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Home , Coxsackievirus, Enanthem, Exanthem, Morbilliform, Skin infection

Childhood : A Differential Challenge Samuel Ecker, DO,* Jacquiline Habashy, DO,** Stanley Skopit, DO, MSE, FAOCD, FAAD***

* 2nd year resident, Larkin Community Hospital- Residency, Miami, FL **Medical Student, 4th year, Western University of Health Sciences, Pomona, CA ***Program Director, Larkin Community Hospital-Dermatology Residency, Miami,FL ; Advanced Dermatology & Cosmetic Surgery, Margate, FL

Disclosures: None Correspondence: Jacquiline Habashy, DO; [email protected]

Abstract Childhood exanthems are frequently related to recent viral or bacterial . Other causes involve medications and inflammatory conditions such as immune-mediated . We present a challenging case of an asymptomatic 7-year-old girl with an atypical and discuss differential diagnoses, focusing on common viral and bacterial causes.

Introduction cryoglobulins, and serum protein electrophoresis, disease, infectiosum and infantum. Viral and bacterial are common causes were all within normal limits except for the anti- Physicians no longer recognize Duke’s disease as a streptolysin O titer. The ASO titer was markedly distinct entity, but rather an atypical presentation of generalized in children, and patients 2,3 may present with systemic signs and symptoms elevated (1248), and throat culture was positive for of another classical exanthem. Overlapping and such as pharyngitis, fever or malaise. Common Group A beta-hemolytic streptococci. Parvovirus atypical exanthematous clinical presentations are infectious agents include adenovirus, echovirus, B19 IgG and IgM anti-bodies were not detected. often encountered. In order to establish a prompt , EBV, HHV6, HHV7, parvovirus diagnosis, it is important to have a detailed 1,3 Biopsy and lab findings were consistent with B19 and pyogenes. Determining the streptococcal toxin-mediated exanthem. Due underlying pathogen relies heavily on characteristic Figure 3 to a history of penicillin intolerance, the patient findings and detailed history gathering of was treated with cefadroxil 30 mg/kg for 10 days, timing, progression and immunization status. hydrocortisone 2.5% cream twice daily as needed The morphology and distribution of cutaneous for two weeks, and camphor/menthol lotion as and mucosal lesions are also essential diagnostic needed. On follow-up, 14 days after initiating clues that help distinguish between childhood treatment, the eruption had completely resolved exanthems. We present a challenging exanthem (Figure 4). diagnosis in a 7-year-old female, providing insights into diagnostic tools that can help guide diagnosis and treatment in patients who present with atypical Discussion physical exam findings. We review characteristic Exanthematous eruptions occur most commonly in features of several childhood exanthems and school-aged children. In the early 1900s, six classical discuss appropriate workup and treatment for each infectious childhood exanthems were described. condition. These include , , , Duke’s Figure 1 Figure 4 Case Report A 7-year-old female presented to our dermatology clinic with a two-day history of a generalized erythematous pruritic eruption. She stated the lesions first appeared on her face, and spread to her trunk and extremities after one day. The patient denied cough, fever, chills, sore throat, abdominal pain, arthritis, dysuria, hematuria, diarrhea, bloody stools, sick contacts or recent travel. On physical exam, there were generalized, bright red, erythematous, blanchable macules and confluent patches affecting the malar cheeks, torso, arms, palms and legs, with sparing of the eyelids, chin, axilla and antecubital fossae (Figure 1). Oral exam revealed a white strawberry tongue (Figure 2). There were no lesions on the buccal or palatal mucosa. Pharyngeal erythema, tonsillar Figure 2 enlargement and exudates were also absent. There was no cervical or axillary .

Two punch biopsies were performed on the lower back. Histopathology showed polymorphous with neutrophils, nuclear dust and red cell extravasation. Fibrinoid necrosis was not observed (Figure 3).

