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J Pediatr Rev. 2013;1(2):42-54

Journal of Pediatrics Review Mazandaran University of Medical Sciences

Fever and Rash Syndrome: A review of clinical practice guidelines in the differential diagnosis

Mohammed Jafar Saffar1* Hiva Saffar2 Soheila Shahmohammadi3 1Antimicrobial Resistant Nosocomial Infection Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran 2Department of Pathology, Shariati Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran 3CRNA, Research Fellow, Mazandaran University of Medical Sciences, Sari, Iran

ARTICLE INFO ABSTRACT

Article type: accompanied by rash is a common finding in pediatric patients. Review Article Although, in most cases, the disease is trivial, in some cases it may be the first and/or the sole manifestation of a serious and life- threatening Article history: condition in patients. The spectrum of differential diagnosis is broad and Received: 15 April 2013 Revised: 23 June 2013 many different infectious and some noninfectious agents cause this Accepted: 12 July 2013 syndrome. To establish a timely diagnosis, providing appropriate therapy and considering proper preventive measures if necessary, a systematic Keywords: approach relying on a clear history, careful clinical examination along Fever, Rash, Syndrome, with particular attention to epidemiological features are the most Narrative Review important factors to pursue this syndrome. In this paper, the aim is to give an overview of how to deal with these patients clinically to establish a timely probable diagnosis of patients, providing proper early medical intervention without applying specific laboratory tests. http://jpr.mazums.ac.ir

Introduction Fever and rash is a common clinical complaint is benign and self-limited, sometimes, it may be in patients presenting to physician office and the first or the only sign of a serious and life- emergency department. The syndrome causes threatening condition. Therefore, to provide an anxiety in both the parents and physicians. The immediate appropriate medical intervention, causes are many and the ranges of differential early clinical diagnosis is necessary. In the diagnosis are very wide and contained a large initial evaluation of a febrile child with rash, a number of infectious and noninfectious proper history and careful clinical examination illnesses. Although in the majority, the disease is essential rather than relying on laboratory *Corresponding author:Mohammed Jafar Saffar, Professor of Pediatric Infectious Diseases Mailing Address: Department of Pediatric infectious disease, Antimicrobial Resistant Nosocomial Infection Research Center, Mazandaran University of Medical Sciences, Sari, Iran Tel:+981512233011 Fax:+981512234506 Email: [email protected]

Saffar MJ et al tests which results may not be immediately and evolution), searching for signs of meningeal available. In most cases, a systematic approach irritation (Kernig's and Brudzinsky signs) with based on tripod of clear history, careful clinical neurological examination, assessment of examination with the special attention to the hepatomegaly, splenomegaly, lymph nodes and types and other characteristics of rash and their other parts of the body are essential to diagnose relation to fever and other signs and symptoms, and differential diagnosis of the disease. along with the properly targeted B. Types and characteristics of skin rash: epidemiological clues can aid to establish Various infectious and noninfectious agents can possible diagnosis and select those patients who cause different skin reactions and/ or similar need immediate medical intervention without clinical syndromes or vice versa. In evaluating a applying specific laboratory tests.1-4 patient with fever and rash, determining the In this paper, our aim was to review a proper type of rash, and its general characteristics such clinical diagnostic approach without applying as the primary site of eruption and progression special laboratory tests to diagnose timely those to the other parts of the body, their distribution patients who require immediate medical and the evolution are very important. intervention relying on the history, physical Dermal manifestations and various kinds of examination and the epidemiological clues. In rash can be categorized based on the form of addition, at the end of the paper, a short rash (macular, papular, vesicular, blistery, overview has been done on number of diseases petechial and purpuric) or according to the with fever and rash that their early diagnosis general term of a disease with rash overall and appropriate therapeutic intervention are known as measles-like rash “Morbiliforme”; considered as medical emergencies. like rubella " Rubelliforme "; or similar scarlet A. Clinical examination. fever " Scarlatiniforme = scarlet-fever like In the initial evaluation of the febrile child with illness"; and so on. In addition, considering the rash, certain factors must be given urgent distribution of rash throughout the body priority, these include: (diffused or localized rash, symmetrical a: Is the patient well enough to be evaluated on bilateral or unilateral, at open or shaded areas), as outpatient setting or needs hospitalization? and how to distribute from the primary site to b: If admission is required, is the patient's life other parts of the body (central: the bulk density threatened from the disease and an urgent on the face, trunk, and abdomen or peripheral medical intervention required? area: the highest density on the extremities) will c: Is there the risk of transmission to others and be useful to distinguish the pathogens from each warranted precaution and isolation? other.1, 3-5 The following definitions are useful d: Does the disease acquire notification from to describe the various types of rash.5 the public health point of view? Macula: A color change of the skin, Papules: Careful clinical examination is essential in any A raised lesion less than 1 cm in diameter, patient presenting with fever and rash. Special Maculopapular: A combination of both attention to the general appearance; macules and papules, Purpura: Cutaneous hemodynamic and respiratory status and lesions caused by leakage of red blood cells, consciousness level to select the minority may be/not be palpable with a diameter more patients at risk are very important of life saving. than 5 mm and : is a similar lesion Full examination of skin and mucosa is very smaller than 5 mm diameter, Vesicle: is a blister important to determine the characteristics of like lesions less than 1 cm diameter containing rash (eruption sites, distribution, progression fluid and the larger lesion is called Bullae:

