Cutaneous manifestations of systemic infection in children

Cutaneous Manifestations of Systemic Infection in Children Neil S. Prose MD Steven D. Resnick, MD Introduction The child with rash and fever presents a particular challenge in the course of pediatric practice. In the vast majority of patients, with the notable exception of those with rheumatic or collagen vascular disease, this combination of findings is due to some form of bacterial, rickettsial, or viral infection. Despite the exciting development of many new laboratory diagnostic methods over the past few decades, it is very often the morphology, distribution, and history of the skin disease that leads the pediatric clinician to the correct diagnosis. It is this simple process of observing the body’s most accessible organ, the skin, that often allows us to differentiate between benign and lifethreatening disorders, and to initiate therapy when required. The focus of this monograph is the cutaneous manifestations of systemic infection in children. For reasons of space, we have not attempted to cover each disease in detail. For a number of infectious disorders, laboratory diagnosis and treatment are mentioned only briefly, and the reader is referred to the many excellent textbooks in general pediatrics and pediatric infectious disease for more complete information. However, we have attempted to illustrate, in both words and pictures, the distinctive cutaneous findings that help to distinguish among childhood infectious diseases, and that allow us to differentiate these infections from other causes of rash and fever in childhood. In addition, we have chosen to highlight some of the exciting new developments in the etiology and treatment of several of the infectious diseases described in this monograph. We therefore hope that this report

Neil S. Prose, MD, is Assistant Professor of Medicine (Dermatology) and Pediatrics, Duke University School of Medicine, Durham, NC. Steven D. Resnick. M.D.. is Assistant Professor of Dermatology and Pediatrics, School of M&L&e, University of North Carolina at Chapel Hill, Chapel Hill, NC.

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will serve as both a review and an update on the cutaneous manifestations of systemic infection in children.

Bacterial Infections Staphylococcal

Infections

Staphylococci are ubiquitous bacteria that include species normally residing on human skin as well as those responsible for colonization and pathogenic infection. Coagulase-negative staphylococci (predominantly Stuphylococcus epidemidis) are universally found on the skin and generally do not produce disease. They are, however, increasingly recognized to produce systemic infection in immunocompromised hosts and newborns, particularly in the setting of indwelling foreign bodies such as central venous catheters and ventriculoperitoneal shunts.l Recently, the association of intravenous lipid emulsion and coagulase-negative bacteremia in neonatal intensive care units was emphasized.2 The most important cutaneous manifestations of systemic staphylococcal infection are associated with coagulase-positive staphylococci, most notably Stuphylococcus uureus. These manifestations result from dissemination of organisms with localized direct effects or from hematogenous dissemination of staphylococcal toxins from focal infections. The former category encompasses the cutaneous manifestations of S. aureus sepsis and the latter includes the staphylococcal scalded skin syndrome (SSSS) and toxic shock syndrome (TSS). Staphylococcal septicemia is generally a disease of debilitated children with pre-existing severe illnesses, including cystic fibrosis, leukemia, human immunodeficiency virus (HIV) disease, and chronic lung disease.3 Previously well infants with acute viral respiratory diseases may develop secondary staphylococcal pneumonia, and subsequently septicemia.