Vasculitis protocol, which included a complete blood count, complete metabolic panel, urine analysis, stool guaiac, anti-streptolysin O titer (ASO), antinuclear antibody, erythrocyte sedimentation rate, antineutrophil cytoplasmic antibodies, rheumatoid factor, hepatitis panel, complement levels, antiphospholipid antibodies,

ECKER, HABASHY, SKOPIT Page 20 understanding of the clinical characteristics that Although our patient had a positive throat culture, Papular-purpuric gloves and socks syndrome help distinguish between various viral, bacterial and we could not rule out the possibility that she was (PPGSS) is another clinical variant of parvovirus inflammatory cutaneous eruptions. a chronic GABHS carrier. In the U.S. population, B19 infection. Many patients experience non- 5% to 15% of children are asymptomatic colonized specific prodromal symptoms including fever, In the following sections, we discuss identifying carriers; therefore, ASO titer may be useful for myalgia, arthralgia and fatigue. As the disease features such as cutaneous distribution and confirmatory purposes.10 The presence of elevated progresses, the hands and feet develop bright progression, associated signs and symptoms, and ASO titer confirmed that our patient had a recent red erythema and edema, as well as papular and appropriate laboratory workup of common viral streptococcal infection. purpuric lesions on the palms and soles.22 and bacterial exanthems. First-line treatment for scarlatina is penicillin Both erythema infectiosum and PPGSS are self- Streptococcal infection (amoxicillin). In the case of an anaphylactic reaction limiting and resolve without treatment. In the Scarlet fever (scarlatina) is caused by infection to penicillin, clindamycin or erythromycin may be United States, the seropositive rate of parvovirus with group A beta-hemolytic streptococcus used. If pruritus is present, oral antihistamines and reaches 50% in adolescents.23 Diagnosis primarily (GABHS), mainly , which emollients may be added to the treatment plan. relies on clinical findings. IgM and IgG antibodies produces pyrogenic exotoxins A, B and C. These Children may return to school or daycare 24 hours are elevated in acute infection, with IgM elevation exotoxins produce local inflammatory mediators after initiation of antibiotics.11,12 lasting two to three months. The vast majority of and alterations of the cytokine milieu, leading to cases resolve without serious long-term sequela. dilation of blood vessels and delayed-type skin The prognosis of scarlatina is excellent when Complications may arise when infection occurs 4 reactivity. Streptococcal infections are most caught in a timely manner. Prior to the existence of during pregnancy, possibly resulting in hydrops commonly seen in children between 1 year old antibiotics, GABHS infections had a 20% mortality fetalis, miscarriage or intrauterine death. These and 10 years old. The infection is spread person- and morbidity rate. Since the introduction of risks are greatest when infection occurs during to-person via respiratory droplets and is typically antibiotics, the mortality rate has fallen to less than the first or second trimester. Complications may 5 easy to contract in close-contact settings, such as 1%. The primary goal of treatment is to prevent also occur when patients with hemolytic anemia 5 schools, daycares, and households. the long-term nonsuppurative complications or sickle-cell disease become infected, imparting of GABHS infections: rheumatic fever and the risk of transient aplastic crisis. Lastly, patients Unlike in our case, once infected, patients typically glomerulonephritis. The sequela of rheumatic who are immunocompromised face the risk of life- develop an abrupt onset of fever with sore throat, fever is specific to GABHS pharyngitis, whereas threatening chronic anemia.20 tonsillar enlargement, headache, nausea, vomiting, glomerulonephritis may be caused by both abdominal pain, myalgias, and malaise. The pharyngeal and cutaneous GABHS infections, Gianotti-Crosti syndrome typically appears 12 hours to 48 hours after the such as perianal streptococcal infection. 13-15 Gianotti-Crosti syndrome (CGS), or papular onset of fever and is classically characterized by acrodermatitis of childhood, is a type IV 6,7 a sandpaper-like texture. Our patient did not Acute rheumatic fever typically occurs two to four hypersensitivity reaction to viral antigens. The most develop sandpaper-like skin findings, nor did weeks post GABHS infection. The Jones criteria common viral triggers include and she experience associated pharyngitis or tonsillar for diagnosis include both major and minor clinical EBV, but other causes include and C, enlargement. Her lesions also lacked the lacey findings. The major criteria include arthritis, , EBV rubella, CMV, coxsackievirus (A16, reticular pattern classically observed in parvovirus pancarditis, Sydenham chorea, subcutaneous