Kliegman: Nelson Textbook of Pediatrics, 18th ed.Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 253 – Roseola (Human Herpesviruses 6 and 7) Charles T. Leach

Human herpesvirus 6 (HHV-6) is a dominant cause of roseola infantum (exanthem subitum or sixth disease), and possibly of other diseases in normal and immunocompromised patients. Disease associations for HHV-7 are fewer, but include a roseola-like illness.

ETIOLOGY.

Primary infection with HHV-6, and less frequently HHV-7, causes the majority of cases of roseola. Other viruses (echovirus 16) probably account for the remainder. Nonetheless, most primary infections with HHV-6 and HHV-7 do not result in roseola.

HHV-6 and HHV-7 belong to the β-herpesvirus subfamily of herpesviruses, which includes human cytomegalovirus (CMV). HHV-6 and HHV-7 share physical and biologic characteristics with other herpesviruses, including a large double-stranded DNA genome, the presence of a nucleocapsid, and the establishment of latency after primary infection. HHV-6 is essentially colinear with HHV-7, and both viruses share much homology with CMV. HHV-6 and HHV-7 most efficiently replicate in CD4 T cells; HHV-6 can also infect other T cells, macrophages, epithelial cells, endothelial cells, fibroblasts, hepatic cells, glial cells, fetal astrocytes, and bone marrow progenitor cells. In the laboratory, HHV-6 and HHV-7 are typically cultivated in mitogen-stimulated human mononuclear cells (isolated from cord blood or peripheral blood) and can be identified by the development of large balloon-like cells accompanied by cell lysis. Two distinct types of HHV-6 (types A and B) exist. Type B causes more than 99% of HHV-6-associated roseola cases. Latent type A virus can be found in immunodeficient as well as healthy patients and may reactivate in severely ill adult patients; however, it has not been consistently linked with disease.

EPIDEMIOLOGY.

Primary HHV-6 infection occurs early in life. Most (>90%) of newborn infants are HHV-6 seropositive, reflecting transplacental transfer of maternal antibodies. Before 6 mo of age, there is a low rate of primary HHV-6 infection (<10%). However, a rapid increase occurs subsequently, and by 12 mo of age 40% of infants are HHV-6 infected, and 80% acquire infection by 2 yr of age. Peak acquisition of primary HHV-6 infection, from 6 to 15 mo of age, corresponds with peak incidence of roseola. The most common symptoms in infants with HHV-6 infection are fever and fussiness (90%). Only ¼ of infected children have clinically recognizable roseola. Curiously, much higher rates of roseola symptoms occur in Japanese infants with primary HHV-6 infection. Primary infection with HHV-7 generally occurs slightly later than HHV-6 infection.

Roseola occurs throughout the year. Unlike some of the other childhood exanthems, children with roseola rarely report contact with other affected children, and outbreaks are uncommon. Sex, race, and geography do not play an important role in acquisition of roseola. The incubation period averages 10 days, with a range of 5–15 days.

Most adults excrete HHV-6 and HHV-7 in saliva and may serve as primary sources for virus transmission to children. Although women may uncommonly excrete HHV-6 and HHV-7 in the genital tract, sexual transmissibility has not been demonstrated. HHV-6 can be transmitted in utero at low rates (<2%), with approximately ⅔ associated with type B; only 1 neonate with symptomatic congenital infection has been described. Most congenitally infected patients are asymptomatic, but reactivation may occur after birth. No congenital HHV-7 infections have been identified. There are rare reports of HHV-6 transmission to susceptible infants via donor bone marrow or solid organs. There is no evidence that infection is spread by breast milk, fecal-oral contamination, or blood transfusion.

PATHOGENESIS.

Virus is probably acquired from the saliva of healthy persons and enters the host through the oral, nasal, or conjunctival mucosa. Cellular receptors for both viruses have been identified: HHV-6 uses the CD46 receptor (widespread among tissues), and HHV-7 uses the CD4 receptor, which is also used by HIV-1. Following viral replication at an unknown site, a high level of viremia develops in peripheral blood mononuclear cells (PBMCs). After acute infection, HHV-6 and HHV-7 establish latency in blood mononuclear cells and possibly in other sites, including salivary glands, kidneys, lungs, and central nervous system. The basis for the unique pattern of rash after resolution of fever in children with roseola is unknown.