Any localized staphylococcal infection may lead to the development of disseminated disease. The localized staphylococcal infections giving rise to sepsis, however, are most often serious disorders such as staphylococcal pneumonia, endocarditis, pericarditis, osteomyelitis, or septic arthritis. The cutaneous signs of S. aureus sepsis are similar to those of other bacterial septicemias, such as meningococcemia. The earliest lesions are erythematous macules presenting in a generalized distribution, sometimes predominantly truncal or acral. Lesions tend to evolve rapidly to form petechial and purpuric areas that may blister and ulcerate. Confluent lesions may form large areas of necrotic, gangrenous tissue; the clinical picture is indistinguishable from purpura fulminans. Staphylococcal Scalded Skin Syndrome. SSSS is a potentially life-threatening, toxin-mediated systemic manifestation of localized infection with certain strains of staphylococci. The syndrome includes a range of limited to extensive cutaneous disease characterized by tenderness, blistering, and superficial denudation of the skin. SSSS results from the effects of one of the two epidermolytic toxins: epidermolytic-A and epidermolytic-B. Most toxigenic strains of S. aureus are identified by group II phage (types 71 and 55), although toxin producers have been identified among phage group I and III staphylococci also.4 The epidermolytic toxins produce blistering and denudation by disruption of the epidermal granular cell layer through interdesmosomal splitting. SSSS is predominantly a disease of infancy and early childhood, with most cases seen before the age of 5 years. Factors responsible for the age distribution probably include renal immaturity leading to decreased toxin clearance in neonates and lack of immunity to the toxins5 Infections leading to SSSS typically originate in the nasopharynx, umbilicus, urinary tract, conjunctivae, or blood. Sudden onset of fever, irritability, cutaneous tenderness, and scarlatiniform erythema heralds the syndrome. The erythema is often accentuated in flexural and periorificial areas. Flaccid blisters and erosions develop within 24 to 48 hours in the Ritter disease form of SSSS. Important clinical clues to diagnosis include prominent denudation in areas of mechanical stress, easy disruption of skin with firm rubbing (Nikolsky’s sign), and skin tenderness (Fig 1). A facies with conjunctival inflammation and circumoral erythema evolving to prominent crusting is characteristically seen (Fig 2). An abortive form of SSSS known as the scarlatiniform variant shows the early erythrodermic and final desquamative stages seen in Ritter’s disease, but the intervening bullous stage is not seen. The diagnosis can be made rapidly with a skin biopsy or exfoliated skin sample prepared for frozen

FIGURE

1

Staphylococcal scalded skin syndrome. Note the symmetrically distributed superficial desquamation near the axillae.

section. Alternatively, a cytologic examination prepared as a Tzanck smear will reveal acantholytic nucleated cells, but correct interpretation requires an experienced observer. The major differential diagnosis is toxic epidermal necrolysis (TEN), a life-threatening, but rare disease in infancy. TEN produces full-thickness epidermal necrosis and histologically demonstrates dermal-epidermal separation, rather than the granular layer split in the outer epidermis seen in ssss. Therapy for SSSS must be directed toward eradication of staphylococci from the focus of infection, which generally requires intravenous antistaphylococcal antibiotics. Antibiotics, supportive skin care, and appropriate attention to fluid and electrolyte management in the face of disrupted barrier function will usually ensure rapid recovery. The superficial nature of the erosions in SSSS makes rapid re-epithelialization with minimal or no scarring a predictable result following appropriate therapy. Toxic Shock Syndrome. The staphylococcal TSS is very uncommon in the pediatric population, but is still an important consideration in the differential diagnosis of toxic exanthematous diseases in children. TSS was formally defined by Todd and coworkers in 1978 in a series of seven children6 Much attention was focused on the association of TSS with menstruation and tampon use in 1980.7, 8 Menstruating women, especially adolescents, continue to be the group at,,highest risk of developing TSS,9 but children or adults with any focal staphylococcal infection are potentially at risk for

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FIGURE 2 Staphylococcal scalded skin syndrome. Periorificial and crusting are prominent features. (Courtesy Weingold, M.D.)

erythema of David

TSS. In 1986,45% of the cases identified by active casefinding were nonmenstrual. Nonmenstrual cases have accounted for approximately 11% of all reported cases of TSS and have been associated with a wide variety of localized staphylococcal infections: empyema, fasciitis, osteomyelitis, peritonsillar abscess, cutaneous abscess, surgical wound infection, postpartum infection, septic abortion, and bacteremia.iO Nonmenstrual TSS has also been associated with S. aureus infection at insulin pump infusion sites in two diabetic patients,l* and the use of the contraceptive sponge12 and the contraceptive diaphragm,13, l4 and has occurred following ear piercing.i5 The association of nonmenstrual TSS with bacterial tracheiti@-I9 and bacterial tracheobronchitis following influenza BzOis particularly important. Ten of the 35 reported cases of nonmenstrual TSS in children occurred in this setting. The rarity of TSS in childhood should nonetheless be emphasized; a large, population-based active surveillance program in 1986, covering five states and Los Angeles County, revealed only one case in children