J Pediatr Rev. 2013;1(2) 43 Fever and Rash syndrome…

Pustule: a pus-containing vesicles, that may hairline and progress to the other parts of the leave scar after healing, Enanthem: A mucosal body and extremities. The concentration of rash rash on the mucous membranes, sometimes in the trunk and abdomen is much higher than mucosal rash (Enanthem) is a specific sign of a in the limbs. This kind of distribution of the disease like Koplik spots in measles, petechial rash to the body and its clinical picture is called lesion on soft palate in rubella, and infectious «Morbilliforme Rash». Fever and other signs/ mononucleosis, anterior oral vesicolo-ulcerative symptoms lasted for 48 hours after rash lesions in Hand- Foot- Mouth disease. eruption and were resolved suddenly, in which C. Determination of the relationship between the patients’ general conditions improved fever, rash and other clinical symptoms: significantly. On the fourth day of the rash Consideration and determining the correct eruption, gradual disappearance of the rash with relationship between fever and rash and also fine desquamation begins from the face and other signs/ symptoms are the crucial points to spreads to the extremities within several days. differentiate between febrile illnesses Measles-like rash has no or a little pruritus.7 accompanied by rash.1, 3- 5 In evaluating a The epidemiological trend of measles changes patient who is suffering from fever and rash significantly following universal vaccination of syndrome, accurate answers to the following children against measles. In most countries, the questions will be helpful in the diagnosis of the incidence of measles was markedly reduced and disease: 5 endemic measles was eliminated in some parts ◙ What is the shape and type of rash? of the world. In these countries, majority of the ◙ When and where the rash started? cases occur among infants, adolescents and ◙ Has the rash progressed to other parts of young people. In Iran, since 1989, after a two- the body? dose of routine mass vaccination against ◙ What is the relationship between fever and measles in children ages 9 and 15 months with rash? high coverage levels, cases of measles in ◙ Has the rash changed morphologically? children have decreased significantly and the ◙ Were there any other signs/ symptoms most reported cases of measles have been in before the rash erupted? older children and adults.7, 8 Considering the ◙ Has treatment begun for the patient? changes in the epidemiology of measles in Iran For example: Measles: An acute viral and around the world, in the differential exanthematous illness that begins with malaise, diagnosis of febrile diseases with rash, measles fever, cough, runny nose and conjunctivitis that is also considered in adolescents, young adults becomes more severe within 3-4 days later. 6 and infants. About 12- 48 hours before the onset of rash, Rubella: An acute mild exanthematous viral measles-specific enanthem appears in the disease with least morbidity in children, which anterior aspects of the cheeks and gums at the clinically is similar to the mild measles (also levels of premolar may spread and involve the called three-day measles).9 Infection in lip, hard palate and gingiva, opposite the pregnancy may result in fetal infection and maxillary second molars on a red halo with a considerable fetal developmental anomalies. bluish-white central dot (Koplik spots). At the The rash of the disease may be presented 1- 3 peak of fever and other clinical symptoms of days after a mild systemic symptoms such as measles, red color maculopapular lesions erupt low-grade fever (less than 38.5 ° C), cough and from the back and anterior of the ears from the runny nose. Rubella rash starts on the face of