HHV-6 can suppress all cellular lineages within the bone marrow; active HHV-6 infection is associated with bone marrow suppression in bone marrow transplant patients. HHV-6 infection also has significant effects on the immune system, including downregulation of the major histocompatibility complex (MHC) type I response, enhancement of natural killer (NK) T-cell activity, suppression of PBMC proliferation, and induction of a proinflammatory cytokine response.

CLINICAL MANIFESTATIONS.

Roseola is the prototypical HHV-6 and HHV-7 infection, although nonspecific infections are common.

Roseola Infantum (Exanthem Subitum).

Roseola is a mild febrile, exanthematous illness occurring almost exclusively during infancy. More than 95% of roseola cases occur in children younger than 3 yr, with a peak at 6–15 mo of age. Transplacental antibodies likely protect most infants until 6 mo of age.

Infants with classic roseola exhibit a unique constellation of findings displayed over a short period of time. Consequently, classic roseola is infrequently confused with other childhood exanthems.

The prodromal period of roseola is usually asymptomatic but may include mild upper respiratory tract signs, among them minimal rhinorrhea, slight pharyngeal inflammation, and mild conjunctival redness. Mild cervical or, less frequently, occipital lymphadenopathy may be noted. Some children may have mild palpebral edema. Physical findings during the prodromal stage have no clear relationship to roseola, and may simply reflect an accompanying respiratory viral infection. Clinical illness is generally heralded by high temperature, usually ranging from 37.9 to 40°C (101–106°F), with an average of 39°C (103°F). Some children may become irritable and anorexic during the febrile stage, but most behave normally despite high temperatures. Seizures may occur in 5–10% of children with roseola during this febrile period. Infrequent complaints include rhinorrhea, sore throat, abdominal pain, vomiting, and diarrhea. In Asian countries, ulcers at the uvulopalatoglossal junction (Nagayama spots) are common in infants with roseola. Fever persists for 3–5 days, and then typically resolves rather abruptly (“crisis”). Occasionally, the fever may gradually diminish over 24–36 hours (“lysis”). A rash appears within 12–24 hr of fever resolution. In many cases, the rash develops during defervescence or within a few hours of fever resolution. The rash of roseola is rose colored, as the name implies, and is fairly distinctive ( Fig. 253-1 ). However, it may be confused with exanthems resulting from rubella, measles, or erythema infectiosum. The roseola rash begins as discrete, small (2–5 mm), slightly raised pink lesions on the trunk and usually spreads to the neck, face, and proximal extremities. The rash is not usually pruritic, and no vesicles or pustules develop. Lesions typically remain discrete but occasionally may become almost confluent. After 1–3 days, the rash fades. Some children experience evanescent rashes that resolve within a few hours. Subtle differences in clinical presentation have been noted between roseola associated with HHV-7 compared with HHV-6. These include a slightly older age, lower mean temperature, and shorter duration of fever in HHV-7-associated cases. However, these differences are insufficient to clinically distinguish HHV-6- from HHV-7-associated roseola. There are reports of children experiencing HHV-6-associated roseola followed later by HHV-7-associated roseola.

Figure 253-1  Roseola infantum. Erythematous, blanchable macules and papules (A) in an infant who had a high fever for 3 days preceding the skin eruption. On closer inspection (B), some lesions reveal a subtle peripheral halo of vasoconstriction.  (From Paller AS, Mancinin AJ [editors]: Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadelphia, Elsevier, 2006, p 434.)

Fever in Infants Without Classic Roseola.

HHV-6 and HHV-7 account for a significant proportion of nonspecific febrile illnesses, without a focus of infection, in infants. Approximately 15% of febrile infants presenting to hospital emergency room have primary HHV-6 or HHV-7 infection.

Central Nervous System Infections.