nodules B4 and B5), adenovirus , respiratory eruptions. Laboratory testing confirmed diagnosis and erythema marginatum. The minor signs include syncytial , parainfluenza virus (types 1 and 2), with a positive throat culture and elevated anti- arthralgia, fever, elevated acute phase reactants, and paravirus B19, HHV 6, echovirus, poxvirus, and 16 streptolysin O antibody titer, strongly supporting a prolonged PR intervals. By the Jones criteria, in HIV. 24 streptococcal etiology. In addition, - order to diagnose rheumatic fever, a patient must specific IgM and IgG antibodies were absent. present with either two major signs or one major plus CGS is typically an abrupt eruption of two minor signs.17 Prompt diagnosis and treatment erythematous, flat-topped affecting the Scarlatina classically begins in the skin folds is essential in order to prevent the severe long-term face, extensor extremities and buttocks. These and then rapidly expands to cover the trunk and complication of rheumatic disease. papules may coalesce into hemorrhagic plaques and extremities; the palms and soles are usually spared. are either asymptomatic or pruritic.25 Diagnosis The skin-fold lesions often exhibit a linear petechial Acute glomerulonephritis is the leading cause of relies exclusively on clinical presentation. Recent character, known as Pastia’s lines, which was not acute nephritic syndrome. It occurs approximately studies have proposed diagnostic criteria for GCS, 5 observed in our case. Desquamation occurs after 10 days after GABHS pharyngitis and two weeks which include the clinical findings described above approximately four to five days in a cephalocaudal after GABHS . Most patients present along with symmetrical distribution, duration of progression. with oliguria, hematuria, flank pain, headache, 10 days, and a lack of truncal lesions and scaled 18 malaise, nausea, vomiting and anorexia. Diagnosis lesions.26 GCS is self- limiting, and treatment is 19 Strawberry tongue is another distinct finding of is based on clinical and serological findings. Acute supportive. scarletina. On day one or two, the tongue has a post-streptococcal nephritis in children generally heavy white coating that overlies edematous red resolves with a return to normal renal function and Epstein-Barr virus papillae, known as the “white strawberry tongue.” carries an excellent prognosis, while adults may Epstein-Barr virus (EBV), also known as human By day four or five, the white coating sloughs experience long-term effects such as hypertension herpesvirus 4, is best known as the causative off, leaving red, edematous papilla that produce a and proteinuria. agent of . Transmission 5 strawberry tongue appearance. occurs via saliva. In the United States, 50% of the Parvovirus B19 population is infected by the age of 5.27 Diagnosis and treatment of strep throat is based Erythema infectiosum, or , is a common on clinical manifestations delineated by the Centor childhood illness caused by parvovirus B19, a Cutaneous involvement is usually seen in children 8 criteria. The main criteria, each of which is worth single-stranded DNA virus that causes suppression and may be the only symptom present. The eruption one point, include: absence of cough; swollen and of erythrogenesis and pancytopenia. Although most is described as an erythematous macular rash in tender anterior cervical lymph nodes; temperature patients are asymptomatic, approximately 15% of a scattered, haphazard distribution. Cutaneous greater than 100.4° F (38° C); tonsillar exudates patients report a prodromal period characterized by findings are seen in 3% to 15% of those infected or swelling; and an age between 3 and 14 years fever, headache and flu-like symptoms. Cutaneous with EBV. Additional symptoms include fever, old. A score of 0-1 indicates a 1% to 10% chance features appear in roughly 25% of patients.20 hepatomegaly, splenomegaly, posterior cervical of GABHS infection, and no further testing or lymphadenopathy and pharyngitis.27 These treatment is required at this point. A score of 2-3 The exanthem typically begins on the malar cheeks symptoms are rare in children but may be seen in has an 11% to 35% probability of infection and as bright red, macular erythema, known commonly adolescents and adults. supports further testing with a rapid antigen test or as a “slapped cheek appearance.” Later, a lacy, throat culture. If either test is positive, antibiotics reticulated macular eruption spreads to the trunk Patients with EBV mistakenly diagnosed as should be administered. A score of 4 or greater has and extremities.21 In addition, approximately 10% streptococcal infection and treated with amoxicillin a 51% to 53% chance of infection and supports of patients develop transient mild arthralgia that or ampicillin will also present with a cutaneous prompt empiric treatment with antibiotics.9 lasts a few weeks.22 eruption. This rash is typically described as a

