Differential diagnosis of

Infectious Diseases Department 2021 The fever is the earliest and the most constant sign of almost all infectious diseases. It is also considered as defensive mechanism of body.

Definition

The fever is thermoregulatory increase of body temperature, which corresponds to organism’s regulated response to disease. It means that the body increases it’s temperature above normal itself. The pyrogens are substances that entering to body from outside or being synthesized inside body cause fever

Depending on origin they can be: – exogenic (bacterial and non bacterial) – endogenic (leucocytar) The mechanism of action can be: – primary – secondary Classification of fever of unknown origin (FUO) by Petersdorf-Bisson (algorithm of diagnostic search)

I. Confirming the presence of FUO criteria a. description of fever (type of increase, height, duration, type of curve, presence and time of organic involvement, influence of drugs etc. ) b. exclusion of acute specific infections, with the exception of HIV infection and TB II. Searching causes of FUO

a. HIV infection b. TB c. non specific infections: – urological (kidney abscesses or carbuncle) – genital infections – subdiaphragmal or subhepatic abscesses – osteomyelitis – cholangitis (torpid course, empyma of gallbldder) – appendicitis – infective (acute and subacute) – surgical sepsis – small pelvic phlebitis – chronic tonsillitis fg: Lymphoma, arm&rus variant with other termsIII. Excluding non-infectious diseases

1.tumors

2. systemic diseases of connective tissue Exclusion of rare causes of FUO

• recurrent thrombosis of small branches of pulmonary arteries • thireoiditis • FMF • fever caused by drugs (fever without chills, sweats, appears no later than 2-nd day of treatment, continues during the all period of drug intake, can last up to 23 days after discontinuation, returns when causative drug reintroduced) • hypothalamic disorders (trauma, organic pathology, etc) • constitutional (less than 1%) • artificial fever of hysteric patients, prisoners Course of fever

I. Phase of increase (st. incrementi) – move of set point to upper level, which brings to increase of themoproduction and decrease of therodissemination II. Phase of high fever (st. fastigii) – action of pyrogens continues III. Phase of decrease (st. decremeti) – action of pyrogens dereases, set point moves to lower level, thermoproduction decreases, termodissemination increases Table 1. Mechanisms of body temperature increase

Normal fluctuations Hyperthermia Fever

Physical work Simple hyperthermia Infectious diseases Excess meals Thermal exhaustion Non infectious Phsycoemotional tension Heatstroke Destructing tumors Circadian rhythms Malignant hyperthermia Acute hemolysis Diseases of connective tissue Myocardial infarction Surgical diseases Gynecological diseases ENT diseases Main diagnostic criteria of fever

1. Type of temperature increase 2. Height of fever 3. Duration of fever 4. Form of curve 5. Time and features of organic involvement 1. Type of temperature increase can be: a. acute influenza, , ornitosis, meningococcal infection, spotted typhus, Brill’s disease b. stepwise enteric fever, paratyphoid Table 2. Height of fever

High (40-40.9C), Sub febrile (37-37.9C) Moderate (38-39.9C) Hyperpyrexia (≥41C) Adevoviral infection Angina Hemorrhagic RS infection Spotted typhus Malaria Brucellosis Brill’s disease Meningococcal infection Viral Felinosis Sepsis Herpes infection Influenza Anthrax (pulmonary form) Candidiasis Yersiniosis Plague (pulmonary form) Meningococcal Leptospirosis Tularaemia (pulmonary nasopharingatis Infectious mononucleosis form) Parainfluenza Anthrax (skin form) Rhinovirus infection Salmonellosis AIDS Enteric fever CMV infection Tularaemia Cholera Plague (bubonic form) Table 3. Infections by fever duration

More than 20 Up to 5 days 6-10 days 11-20 days days Influenza Brill's disease Brucellosis (acute) Amebiasis ARI Felinosis Malaria Brucellosis Shigellosis Hemorrhagic Ornitosis (chronic) Meningococcal fevers Enteric fever Sepsis infection Mumps Spotted fever AIDS Erysipelas Measles Tularaemia Toxoplasmosis Anthrax (skin form) Meningococcal (pulmonary form) Visceral Scarlet fever infection leishmaniasis Rubella Infectious Viral hepatitis mononucleosis Salmonellosis Tetanus CMV infection Plague (bubonic) Tularaemia (bubonic) Factors affecting duration of fever