44 J Pediatr Rev. 2013;1(2) Saffar MJ et al the patient. The type of rash in rubella is a red trunk, neck, sometimes on the face and the maculopapular that initially appears on the face proximal part of the arms that appear within a and spreads to the extremities in less than 48 few hours after a sudden fever lysis. In some hours. The most concentration of rash appears cases, adenopathy in the postauricular – on the face and trunk with discrete lesions in the occipital area can be detected. Because of the extremities. As a view point of clinical feature, special relationship between the fever and the such spreading of rash on the body is called rash eruption, clinical diagnosis of the disease is «Rubelliforme Rash». The main characteristic simply possible and less confused with other of the disease is severe painful febrile diseases with rash.11 behind the head or behind of Parvovirus B19 Infection "Erythema the ears that present before the rash eruption Infectiosum": Infection results in a wide and remains for a week. In some cases, a few spectrum of clinical presentations. Usual enanthems may be presented like a petechia on clinical manifestations of the disease mainly the soft palate.9 Diagnosis of rubella is occur in children and have three distinct stages: important to prevent transmission of the The first stage begins with nonspecific infection to pregnant women Acquiring rubella symptoms such as headache, malaise, mild infection in the first few months of pregnancy is fever, cough and mild runny nose for 2-3 days. associated with severe complications in the One week later, the first exanthematous phase fetus and the risk of congenital rubella of illness starts with a raised fiery red rash syndrome. In some areas of the world where appearing on the cheeks of the patient like a rubella vaccination is not carried out, rubella is “Slapped- Cheek" and with circumoral Pallor. a childhood disease; affecting children and The lesions are aggravated with exposure to the adolescents in the age groups of 5-15 years. In heat. The second phase of enanthem starts 1-4 these areas, most girls and women in days after the facial rash with the development childbearing age, following normal exposure to of a maculopapular rash on the trunk and the infection have acquired immunity, so that, extremities that initially are discreted and in the reproductive age if once exposed to the gradually spread to involve all parts of the patient infected with rubella, the risk of body. Several days after the appearance of the infection is very low.10 In faced to a pregnant rash, the central part of the lesions gradually is woman exposed to a febrile patient with rash cleared and lesions extended peripherally and confirmed or suspected to rubella, immediately make a reticular appearance that is the testing for rubella specific IgG antibodies beginning of third stage of the disease. This should be performed. If the test result is stage last for 1-3 weeks. After the rash has positive, it means that the pregnant woman is disappeared, frequent recurrency may occur immune and her fetus is not threatened. following exercise or heat exposure. The major Roseola: " Subitum"; An acute parts of the body that rash can present in the febrile disease is caused by the human herpes third stage are the extensor surfaces of viruses 6 and 7.11 The sudden onset of high extremities without the involvement of the fever, malaise, and sometimes seizures without palms and sole Rash is prurutic but no other significant clinical signs/ symptoms in 3- desquamation occurs.12 36 months old children with nontoxic : An acute infection that is caused appearance will occur. The most important by Strep group A. In most cases, the disease is characteristic of the disease is a reddish observed in children ages 5-15 years, which maculopapular rash without pruritus on the starts with a sudden high fever, sore throat,