Both HHV-6 and HHV-7 are neurotropic and can invade the CNS. Primary HHV-6 infection is responsible for approximately 10–20% of febrile seizures in infants. Most of these children do not subsequently experience a rash. Smaller studies suggest that HHV-7 is also linked with some febrile seizures. HHV-6 and HHV-7 are associated with rare cases of encephalitis and meningoencephalitis, mostly occurring in immunocompromised patients. HHV-6 DNA is present in cerebrospinal fluid from 6% of children and adults with focal encephalitis of unknown cause.

Mononucleosis-like Illness and Hepatitis.

Several heterophile-negative mononucleosis-like infections associated with HHV-6 have been reported in adults. HHV-6 and HHV-7 may rarely cause clinical symptoms of hepatitis. There is controversy regarding the association of HHV-6 with some cases of fulminant liver failure in infants.

Infections in Immunocompromised Patients.

Numerous severe and occasionally fatal HHV-6-associated infections (encephalitis, pneumonitis) have occurred in immunocompromised patients, including patients with AIDS or organ transplants. These have occurred predominantly in stem cell transplant recipients and usually reflect reactivated HHV-6 infection. Concomitant HHV-6 and HHV-7 infections may augment CMV-associated disease following organ transplantation.

Because HHV-6 shares CD4 cell tropism with HIV, upregulates HIV, and stimulates in vitro replication of HIV, there has been considerable interest in the role of HHV-6 as a cofactor for clinical progression of AIDS. Epidemiologic studies in adults do not support a significant role for HHV-6 as a cofactor. Only 1 small pediatric study suggests more rapid progression of immune deficiency in HIV/HHV-6 co-infected infants. Further prospective studies are necessary to assess the impact of HHV-6 on HIV-infected children.

Other Diseases Possibly Associated with HHV-6 or HHV-7.

Rash illness without fever has been described in a small number of infants with primary HHV-6 infection. Small studies or case reports have suggested that HHV-6 may be associated with a wide range of other diseases, including some cases of hemophagocytic syndrome, intussusception, idiopathic thrombocytopenic purpura, recurrent aphthous stomatitis, myocarditis, drug hypersensitivity, Gianotti-Crosti syndrome, progressive multifocal leukoencephalopathy, influenza encephalopathy, large vessel arteritis, Kikuchi's necrotizing lymphadenitis, histiocytosis, and chronic fatigue syndrome. Controversy continues regarding a relationship between HHV-6 and multiple sclerosis. There are conflicting data linking HHV-7 and pityriasis rosea. HHV-6 DNA has been detected in various malignancies, including non-Hodgkin lymphoma, Hodgkin disease, cervical and oral carcinoma, and leukemia. No consistent etiologic relationship has been established with any of these cancers.

DIAGNOSIS.

The most important reason for establishing the diagnosis of roseola is to differentiate this generally mild illness from other potentially more serious childhood rash illnesses such as measles. It is also important to identify other, more serious illnesses caused by HHV-6, such as encephalitis and pneumonitis, especially in immunocompromised patients, for timely consideration of antiviral therapy.

The diagnosis of roseola can be established primarily on the basis of age, history, and clinical findings. HHV-6- and HHV-7-associated roseola cases cannot be distinguished solely on clinical grounds. Specific testing for HHV-6 or HHV-7 infection may be performed using laboratory methods, including serology, virus culture, and polymerase chain reaction (PCR).

HHV-6 serologic testing is available from many commercial laboratories; few offer HHV-7 serology. An HHV-6 immunoglobulin M (IgM) response typically develops by the 5th–7th day of illness, peaks at 2–3 wk, and resolves within 2 mo. Unfortunately, the accuracy of currently available IgM tests varies widely, and none have been sufficiently evaluated to provide unequivocal evidence of acute HHV-6 infection. Seroconversion of HHV-6 or -7 IgG antibodies in serum samples collected 2–3 wk apart is a more reliable means of establishing primary infection, but is not timely. Four-fold increases or decreases in HHV-6 or -7 IgG antibodies also suggest active infection (primary or reactivated). Because of the high seroprevalence of these viruses in the general population, a single positive HHV-6 or -7 IgG test is of no significance for diagnosis of acute infection. CMV antibodies can cross react with HHV-6 and HHV-7; therefore, diagnosis of HHV-6 and HHV-7 infections by serologic means requires exclusion of CMV infection.