Page 21 CHILDHOOD EXANTHEMS: A DIFFERENTIAL CHALLENGE bright red, morbilliform eruption that occurs There are also two variants of the measles: modified The gold standard of treatment includes the full approximately one week after receiving improper and atypical. Modified measles is a milder dose of intravenous immunoglobulin (IVIG) and treatment. The eruption resolves spontaneously presentation with a longer incubation period, and high-dose aspirin. It is also imperative to screen for after treatment is discontinued.28 Infectious it occurs in patients who have preexisting measles coronary artery aneurysms with EKG at the time mononucleosis is self-limited and only requires immunity.36 Atypical measles, on the other hand, of diagnosis, at two weeks, again at six to eight supportive care. occurs in patients who received the previous weeks, and finally at one year after the onset of killed-virus vaccine rather than the live-attenuated symptoms.45 Coxsackie A16 virus vaccine. Because the killed-virus vaccine was Coxsackievirus is a single-stranded RNA distributed between 1963 and 1967, the atypical Henoch-Schönlein purpura enterovirus that most commonly affects children variant occurs in the current adult population.37 Henoch-Schönlein purpura (HSP), a vasculitis and infants. The virus is spread through multiple mediated by immunoglobulin A (IgA), affects routes, including fecal-oral and respiratory Measles can be diagnosed by clinical presentation small vessels mainly of the skin, kidneys, joints and droplets.29 are associated with a alone, but confirmation by laboratory testing is gastrointestinal tract. Although there is a confirmed variety of clinical manifestations including upper required due to the necessity of reporting any role for IgA in HSP, infectious, genetic, antigenic respiratory tract infection, , meningitis measles case to public health officials. Tests should and environmental factors are all thought to play and non-specific cutaneous eruptions. Coxsackie include a complete blood count, liver enzymes, a role in the disease. HSP is the most common A16 is responsible for the exanthem hand, foot serological markers (IgG and IgM antibodies), viral vasculitis in children, with 90% of cases presenting and mouth disease (HFMD) and the cultures, and reverse transcriptase polymerase chain between the ages of 3 years and 10 years, but it can . reaction testing.31 The measles virus is self-limited, also occur in adults.46 but patients should be given supportive care and HFMD begins as vesicular lesions typically on the vitamin A supplementation. Vitamin A has been The cutaneous eruption is usually the complaint palms, soles, and oral mucosa but can also present on shown to reduce mortality in up to 50% of cases, upon presentation. It typically occurs symmetrically 30 the extremities, trunk and neck. Herpangina, on as well as prevent ocular damage and blindness.38 and in crops, with new crops occurring for up to the other hand, presents as vesicles in the posterior three weeks.47 The rash usually begins as a macular oropharynx. In HFMD and herpangina, patients or urticarial eruption on the lower extremities and often report sore throat, fever and headache. Kawasaki disease is a febrile vasculitis affecting buttocks. The initial lesions coalesce and form small- and medium-sized vessels. It is the leading petechiae and palpable purpura, marking the Diagnosis of HFMD and herpangina relies cause of acquired cardiac disease in children.39 hallmark finding of HSP. primarily on clinical exam findings; however, viral Although the cause of Kawasaki is unknown, it is culture of vesicular fluid may be performed for theorized to be an infectious process worsened by The American College of Rheumatology has confirmatory purposes. Both conditions are self- genetic components.40 developed clinical diagnostic criteria for HSP, which limited, and treatment consists of supportive care. include: palpable purpura, presentation before age Patients with Kawasaki disease go through three 20, abdominal pain, and a cutaneous biopsy showing Measles clinical phases: acute, subacute and convalescent. granulocytes in the walls of arterioles or venules.48 Measles, also known as rubeola, is a highly In the acute phase, patients initially present with If suspicion is present, the vasculitis workup should contagious, single-stranded RNA virus most an abrupt onset of fever that does not subside with also be completed as a confirmatory measure. In our commonly seen in children, though it can occur antibiotic or antipyretic treatment. This phase may patient, the distribution and at any age. Individuals who are susceptible to the last for up to four weeks. The cutaneous findings of absence of abdominal pain