J Pediatr Rev. 2013;1(2) 45 Fever and Rash syndrome… abdominal pain and vomiting. Physical especially without the involvement of limb, examination reveals pharyngitis with / without redness and inflammation of the oral mucosa exudates, and painful submandibular adenitis. (strawberry tongue , redness and transverse 12- 48 hours after the onset of the disease, cracking and bleeding of the lips, inflammation erythematous macular rash appears on the of the pharynx and oral mucosa together or patient's face (Slapped- cheek) with circumoral separately), multiform skin rash especially a red pallor, and also a red maculopapular rash on the maculopapular rash most notably occurs on the trunk and abdomen that in some cases within trunk or redness in the perineum area with several hours spread to all parts of the body. desquamation, red indurated - painful stiffness Although the rash may fade with pressure in the of extremities in the acute phase and/or large different parts of the body but in the wrinkles of and huge desquamation of nail bed from the elbow and wrist become more colored “known second week and ultimately cervical as Pastia line / sign.” On the throat, in addition adenopathy more than 1.5 cm anterior to the to the evidence of pharyngitis, enanthem of the neck without redness with mild pain. In the disease can be seen as petechic spots on the soft usual case of the disease, diagnosis is not a palate and anterior pillar of the tonsils. Smooth problem.15 desquamation, especially on fingertips occurs in Enterovirus infections: Enterovirus infections all patients that last for 1-3 weeks.13 manifest with a variety of muco-cutaneous rash. Infectious Mononucleosis: The disease is One of the characteristics of the clinical caused by Epstein - Barr virus. One week syndrome due to enterovirus infections is Hand- before the onset of the main symptoms of the Foot- Mouth disease which is associated with disease, there are general malaise, fatigue, and fever and vesicular lesions in the distal parts of mild fever in the patient. The common the limbs, wrists and the anterior area of mouth characteristics of the disease are manifested by that are not "crusted". Another clinical high fever 38.5 – 40.5° C for 1-2 weeks, syndrome caused by enterovirus infection is pharyngitis; mostly with white membrane, and Herpangina. In this disease, vesicular lesion 2-4 cervical lymph node enlargement. mm in diameter occurs into the mouth, Splenomegally occurs in one-third or half of the especially on the soft palate. In some clinical patients. A few days after the onset of typical syndromes and infections caused by ECHO symptoms of the disease, a red maculopapular viruses, fever and petechic-purpuric type of rash rash appears on the trunk in 10-15% of the may occur. Also, many enterovirus species are patients. Also, 5-7 days after the administration able to create fever with maculopapular rash on of ampicillin or beta-lactam antibiotics to the the trunk. With regard to the different clinical patients with infectious mononucleosis, a red syndromes of fever with rash resulting from maculopapular rash without pruritus appears on enterovirus infections, the majority of the above the trunk, face and extremities.14 mentioned infections are in the differential Kawasaki Disease (KD): KD is an unknown diagnosis of febrile illness with rash. The most etiologic febrile disease with rash. The epidemiologic features of enterovirus infections diagnostic criteria of the disease are based on are that they most commonly occur during the clinical evidences including; a fever lasting summer and autumn seasons. In this period, a more than 5 days associated with four out of variety of clinical syndromes may be observed the five following symptoms: bilateral non- in the community.16 purulent severe redness of conjunctiva,