Identification of HHV-6 or HHV-7 in PBMCs by virus culture firmly establishes the presence of active infection in immunocompetent hosts; association with specific disease is more problematic in immunocompromised patients as a result of a low background rate of viremia. Identification of HHV-6 and HHV-7 by culture requires incubation of PBMCs (with or without co-cultivation with exogenous PBMCs) for days to several weeks, and is presently available only in research laboratories. A commercial HHV-6 rapid (shell-vial) culture is available.

PCR amplification tests for HHV-6 are becoming available and may provide more timely information for diagnosis. Active, replicating infection is indicated if HHV-6 DNA is detected in acellular specimens such as serum or cerebrospinal fluid. It should be noted that detection at other sites (PBMCs, saliva, tissues) does not necessarily indicate active infection, because HHV-6 exists in latent form in many tissues after primary infection. Quantitative PCR and reverse transcriptase PCR may be more useful for diagnosis of active infection using cellular blood specimens, if suitable cutoff thresholds are established. Several commercial laboratories offer quantitative as well as qualitative PCR testing on a variety of specimens. Although not widely available, other diagnostic tests for consideration in selected circumstances include in situ hybridization, immunohistochemistry, and antigen assays.

LABORATORY FINDINGS.

White blood cell (WBC) counts of 8,000–9,000 WBCs/μL may be found during the 1st few days of fever in children with roseola, but by the time the exanthem appears, the WBC count falls to 4,000–6,000 WBCs/μL with a relative lymphocytosis (70–90%). The cerebrospinal fluid in

children with HHV-6-associated febrile seizures typically is normal. The cerebrospinal fluid from rare cases of HHV-6-associated meningoencephalitis and encephalitis is characterized by a mild pleocytosis with predominance of mononuclear cells, normal glucose, and normal to slightly elevated protein.

DIFFERENTIAL DIAGNOSIS.

Children with roseola typically present at 2 different stages of the illness: at the time of fever before the rash (pre-eruptive) and after the rash has appeared. During the pre-eruptive stage, many conditions may be confused with roseola. However, the pattern of fever in a generally well child without significant physical findings, rather precipitous defervescence, and a subsequent rash is unique for roseola.

Roseola historically has been most commonly confused with rubella and measles; with the virtual elimination of these diseases in the United States, there should be little reason to confuse roseola with these diseases, unless there is an exposure history. In contrast to the absence of a distinct prodrome in children with roseola, children with rubella invariably have a mildly symptomatic prodromal period, including prominent occipital and postauricular lymphadenopathy (see Chapter 244 ). Lymphadenopathy is an inconsistent finding in roseola; when present, the occipital lymph nodes are more frequently affected than those in the postauricular region. Rubella usually causes only low-grade fever, which is coincident with the exanthem. The rubella rash is typically more extensive than that seen with roseola, and coalescence is more common. The development of an exanthem at the height of the fever as well as the presence of cough, coryza, conjunctivitis, and Koplik spots on the buccal mucosa in the early stages of measles should clearly differentiate measles from roseola (see Chapter 243 ).

Outbreaks of roseola-like illnesses have been associated with many different viruses, most commonly enteroviruses. In summer and fall months, some cases of roseola-like illnesses may be attributable to enteroviruses.

Scarlet fever may also resemble roseola. Important features of scarlet fever are its rarity in infancy, the simultaneous presence of fever and rash, and the discrete, small, sandpaper-like rash lesions.

Drug hypersensitivity is a common condition resembling roseola. Antibiotics are frequently prescribed to children with roseola during the febrile phase before onset of the rash. A child who acquires a drug rash may do so soon after resolution of the fever, which is the characteristic pattern for children with roseola. However, the usually morbilliform nature, pruritus, and resolution after discontinuation of the implicated drug should distinguish a drug rash.

It may be difficult to distinguish central nervous system disease caused by HHV-6 from other causes. Development of a roseola-like illness in association with febrile seizures, meningoencephalitis, or encephalitis makes HHV-6 infection more likely, yet this occurs infrequently. Hepatitis and heterophile-negative mononucleosis are rarely associated with HHV-6, and other causes for these infections should first be sought.