made the diagnosis of virus have a 90% chance of becoming infected upon perianal, palm and sole erythema and desquamation HSP unlikely. Furthermore, our biopsy did not show exposure. Transmission occurs through respiratory present in the acute phase, as well. The rash begins granulocytes on the walls of the vasculature. droplets, either airborne or on a surface. People to evolve into a macular, morbilliform eruption on immunized with the live-attenuated vaccine are the trunk and extremities. Bilateral nonexudative Because HSP is self-limiting, treatment is typically protected from contracting the virus upon , anterior uveitis, strawberry tongue, supportive. If gastrointestinal and renal complaints 31 exposure. lip fissures, secondary organ dysfunction and are present, hospitalization is required to monitor lymphadenopathy may also present in the acute patients to prevent further complications. Those In 2000, the virus was considered to be eliminated phase. When the fever begins to subside, the who do not require hospitalization need close in the United States, but due to a decrease in patient has entered the subacute phase. The follow-up with urine studies to confirm the childhood vaccinations, measles has been on an hallmarks of this phase are desquamation on the disease has run its course without further systemic uptrend. Between 2000 and 2014, 288 cases were complications.48 32 digits and a risk of coronary aneurysm that may confirmed by the CDC. Of those infected, lead to sudden death. Once the clinical signs and patients were either unimmunized or had an symptoms have cleared, with the exception of unclear vaccination history. Beau’s lines,41 the patient is considered to be in Erythema multiforme (EM) is considered a type the convalescent phase. IV hypersensitivity reaction to infection, drugs, The clinical manifestation of measles occurs in radiation, autoimmune diseases, malignancies and four stages: incubation, prodromal, exanthematous various other factors. Of reported cases, 90% were 33 The diagnosis of Kawasaki disease is clinical; and recovery. In the incubation period, which laboratory tests and imaging are confirmatory. caused by an infectious process, and of those, HSV lasts for up to three weeks post exposure, patients The diagnostic criteria, created by Tomisaku was the most common. pneumoniae is are typically asymptomatic or may begin to show also a common cause, mainly in children.49 34 Kawasaki, include a fever that lasts for at signs of fever, respiratory symptoms and rash. least five days and at least four out of the five The prodromal period usually lasts for two to following signs: bilateral conjunctival , As the name implies, erythema multiforme has a four days and marks the stage of characteristic mucosal changes (erythematous or fissured lips, wide range of cutaneous presentations; however, symptoms including cough, coryza and the hallmark of EM is a target lesion. This may 35 erythematous , or strawberry tongue), conjunctivitis. Fever, malaise, and anorexia are extremity changes (erythematous or edematous be the initial presentation, or it may start as an also seen in this stage. The cutaneous outbreak palms or soles, or desquamation), polymorphous erythematous macule, or urticarial plaque occurs two to four days after the fever begins, cutaneous eruption, and cervical lymphadenopathy that later morphs into a target lesion. A target whether in the incubation or prodromal phase. (measuring greater than 1.5 cm). Patients who do lesion has a central clearing and/or blistering, along The rash is described as blanchable, erythematous, with an edematous and pale periphery surrounded not meet the criteria but prompt high suspicion for 50 maculopapular lesions that begin on the face and the diagnosis are considered to have incomplete by an erythematous halo. spread downward to the trunk and extremities. Kawasaki disease.42,43 The soles and palms are typically spared. The The diagnosis is based on clinical findings; however, rash usually lasts for two days and then begins to Appropriate laboratory testing includes complete a skin biopsy is warranted in the case of uncertainty improve, indicating the recovery phase. Although blood count, liver enzymes, C-reactive proteins, due to atypical presentation or suspicion of the description, distribution and time frame of erythrocyte sedimentation rate and urine analysis. underlying . Due to the high the rash fits our case, the prodromal characteristic In studies, urine proteins filamin C and meprin A incidence of HSV and mycoplasma pneumoniae, findings were absent. have shown promise as confirmatory biomarkers.44 serological testing for both is also warranted.

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