1. Atypical, abortive forms of disease, for which fever is typical (enteric fever) 2. Influence of drugs (antibiotics, antipyretics, corticosteroids, chemotherapy) 3. Complications of disease, for which short fever is typical (influenza) Table 4.1 Diseases by fever curve

Continuous Remittent Intermittent Recurrent Enteric fever Leptospirosis 3-day malaria Sodoku Paratyphoid Ornitosis 4-day malaria Louse borne Spotted typhus Plague (bubonic spotted fever Brill’s disease form) Salmonellosis Hemorrhagic fevers (typhoid form) Brucellosis (acute) Pseudotuberculosis Yersiniosis Meningococcal Infectious mononucleosis Table 4.2 Disease by type of fever curve

Atypical, Wave like Hectic Inverse irregular Influenza Sepsis Malaria (3-day) Any infection with (complicated) Herpes infection atypical course Infectious (generalized) mononucleosis Toxoplasmosis Enteric fever Salmonellosis Leptospirosis (septic form) Brucellosis Time and features of organic involvement Fever and rash

Table 5. Time of appearance of rash in infections

1-2 day 3-5 day Later than 6th day Herpes infection Spotted typhus Leptospirosis Rubella Herpes Zoster Infectious Meningococcemia Measles mononucleosis Scarlet fever Sepsis Enteric fever Varicella Hemorrhagic fever Paratyphoid Pseudotuberculosis Herpes Simplex of skin: zoster like (1), relapse (2) 1.

2. Primary Herpes Symplex of skin Measles or Rubella Rubella, first day of rash Scarlet fever Scarlet fever, small spotted rash Scarlet fever, rash on hip Varicella Varicella, polymorphism of elements Measles Measles, 2nd day of rash Leptospirosis, conjunctival hyperemia Leptospirosis, patient’s habitus in Veil’s disease Infectious erythema on the face Infectious erythema on the trunk Meningococcemia ( 1 ) Meningococcemia ( 2 ) Meningococcemia, necrosis of skin ( 3 ) Table 7. Time of enanthema appearance in infectious diseases

Time of Disease Appearance of affection appearan ce Candidiasis White caseousus thrush on oral mucosa 1-2 day

Measles Koplic's spots on buccal surface against small 1-2 day molars Mumps Mursou’s symptome, oedema and hyperemia 1-2 day around the orifice of parotid gland duct Spotted typhus Rosenberg-Vinokurov-Lendorf's enanthema on 3rd day soft palate and uvula (petechia), Kiari-Avtsin’s spots on lower conjunktival fold (petechia) Herpes infection Grouped small vesicles on hyperemic base 1-2 day

Herpangina Aphtas on anterior palatine folds, uvula and 1-2 day tonsils Varicella Vesicles on mucous membranes of mouth, nose, 1st day pharynx Oral candidiasis Oral chronic candidiasis Koplic’s spots Koplic’s spots and rash Mumps Primary herpetic stomatitis Herpangina Varicella, vesicles on soft palate Varicella, vesicles on tongue Hemorrhagic rash and fever

Hemorrhagic fevers Yellow fever Leptospirosis Meningococcemia Anthrax (pulmonary form) Plague (bubonic and pulmonary forms) Sepsis Hyperemia of face, neck, upper shoulder (hood symptom) and fever

This symptom appears in some infectious diseases from the first days and always is accompanied with conjunctival hyperemia and sore throat. “Hood” symptom is peculiar to: – Spotted typhus – Brill’s disease – Influenza – Leptospirosis – Pseudotuberculosis – Hemorrhagic fevers – Yellow fever Fever and inflammation of upper airways ( 1 )

Combination of fever inflammation of upper airways may be present during the following infections: – ARI – Influenza – Parainfluenza – Adenoviral infection – RSV infection – Reoviral infection – Rhinoviral infection Fever and inflammation of upper airways ( 2 )

1. During the following infections as a symptom: – Nasal diphtheria – Pertussis – Measles – Rubella – Herpangina – Q fever – Varicella – Anthrax (pulmonary form) fg: TB is stated as symptomatic&pri mary pneumonia? Fever and pneumonia

Pneumonia may be: 1. Independent disease:

Bacterial Non-bacterial Primary aseptic

Pneumococcal Ornitosis Chemical (benzin, Streptococcal Mycoplasma nitrogen oxides etc.) Staphylococcal Hystoplasma Allergic Esherichia, Proteus Pneumocystis carinii Aspiration Legionalla Cryptosporoidosis TB Cytomegalovirus Fever and pneumonia