TREATMENT.

HHV-6 is inhibited by ganciclovir, cidofovir, and foscarnet (but not acyclovir) at levels that are achievable in serum; HHV-7 is inhibited by cidofovir and foscarnet. Case reports have indicated successes and failures with these drugs. Adequate prospective trials evaluating the clinical efficacy of antiviral agents for HHV-6 or HHV-7 infections have not been performed. There is not an approved treatment of these infections. The generally benign nature of roseola precludes consideration of antiviral therapy in immunocompetent persons. Treatment is warranted for immunocompromised children with severe disease confirmed to be associated with HHV-6 or HHV-7. Ganciclovir and cidofovir are most commonly used, with duration of therapy typically 2–3 weeks.

Children in the febrile, pre-eruptive phase of roseola usually are quite comfortable and require little supportive therapy. Those children who are uncomfortable and irritable, or in whom histories of febrile convulsions exists, may benefit from treatment with acetaminophen or ibuprofen. Adequate fluid balance should be maintained in all affected children. Referral should be considered in those unusual circumstances in which serious disease develops, such as encephalitis, hepatitis, or pneumonitis.

PROGNOSIS.

The prognosis for the great majority of children with roseola is excellent, with no obvious sequelae. Before the discoveries of HHV-6 and HHV-7, rare complications of roseola (hemiparesis, mental retardation) were attributable to brain anoxia during prolonged febrile seizures, though damage resulting from direct viral invasion of the brain, liver, and other organs has been demonstrated for HHV-6. Deaths directly attributable to HHV-6 have been reported in normal as well as immunocompromised patients in whom encephalitis, hepatitis, pneumonitis, disseminated disease, or hemophagocytosis syndrome developed.

PREVENTION.

Very little information is available on which to base guidelines for prevention of HHV-6 or HHV-7 infection. Experimental evidence suggests that roseola may be transmitted via blood or saliva, and both HHV-6 and HHV-7 are shed in the saliva. It is likely that healthy immune carriers with latent viral infections transmit infection to susceptible infants and children via saliva.

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current diadnosis & treatment pediatric edisi 19Viral Infections: Introduction

Viruses cause most pediatric infections. Mixed viral or viral-bacterial infections of the respiratory and intestinal tracts are rather common, as is prolonged asymptomatic shedding of some viruses in childhood. Thus the detection of a virus is not always proof that it is the cause of a given illness. Viruses are often a predisposing factor for bacterial respiratory infections (eg, otitis, sinusitis, and pneumonia).

Many respiratory and herpes viruses can now be detected within 24–48 hours by combining culture and monoclonal antibody techniques ("rapid culture technique"). Diagnosis of many viral illnesses is also possible through antigen or nucleic acid detection techniques. These techniques are more rapid than isolation of viruses in tissue culture and in most cases are equally sensitive or more so. Polymerase chain reaction (PCR) amplification of viral genes has led to recognition of previously undetected infections. New diagnostic tests have changed some basic concepts about viral diseases and made diagnosis of viral infections both more certain and more complex. Only laboratories with excellent quality-control procedures should be used, and the results of new tests must be interpreted cautiously. The availability of specific antiviral agents increases the value of early diagnosis for some serious viral infections. Table 38–1 lists viral agents associated with common clinical signs, and Table 38–2 lists diagnostic tests. The viral diagnostic laboratory should be contacted for details regarding specimen collection, handling, and shipping. Table 38–3 lists common causes of red rashes in children that should be considered in the differential diagnosis of certain viral illnesses.

Table 38–1. Some Viral Causes of Clinical Syndromes.