46 J Pediatr Rev. 2013;1(2) Saffar MJ et al

Chickenpox: An acute that is illness is manifested in children. However, in characterized by extremely itchy small vesicles. older children, less commonly disease is Usually, after 12-24 hours of fever and malaise, presented with skin rash. 12 Kawasaki disease is cumulative and sudden skin rash known as an acute unknown etiology childhood illness "crop" begins to erupt on the scalp, face and with skin rash. 15 Scarlet fever and infectious trunk. There are various types of skin lesions mononeuclosis are the two diseases among the from macula up to crusted lesion at different pediatric patients aged 5-15 years caused by anatomical regions on physical examination. strep A and Epstein-Barr viruses, There is a red halo around the lesion. The lesion respectively.9,14 Enterovirus infections is umbilicated. The distribution of rash is associated with rash mainly occur in infant and centric and the most concentration of rash is on younger children. 16 In the past, some viral the face, trunk and abdomen. Also, lesions of diseases preventable by vaccination such as chickenpox occur in the various mucosa of the measles7, rubella9 and chickenpox17 were body. In cases of localized vesicular lesions, childhood diseases. With the universal routine herpetic lesions, zoster, bites and poison ivy vaccination against the above mentioned viral should be considered.17 infections and changing the epidemiological D. Epidemiological Features and Etiology: trend of the disease, more cases occur in The relative role of each pathogen is not the adolescents and young adults which should be same in different regions or different considered. individuals. Information about the relationship 2. Season of the year: A large number of between patient and a pathogen and their infectious agents that are associated with fever environments is a very important point when and rash have specific seasonal activity. faced with a patient with fever and rash Considering the seasonal activity of the syndrome (FRS). If the epidemiology of the pathogens can assist the physician in restricting different agents is well understood and used, it the differential diagnosis of FRS. For example, will be very helpful to differentiate between a the peak activities of enterovirus species occur pathogen from other causes of similar clinical in the summer and autumn16, Measles6 and syndrome. The epidemiologic characteristics Rubella9 present in the spring, parvovirus B1912 that require special attention are: patient age; and meningococcal bacteria18 occur in the geographic region; season; history of travel to winter and early spring, and -borne other location; contact with insects, animals, diseases such as Lyme diseases, food or plants and similar patients; history of infection and Rocky Mountains vaccination and history of prior illness; the (RMSF) may also occur in the summer.19, 20 immune status of host and medications.5 3. Geographic area: Some pathogens or their 1. Age of the patient: Some diseases that are carriers can survive or are active in special presented with rash especially "viral diseases" climates. As a result, some of the diseases are mainly occur in childhood. Considering the age observed or limited to some particular of the patient can help to narrow the range of geographic regions. Staying or traveling to differential diagnosis of the diseases. these areas are likely to be associated with the Roseola infantum is an infection mostly occurs risk of acquiring the diseases. For example, in children 3-36 months of age.11 Erythema RMSF or 19, 20 are active in some infectiosum also known as "Fifth disease" is areas of America or dengue fever and dengue referred to the clinical manifestations of hemorrhagic fever are also active in South East Parovirus B-19 (PB-19) infection. The classic Asia.21 Traveling to some areas like South

J Pediatr Rev. 2013;1(2) 47 Fever and Rash syndrome…

Africa, India, Russia and the Mediterranean 7 days suggest enterovirus infections.16 countries is associated with the risk of Sometimes the interval between the bite and rickettsiae conori infection. 19 There is a risk of expression of the symptoms will be the key in infection to a number of other rickettsial differential diagnoses, like 14-17 days interval diseases such as Rickettsial Pox and between tick bites and presence of skin lesion in Boutonneuse fever among the travelers from Lyme disease or in RMSF.19, 20 other parts of the world such as China, India, 5. Exposure History: There are a variety of Nepal, the Mediterranean countries and Russia infectious agents around our non-living and (Table 1).19, 20 People who travel to India, living environments. There is a risk of Pakistan or Mexico are at risk of exposure to acquisition of disease following professional or . 22, 23 non-occupational exposure to the etiologic 4. Incubation period: The history of contact agents. Exposure to animals, food, plants and with a known exanthematous infections, the other patients are the most remarkable points in interval from exposure to rash onset of the the differential diagnosis of the diseases with disease (incubation period) can help the fever and rash. For example, there is a physician to identify the pathogen. For possibility of being infected by direct contact example, an interval of 14 days from exposure with the skin and mucous membrane of the to onset of rash suggests measles6 18-21 days infected people with HSV, , for rubella, 14-18 days for chickenpox17, and 4- and HIV.

Table1. Summary of characteristics of the different types of Rickettsia Type of Geological region Incubation Onset of Type of rash and kind of Other signs& disease period (day) rash distribution symptoms following fever Boutonneuse Southern Europe 7-14 days 4-7 days Maculopapular, trunk Headache, fever and the Middle malaise East, Russia, India and Pakistan

Typhus pandemic 7-15 days 5-7 days Maculopapular and petechic, Very severe and groups peripheral distribution without uncontrolled palms and soles involvement headache

Spotted pandemic Maculopapular and petechic, Headache, groups from peripheral to central parts malaise, myalgia

Reckettsial pandemic 9-14 days 4-7 days Maculopapular and vesico- headache pox bollouse from peripheral to central parts without involvement of oral mucosa, palms and soles