2. Symptom of disease: – Brucellosis – Enteric fever (pneumotyphus) – Meningococcal pneumonia – Anthrax (pulmonary form) – Tularemia (pulmonary form) – Plague (pulmonary form) – Pulmonary TB – Lung eosiniphylic infiltrates (ancylostomidosis, ascariasis, strongyloidosis) Fever and pneumonia

3. Complication of main disease, caused by secondary microflora: – Adenoviral infection and other ARI – Spotted typhus – Brill’s disease – Botulism – Pertussis and parapertussis – Measles – Enteric fever and paratyphoid – Sepsis Fever and tonsillitis

Tonsillitis is referred as inflammation of palatinal amygdales. It may be as a separate disease (strep. angina) or expression of infectious or non-infectious disease (acute or chronic symptomatic tonsillitis). Acute and chronic symptomatic tonsillitis

Infectious diseases Non-infectious disease Adenoviral infection Agranulocytosis Enteric fever Aplastic anemia Tularemia Acute leucosis Herpangina Ionizing radiation disease Herpes infection Cytostatic disease Influenza and ARI Burns, trauma Diphtheria Scarlet fever Infectious mononucleosis Candidiasis Listeriosis Fever and diarrhea

Diarrhea in patients with fever almost always says for infectious disease. Exceptions are botulism and cholera, which occur without fever.

Enterocolitis (without Colitis (with blood in Gastroenteritis emesis and blood in stool) stool) Dysentery Sonnei Salmonellosis Amebiasis Paratyphus B Dysentery Salmonellosis Food poisoning (staph. Esherichiosis Dysentery toxin) Yersiniosis EIEC, EHEC Proteosis Leptospirosis Campylobacteriosis Salmonellosis (GI form) Campylobacteriosis Esherichiosis Liambliosis Rotaviral infection Enteric fever Fever and hepatolienal syndrome Concomitant affection of liver and spleen is described by common innervation, large amount of macrophages and links with portal system.

Diseases with affection of liver and spleen dominates Hepatomegaly dominates

Malaria Viral hepatitis Infectious mononucleosis Pseudotuberculosis CMV Yersiniosis Brucellosis Leptospirosis Enteric fever Amebiasis Recurrent typhus (tick borne, louse Yellow fever borne) Visceral leishmainiosis Sepsis Fever and

Diseases with lymphadenopathy Bubons Generalized lymphadenopathy Mesadenitis

Plague Adenoviral infection Yersiniosis Tularemia Infectious mononucleosis Pseudotuberculosis Sodoku Sepsis Enteric fever and Felinosis AIDS paratyphoid Enteric fever Toxoplasmosis Toxoplasmosis TB Brucellosis fg: Tick borne enceph? in theFever and CNS involvement column of meningitis? Diseases with CNS involvement

Meningitis Encephalitis (meningoencephalitis) Purulent Serous Meningococcal Leptospirosis -Clinical form Pneumococcal Mumps Herpes infection Staphylococcal Poliomyelitis Meningococcal encephalitis Streptococcal TB Mumps encephalitis CMV Toxoplasma encephalitis Lymphocytic CMV encephalitis choriomeningytis -Complication Influenza Measles Rubella Varicella AIDS Spotted typhus Fever and jaundice

Jaundice occurs in many infectious and non-infectious diseases. In infectious diseases jaundice appears:

Frequent Seldom

Viral hepatitis Ornitosis Herpes hepatitis Salmonellosis CMV hepatitis Infectious mononucleosis Yellow fever Pseudotuberculosis Leptospirosis Amoeba hepatitis Malaria For differential diagnosis it is important to know about epidemiological data:

• Travel to tropics • Season • Blood transfusions, consideration of incubation period • Contacts with patients in the case of air borne infections • Contacts with animals if is suspected

Sometimes the action of etiotropic agents is very important In the case if the cause of fever is still unknown, it is recommended to continue with FUO diagnostic algorithms. Conclusions

• Underlines importance of early diagnosis and differential diagnosis in infectious diseases. • Fever is the early and common symptom of the most infectious diseases. • It is important to exclude normal fluctuation of body temperature and thermal diseases based on main diagnostic criteria of fever. • Justified exclusion of specific infections helps much in further diagnostic search for non-infectious and non-specific infectious diseases. This exclusion results in establishment of FUO criteria and search for rare causes of fever. Thank you for your attention!