Rash  Adenopathy  Arthritis (Arthralgia) 

  Enterovirus   Epstein-Barr virus   Parvovirus B19

  Adenovirus   Cytomegalovirus   Rubella

  Measles   Rubellae

   Hepatitis B

  Rubella   HIV Dengue

  Human herpes virus type 6a or 7a

 Croup  Congenital or perinatal

infection 

  Varicella   Parainfluenza   Adenovirus

  Parvovirus B19b

   Influenza   Cytomegalovirus

  Epstein-Barr virus   Adenovirus   Hepatitis B

  Dengue   Other respiratory viruses

  Hepatitis Cl

 

  Human immunodeficiency virus (HIV), acute syndrome

Bronchiolitis    Rubella

  Respiratory syncytial virusf

 

  HIV

Fever    Adenovirus   Parvovirus B19

  Enterovirus   Parainfluenza   Enterovirus

  Epstein-Barr virus   Influenza   Varicella

  Human herpes virus type 6a or 7 

  Human metapneumovirus

  Herpes simplex virus

  Cytomegalovirus Pneumonia  Meningoencephalitis 

  Influenza   Respiratory syncytial virus

  Enterovirus

  Rhinovirus   Adenovirus   Mumps

  Most others   Parainfluenza   Other Arthropod-borne viruses

Conjunctivitis    Hantavirus   Herpes simplex virus

  Adenovirus   Measles   Cytomegalovirus

  Enterovirus 70   Varicellag

   Lymphocytic choriomeningitis virus

  Measles   Cytomegalovirush,i

   Measles

  Herpes simplex virusc

   Influenza   Varicella

Parotitis  Enteritis    Adenovirus

  Mumps   Rotavirus   HIV

  Parainfluenza   Enteric adenovirus   Epstein-Barr virus

  Enterovirus   Enterovirus   Influenza

  Cytomegalovirus   Astrovirus   West Nile virus

  Epstein-Barr virus   Calicivirus  

  HIV   Novovirus  

Pharyngitis    Cytomegalovirus  

  Adenovirus Hepatitis   

  Enterovirus   Hepatitis Aj, B, C, D, E 

 

  Epstein-Barr virus   Epstein-Barr virus  

  Herpes simplex virusd

   Adenovirus  

  Influenza   Cytomegalovirus  

  Other respiratory viruses   Varicellak

  

    Parvovirus B19  

aRoseola agent.

bErythema infectiosum agent.

cConjunctivitis rare, only in primary infections; keratitis in older patients.

dMay cause isolated pharyngeal vesicles at any age.

eMay cause adenopathy without rash; especially post-auricular.

fOver 70% of cases.

gImmunosuppressed, pregnant, rarely other adults.

hUsually only in young infants.

iSeverely immunosuppressed at risk.

jAnicteric cases more common in children; these may resemble viral gastroenteritis.

kCommon, but only mild laboratory abnormalities.

lEspecially when the mother is HIV-positive.

Table 38–2. Diagnostic Tests for Viral Infections.

Agent Rapid Antigen Detection (Specimen)

Tissue Culture Mean Days to Positive (Range)

Serology  Comments

Acute  Paired  PCRa 

Adenovirus + (respiratory and enteric)

10 (1–21) – + + "Enteric" strains detected by culture on special cell line, antigen detection, or

PCR

Arboviruses – – + + + Acute serum may diagnose many forms

Astrovirus – – – – + Diagnosis by electron microscopy

Calicivirus – – – – + Diagnosis by electron microscopy

Colorado tick virus On RBC – – RL, CDC

+

Coronavirus – RL – + +

Cytomegalovirus + (tissue biopsy, urine, blood, respiratory secretions)

2 (2–28) + + + Diagnosis by presence of IgM antibody

Enterovirus – 2 (2–14) – + +

Epstein-Barr virus – – + + + Single serologic panel defines infection status; heterophil antibodies less sensitive

Hantavirus – – + ND RL Diagnosis by presence of IgM antibody

Hepatitis A virus – – + ND RL Diagnosis by presence of IgM antibody

Hepatitis B virus + (blood) – + ND + Diagnosis by presence of surface antigen or anti-core IgM antibody

Hepatitis C virus – – + ND + Positive serology suggests that hepatitis C may be the causative agent. PCR is confirmatory.

Herpes simplex virus

+ (mucosa, tissue biopsy, respiratory secretions, skin)

1 (1–7) + + + Serology rarely used for herpes simplex. IgM antibody used in selected cases.