48 J Pediatr Rev. 2013;1(2) Saffar MJ et al

There is a probability of cat scratch disease and throughout the body. For instance, a disease visceral larva migrans in contact with cats and such as syphilis can cause a variety of rashes. dogs, and rat-bite fever likely Rash at the early stage of the disease may follow contact with mouse, rodents and/ or cow appear as painless ulcer with a raised red and rickettsia or lyme disease may occur in border, highlight color, and stiffer than the contact with tick or mosquitoes. Contact with surrounding tissue. In the second stage of the water, soil or plants may lead to some dermal disease, a red maculopapular rash distributed in and topical diseases.1, 4, 5 all parts of the body including the palms and 6. Drug History: Various drugs can cause a soles may occur. At this stage, in wet areas of variety of skin rashes that is sometimes the body, Condyloma-lata lesions especially in accompanied by fever. Unlike the popular the anal area and mucosal ulcers of the mouth belief, association of fever and rash caused by are observed. About 2-6 weeks after exposure drugs is not so common. For example, in a to HIV, fever, headache, sore throat, diffused study, only 20% of patients with drug fever had lymphadenopathy, mucosal ulcers, transient skin rash that half of them were urticarial. In maculopapular rash without pruritus on the face another study performed on 20,000 patients and trunk areas are develop. The disease may admitted to the hospitals, only 2% of the not be differentiated with other diseases, patients showed the drug induced rash, as most especially infectious mononucleosis.1, 2, 5 of them used antibiotics or anticonvulsant drugs Laboratory Evaluation: Applying and using for the treatment. Serious skin reaction of laboratory facilities are not much helpful to stevens - Johnson syndrome or toxic epidermal differential diagnosis of the diseases in patients necrolysis "TEN" occurs in 5% of those suffering from fever with a rash, particularly in affected patients. Drug-included skin reaction the early stages of the disease, and have a low usually occurs about 1-3 weeks after treatment. diagnosis value in serious illnesses. However, 1, 4, 5 in suitable conditions, the application of the 7. History of Vaccination and Immunization: following tests is recommended: Full vaccination against a disease or history of a ● Nonspecific tests such as complete blood natural infection is against the diagnosis of a count (CBC) and urinalysis particular infection. In the past, however in ● Specific tests included: blood culture in some cases, sometimes 1-3 weeks after specific media based on the condition of the vaccination, fever and/or rash related to live patients, serological tests suitable for clinical vaccine25 or allergic reaction to vaccine and epidemiological conditions combined with component can occur. Considering the interval antigen investigation in appropriate samples are between the administration of the vaccine and more important. Fluid and discharge samples the appearance of symptoms will be helpful in from the pustules, blister, vesicle, ulcerative the differential diagnoses.1, 4, 5 lesions and petechic lesions prepared for culture 8. History of sexual activity: Every patient and smear may be helpful to diagnosis the present fever and rash with unknown etiology agent. Finally, microbiological and histological should be evaluated carefully and in sexual evaluation of skin biopsy may be useful for the activity. A thorough proper examination of the diagnosis of the disease.1- 5 anogenital area is essential.2, 5 Human herpes (HSV1 and HSV2), syphilis, are Some Diseases as Medical Emergencies: diseases which may be associated with Meningococcal Infections: Although gram- localized rash in genital area or disseminated negative cocci of causes

