization mode: 160 degrees - 60 minutes. Is the sterilization performed correctly? Sample answer. In a dry heat cabinet, sterilization in an open container can be carried out. But the sterilization regime is insufficient. It takes 180 degrees 60 minutes. Test control. 1. The complete destruction of microbes, spores and viruses is called: A. disinfection B. sterilization C. disinsection D. deratization E. all mentioned

2. The sterilization time of instruments in 6% hydrogen peroxide solution at room temperature is (in min): A. 360 B. 180 C. 90 D. 60. E. No right answer

3. Daily wet cleaning in the wards is carried out: A. 4 times B. 3 times C. 2 times D. 1 time E. every 3 hours

4. Exposure during disinfection in 5% chloramine solution of objects with which the tuberculosis patient came into contact (in minutes): A. 240 B. 180 C. 90 D. 60 E. 120

5. Treatment of the skin upon contact with HIV-infected material is carried out: A. 96 degrees alcohol B. 70 deg. alcohol C. 6% hydrogen peroxide solution D. 3% hydrogen peroxide solution E. 3% chloramine solution

6. Cleaning of chambers in case of anaerobic infection is carried out: A. 3% chloramine solution B. 3% bleach solution C. 3% hydrogen peroxide solution D. 6% hydrogen peroxide solution with E. 0.5% detergent solution

7. Air sterilization mode: A. 180 deg. 60 minutes B. 160 deg. 60 minutes C. 120 degrees 60 minutes D. 110 deg. 60 minutes E. 180 deg 30 minutes

8. A positive azopyram occult blood test gives staining: A. green B. pink C. red D. violet (blue-violet) E. black

9. The duration of the preservation of medical instruments in kraft packages (in hours) A. 72 B. 48 C. 24 D. 12 E. 9

10. The duration of use of a covered sterile table (in hours): A. 24 B. 18 C. 12 D. 6 E. 72

9. Materials for self-training of students for a lecture: - on the topic outlined in the lecture (see paragraph 8) - on the topic of the next lecture

LITERATURE

BASIC

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases E-Book: 2- Volume Set/ by John E. Bennett (Author), Raphael Dolin (Author), Martin J. Blaser (Author). – Elsevier; 9 edition, 2019. – 4176 p.

2. Comprehensive Review of Infectious Diseases/ by Andrej Spec (Author), Gerome V. Escota (Author), Courtney Chrisler (Author), Bethany Davies (Author). - Elsevier; 1 edition, 2019. – 776 p.

3. Harrison's Infectious Diseases, Third Edition (Harrison's Specialty)/ by Dennis L. Kasper (Author), Anthony S. Fauci (Author). - McGraw-Hill Education / Medical; 3 edition, 2016. – 1328 p.

4. Infectious Diseases: textbook / O.A. Holubovska, M.A. Andreichyn, A.V. Shkurba et al.; edited by O.A. Holubovska. — Kyiv: AUS Medicine Publishing, 2018. — 664 p. + 12 p. colour insert.

ADDITIONAL

1. Infectious Diseases in Context Set / by Brenda Wilmoth Lerner (Editor), Adrienne Wilmoth Lerner (Editor). – Gale Research Inc; 1 edition, 2007 – 1078 р. 2. Human Emerging and Re-emerging Infections / by Sunit K. Singh (Editor). - Wiley- Blackwell; 1 edition, 2015. – 1008 p. 3. Essentials of Clinical Infectious Diseases/ by MPH Wright, William F., DO (Editor). - Demos Medical; 2 edition, 2018 – 485 p.

INFORMATIONAL RESOURCES

1. Сайт МОЗ України: www.moz.gov.ua 2. Сайт ВООЗ: www.who.int 3. Centers for Disease Control and Prevention (Центр з контролю та профілактики захворювань, США): http://www.cdc.gov/

Methodical instruction is prepared by V.A. Bodnar ______O. H. Marchenko ______

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2019, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2020, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2021, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2022, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2023, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2024, Protocol No. ______Head of the Department T. I. Koval

Approved at a meeting of the Department of Infectious Diseases and Epidemiology «___» ______2025, Protocol No. ______Head of the Department T. I. Koval