Human herpesvirus-6 and 7

– 2 + + + Roseola agent

Human immunodeficiency virus

+ (blood) (acid dissociation of immune complexes)

15 (5–28) + ND + Antibody proves infection unless passively acquired (< age 15 mo); culture not widely available; PCR definitive for early diagnosis in infant

Human metapneumovirus

+ 2 – + +

Influenza virus + (respiratory secretions)

2 (2–14) – + + Antigen detection 70–90% sensitive

Lymphocytic choriomeningitis virus

– – – + RL Can be isolated in suckling mice

Measles virus + (respiratory secretions)

– + + + Difficult to grow; IgM serology diagnostic

Mumps virus – > 5 + + + IgM ELISA antibody may allow single-specimen diagnosis

Parvovirus B19 – – + ND + Erythema infectiosum agent

Parainfluenza virus + (respiratory secretions)

2 (2–14) – + +

Rabies virus + (skin, conjunctiva, suspected animal source tissue biopsy)

– + + CDC Usually diagnosed by antigen detection

Respiratory syncytial virus

+ (respiratory secretions)

2 (2–21) – + + Rapid antigen detection; 90% sensitive

Rhinovirus – 4 (2–7) – – + Too many strains to type serologically

Rotavirus + (feces) – – – + Electron microscopy useful for many enteric viruses

Rubella virus – > 10 + + + Recommended that paired sera be tested simultaneously

Varicella-zoster virus

+ (skin scraping)

3 (3–21) RL

+ + +  

West Nile virus – RL + + +  

aUseful only when performed on selected specimens by qualified laboratories.

Key:

Plus signs signify commercially or widely available; minus signs signify not commercially available. Note: Results from some commercial laboratories are unreliable.

RL, CDC: Specific antibody titers or PCR available by arrangement with individual research laboratories or the Centers for Disease Control and Prevention.

ND: Not done.

ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; RBC, red blood cell.

Table 38–3. Red Rashes in Children.

Condition Incubation Period (days)

Prodrome Rash Laboratory Tests Comments, Other Diagnostic Features

Adenovirus 4–5 URI; cough; fever

Morbilliform (may be petechial)

Normal; may see leukopenia or lymphocytosis

Upper or lower respiratory symptoms are prominent. No Koplik spots. No desquamation.

Drug allergy — None, or fever alone, or with myalgia, pruritus

Macular, maculopapular, urticarial, or erythroderma

Leukopenia, eosinophilia

Rash variable. Severe reactions may resemble measles, scarlet fever; Kawasaki disease; marked toxicity possible.

Enterovirus 2–7 Variable fever, chills,

Usually macular,

Variable Varied rashes may resemble

myalgia, sore throat

maculopapular on trunk or palms, soles; vesicles or petechiae also seen

those of many other infections. Pharyngeal or hand-foot-mouth vesicles may occur.

Ehrlichiosis (monocytic)

5–21 Fever; headache; flulike; myalgia; GI symptoms

Variable; maculopapular, petechial, scarlatiniform, vasculitic

Leukopenia, thrombocytopenia, abnormal liver function. Serology for diagnosis; morulae in monocytes.

Geographic distribution is a clue; seasonal; tick exposure; rash present in only 45%.

Erythema multiforme

— Usually none or related to underlying cause

Discrete, red maculopapular lesions; symmetrical, distal, palms and soles; target lesions classic

Normal or eosinophilia

Reaction to drugs (especially sulfonamides), or infectious agents (mycoplasma; herpes simplex virus). Urticaria, arthralgia also seen.

Kawasaki disease

Unknown Fever, cervical adenopathy, irritability

Polymorphous (may be erythroderma) on trunk and extremities; red palms and soles, conjunctiva, lips, tongue, pharynx. Desquamation is common.

Leukocytosis, thrombocytosis, elevated ESR or C-reactive protein; pyuria; decreased albumin; negative cultures and streptococcal serology; resting tachycardia

Swollen hands, feet; prolonged illness; uveitis; aseptic meningitis; no response to antibiotics. Vasculitis and aneurysms of coronary and other arteries occur (cardiac ultrasound).