J Pediatr Rev. 2013;1(2) 49 Fever and Rash syndrome… a wide range of clinical conditions, the most 38.9 ° C, hypotension (shock) and diffuse important and the Life- Threatening clinical erythema of the skin accompanied by three form of it is septicemia (Meningococcemia). different organs involvement such as Meningococcemia with / or without meningitis gastrointestinal tract, liver, kidney, nervous is a severe and life-threatening disease that system, blood, and etc. Disease should be frequently affects children and adolescents. The differentiated from illnesses such as disease occurs more frequently in overcrowded leptospirosis, measles, Kawasaki, and rickttsial conditions, such as barracks, dormitories, and infections. The most common clinical kindergartens. Early diagnosis of the disease is manifestation of the disease are conjunctivitis, a medical emergency because of the very rapid red mouth, diarrhea, vomiting, muscle pain, progression and high morbidity and mortality of liver and kidney dysfunction, disseminated the disease without early and proper treatment. intravascular coagulopathy (DIC), The clinical manifestations of the disease thrombocytopenia, and impaired consciousness. include: fever, headache, myalgia, nausea, In this patient, fever and rash (erythroderma) vomiting, and hypotension (shock). In some started together. To reduce morbidity and patients, loss of consciousness and signs of mortality, early diagnosis and appropriate meningeal irritation (stiff neck, kernig and supportive treatment with an immediate brudzinski signs) and concurrent skin rash are correction of the hypotension is essential.28, 29 present in patients with Meningococcemia. Staphylococcal Scalded Skin Syndrome: Initially, skin rash is a red maculopapular lesion Reiter's disease (SSSS): The disease is caused on the trunk and limbs (without the involvement by a toxin produced by staph aureus bacteria. of the palms and soles) that will become Most cases of the disease occur in the first few petechic-purpuric within few hours. Due to months of life. The disease onset is acute with rapid progression of the disease and possibly sudden high fever, restlessness, severe and serious complications of delayed diagnosis, in extensive redness of skin (Tender any case with fever and petechic-purpuric skin erythroderma). The patient's skin is red, swollen rash with or without involvement of the central and extremely painful that within 1-3 days, with nervous system, to save a patient’s life and to a light pressure large thin-walled blisters will prevent the transmission of infection to others, appear (positive Nikolsky sign) which can be an immediate appropriate special treatment of easily torn. After tear off the blister, a red infection along with other control measures moisture surface appears that will change to a should be started against meningococcemia and fine desquamation over the next few days. In meningitis until it is ruled out or confirmed.18, uncomplicated cases, recovery occurs within 25-27 two weeks. An early diagnosis and : A known clinical establishment of an appropriate specific syndrome that is caused by a toxin released treatment (anti-staphylococcal antibiotic) from Staph, aureus and Strep A bacteria. combined with fluid therapy and appropriate Although, most cases occur in children, it may supportive treatment like those for burns is also occur in older children and women after essential to reduce morbidity and mortality of the use of tampon, or in patients with burns, the disease.28, 30 surgical wounds and from the skin lesion. The Toxic Epidermal Necrolysis (TEN): Erythema diagnosis of the disease in acute phase is based multiform, Stevens-Johnson Syndrome, and on clinical criteria including a fever more than Toxic Epidermal Necrolysis TEN are actually a

50 J Pediatr Rev. 2013;1(2) Saffar MJ et al syndrome with three different clinical particularly drugs that have been responsible for presentations. Erythema multiforme is the causing the syndrome. Early diagnosis and milder form of the syndrome and very severe prompt discontinuation of the responsible and dangerous form of it is called TEN. Many drug(s) in combination with supportive therapy infectious and noninfectious agents are involved similar to those of extensive burns associated in the development of the disease. In most with corticosteroid therapy and IVIG will be cases, Erythema multiforme usually occurs in useful to reduce morbidity and mortality. The burning older children and adults. There is most important differential diagnoses of TEN burning and itching sensation before the onset are Reiter's disease (SSSS), pemphigus and of cutaneous lesions. The most important toxic shock syndrome. 1, 31, 32 disease-specific lesion is «Target lesion» Rickettsial Infections and RMSF: including a central lesion with discoloration and and RMSF is a set of vector-borne central necrosis with a normal skin in the diseases that are transmitted from animals to margins. There is also a red color change again humans by arthropods. (Table 1) at the margin of normal skin. The primary There are several common features such as central lesion starts as a red maculopapular or sudden onset of high fever, various skin rash, urticarial rash and rapidly evolves to central damage to small vessels and capillaries, rapid necrosis or may transform to vesiculobullous progression to a severe and life-threatening lesions. The distribution of lesions in the body disease, and presence of at the site of is symmetrical and occurs at the extensor bite. With respect to the role of arthropod in surface of the upper extremities (the least transmission of microorganisms, these groups lesions are seen on face and lower extremities). of diseases have a specific regional and The frequency and severity of these lesions are seasonal incidence. The diagnosis was based on higher in Stevens - Johnson syndrome and clinical and epidemiological evidences and involve about 30% of the body surface area measurement of specific antibodies or PCR. (more lesions are seen on trunks and limb Immediate and empirical disease-specific areas). In these patients, mucosal lesions in treatment is essential to reduce or prevent the more than one mucous membrane (eyes, ears, complications of the disease before specific nose, mouth, anogenital area, respiratory and diagnosis. RMSF is a tick borne Rickettsial gastrointestinal tract involvement) also occur. infection and active in the defined geographical Burning sensation and swelling of the mucous area in America. The incubation period of the membrane occur before lesions development. disease is 4- 5 days. The onset of the disease is Redness, blister, ulcer and/or hemorrhagic sudden with high fever, headache, general crusting on lip, oral mucousa may develop. In a malaise, myalgia congestion and redness of the number of cases, fever and chills, pain, burning conjunctiva. 4-5 days after the onset of fever sensation of mucosa and skin can be seen and initial symptoms of the disease, a red before eruption of the skin rash. In cases of maculopapular skin rash appears on wrist and TEN syndrome, initially painful erythrodermi ankle areas of the body. The initial rash will be of the skin and then a very large, thin-walled converted to pethecic- purpuric lesions in a blister occur. Target signs may not be present. short time. Over the next few days, the rash Few to 48 hours before skin eruption fever and will be distributed and progressed downwards mucosal are present. In an uncomplicated case, and upwards to the palms and soles and "arms recovery occurs within 10-14 days. There are and thighs respectively". In this phase, various infectious and noninfectious agents differentiation of the disease from