Leptospirosis 4–19 Fever (biphasic), myalgia, chills

Variable erythroderma

Leukocytosis; hematuria, proteinuria; hyperbilirubinemia

Conjunctivitis; hepatitis, aseptic meningitis may be seen. Rodent, dog

contact.

Measles 9–14 Cough, rhinitis, conjunctivitis

Maculopapular; face to trunk; lasts 7–10 d; Koplik spots in mouth

Leukopenia Toxic. Bright red rash becomes confluent, may desquamate. Fever falls after rash appears. Inadequate measles vaccination.

Parvovirus (erythema infectiosum)

10–17 (rash)

Mild (flulike) Maculopapular on cheeks ("slapped cheek"), forehead, chin; then down limbs, trunk, buttocks; may fade and reappear for several weeks

IgM-EIA; PCR Purpuric stocking-glove rash is rare, but distinctive; aplastic crisis in patients with chronic hemolytic anemia. May cause arthritis or arthralgia.

Rocky Mountain spotted fever

3–12 Headache (retro-orbital); toxic; GI symptoms; high fever; flulike

Onset 2–6 d after fever; palpable maculopapular on palms, soles, extremities, with spread centrally; petechial

Leukopenia; thrombocytopenia; abnormal liver function; CSF pleocytosis; Serology positive at 7–10 d of rash; biopsy will give earlier diagnosis

Eastern seaboard and southeastern United States; April–September; tick exposure.

Roseola (exanthem subitum) (HHV-6)

10–14 Fever (3–4 d) Pink, macular rash occurs at end of febrile period; transient

Normal Fever often high; disappears when rash develops; child appears well. Usually occurs in children 6 mo–3 y of age. Seizures may complicate.

Rubella 14–21 Usually none Mild Normal or Postauricular,

maculopapular; rapid spread face to extremities; gone by day 4

leukopenia occipital adenopathy common. Polyarthralgia in some older girls. Mild clinical illness. Inadequate rubella vaccination.

Staphylococcal scalded skin

Variable Irritability, absent to low fever

Painful erythroderma, followed in 1–2 d by cracking around eyes, mouth; bullae form with friction (Nikolsky sign)

Normal if only colonized by staphylococci; leukocytosis and sometimes bacteremia if infected

Normal pharynx. Look for focal staphylococcal infection. Usually occurs in infants.

Staphylococcal scarlet fever

1–7 Variable fever

Diffuse erythroderma; resembles streptococcal scarlet fever except eyes may be hyperemic, no "strawberry" tongue, pharynx spared

Leukocytosis is common because of infected focus

Focal infection usually present.

Stevens-Johnson syndrome

— Pharyngitis, conjunctivitis, fever, malaise

Bullous erythema multiforme; may slough in large areas; hemorrhagic lips; purulent conjunctivitis

Leukocytosis Classic precipitants are drugs (especially sulfonamides), Mycoplasma pneumoniae and herpes simplex infections. Pneumonitis and urethritis also seen. 

Streptococcal scarlet fever

1–7 Fever, abdominal

Diffuse erythema,

Leukocytosis; positive group A

Strawberry tongue, red

pain, headache, sore throat

"sandpaper" texture; neck, axillae, inguinal areas; spreads to rest of body; desquamates 7–14 d

Streptococcus culture of throat or wound; positive streptococcal antigen test in pharynx 

pharynx with or without exudate. Eyes, perioral and periorbital area, palms, and soles spared. Pastia lines. Cervical adenopathy. Usually occurs in children 2–10 y of age.

Toxic shock syndrome

Variable Fever, myalgia, headache, diarrhea, vomiting

Nontender erythroderma; red eyes, palms, soles, pharynx, lips

Leukocytosis; abnormal liver enzymes and coagulation tests; proteinuria

Staphylococcus aureus infection; toxin-mediated multiorgan involvement. Swollen hands, feet. Hypotension or shock. 

CSF, cerebrospinal fluid; EIA, enzyme immunoassay; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HHV-6, human herpesvirus 6; IFA, immunofluorescent assay; PCR, polymerase chain reaction; URI, upper respiratory infection.