J Pediatr Rev. 2013;1(2) 51 Fever and Rash syndrome… meningococcemia is difficult. Residing in or the patients will worsen and cardiovascular history of travel to endemic areas, a history of collapse and shock occurs. At this stage, the tick bite, and attention to rash distribution and patient is restless and irritable with cold progression, the relation between rash and extremities and in some patients; diffused fever, accompanied with leukopenia, and petechiae develop on the forehead and limbs. increasing liver transaminase is helpful and There are spontaneous ecchymosis and beneficial for diagnosis of RMSF. The most tendency to bleeding. Cyanosis, rapid and important differential diagnosis of the disease is shallow breathing, weak and narrow pulse and meningococcemia. In addition, bacterial short interval between systolic and diastolic endocarditis, measles, second stage of syphilis, phases of blood pressure, hepatomegaly, and other rickettsial diseases are also discussed. accumulation of fluid in the pleural cavity However, in the exposure to a patient with fever (pleurisy) can occur. This phase lasts for 24-36 and purpuric rash, especially in endemic areas hours. Establishing early diagnosis and of the disease, immediate empirical disease- appropriate supportive treatment is essential to specific and supportive treatment is strongly reduce complications. 21, 35, 36 recommended.19, 20, 33, 34 Dengue Fever and Dengue Hemorrhagic Conclusion

Fever: Is an acute viral disease transmitted by Fever associated with rash is a common clinical flies. Incubation period is 2-7 days. Although, syndrome in patients presenting to physicians’ it has been reported worldwide, but the majority offices and emergency departments. The causes of cases are reported from Southeast Asia. are many and in most instances are benign and Diseases begin suddenly with high fever, severe self-limited. However, in a small number of headache (most prominent on for ehead and cases it may be the only sign of a severe and retro orbit), back pain, and lymphadenopathy. life-threatening or contagious infection. Within 24- 48 hours of fever, a temporary red The differential diagnosis of fever and rash is maculopapular rash for 1-2 days develop. extremely broad, but systematic approaches Bradycardia in proportion to fever is present. could help clinicians for establishing a timely Musculoskeletal pain is very intense and diagnosis, providing early treatment when intractable. appropriate and considering preventive After 2-7 days, the clinical symptoms of the measures if necessary. disease subside and the patient recovers In this regard careful physical examination, temporarily. After 1-2 days of defeverness, a taking a clear history along with diffuse maculopapular measles-like rash epidemiological clues is very important to appears without the involvement of the palms pursue. and soles. In endemic areas, reinfection in people with Conflict of Interest previous history of the disease, or primary None declared. infection in infants and young children who have saved maternal antibody, the early symptoms of the disease are manifested Funding/Support abruptly by fever, headache and cough for 2-5 None declared. days and endured for 2-5 days. One to two days after the initial period, the general condition of

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