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less than 15 years old.9 Given the prevalence of staphylococcal infections in childhood, the paucity of TSS cases has been an enigma. The microbial epidemiology of TSS in children was the subject of recent studie& ** and pediatric TSS was recently reviewed.23 TSS is caused by infection or colonization with certain strains of S. aureus, and results, in part, from the effects of secreted staphylococcal proteins. The full expression of the clinical syndrome is dependent on the interaction of bacterial and host factors that are incompletely understood at this time. Toxic shock syndrome toxin-l (TSST-l), a 22,049-kd protein with a known nucleotide sequence, is one of the significant mediators of pathogenicity in TSS, but its role is not exclusive. TSST-1 is synthesized by strains from virtually all patients with the menstrual and many with the nonmenstrual type of TSS.24-26 Nonmenstrual TSS, however, is more likely to be due to strains of S. aureus that do not produce TSST-1; 40% to 64% of nonmenstrual isolates produce the toxin, compared to 91% to 100% of menstrual isolates. The staphylococcal enterotoxins (A through E) may also cause TSS under certain conditions, or may worsen disease caused by TSST-1 in others.27 In addition, gramnegative endotoxinemia may play a complicating role. The immune status of the host is also important; a lack of specific immunity to TSST-1 is a relative risk factor for development of TSS, at least in settings with infection by TSST-l-producing strains. Finally, host responses, including production of monokines (especially interleukin-1 [IL-l] and tumor necrosis factor [TNF]) and lymphokines, mediate or amplify the effects of staphylococcal proteins to produce the full TSS.27 The details of pathogenesis in TSS were recently reviewed.23 The clinical presentation of TSS is characterized by sudden onset of high fever associated with vomiting, diarrhea, headache, pharyngitis, profound myalgia, and significant hypotension.28 Multisystem organ involvement (renal, hepatic, central nervous system, hematologic) is an additional characteristic feature that results from both poor tissue perfusion and direct damage from mediators (and probably from toxins). Potentially fatal complications include refractory shock, oliguric renal failure, ventricular arrhythmia, disseminated intravascular coagulation, and adult respiratory distress syndrome. Cutaneous and mucocutaneous findings are prominent in TSS. A diffuse, flexurally accentuated, scarlatiniform exanthem is seen early in the illness. The eruption may initially appear over the trunk but inevitably spreads to the arms and legs.29 Petechiae, vesicles, and bullae are uncommon. Erythema and edema of the palms and soles have been noted in seven of a series of eight patients with TSS30 as well as in other

series.31 “Strawberry tongue” may occur, along with intense erythema of the mucous membranes. Intense conjunctival hyperemia is a very frequent and characteristic finding, but may also be seen in leptospirosis, Kawasaki’s disease, erythema multiforme, Rocky Mountain spotted fever (RMSF), rubeola, and enteroviral infections. These diseases, along with early SSSS, comprise the important differential diagnosis of TSS. Generalized desquamation with involvement of the hands and feet is usually seen 10 to 21 days after presentation. A late-onset, pruritic, generalized maculopapular skin eruption appearing 9 to 13 days after initial onset of symptoms was seen in 12 of 33 patients32 and was described by others in more than half of patients.31 Reversible patchy alopecia and shedding of fingernails were described in one series as occurring in 25% of patients with TSS.33 The hair loss was chamcterized as a typical telogen effluvium,31 a problem commonly associated with severe illness, high fever, or prolonged surgical procedures. In this condition, abnormally large numbers of hair follicles are synchronously shifted into the telogen phase of the normal hair growth cycle, a phase that normally precedes shedding of the hair. Streptococcal Infections Streptococcus pyogenes, a group A /3-hemolytic streptococcus, causes impetigo, erysipelas, pharyngitis, tonsillitis, myositis, necrotizing fasciitis, and bacteremia. Late complications include poststreptococcal rheumatic fever and acute glomerulonephritis. Both of these conditions result from immune-mediated reactions to group A streptococci or their products. Scarlet fever is the streptococcal systemic illness with the most prominent cutaneous features. The illness is caused by pyrogenic exotoxin-producing, group A streptococcal infections. The following discussion is focused on scarlet fever and the streptococcal toxic shock-like syndrome (STSLS), a more recently described toxin-mediated syndrome caused by S. pyogenes infection. Scarlet fever usually occurs in children under 10 years old and presents with the abrupt onset of fever, headache, vomiting, malaise, and sore throat.% An enanthem is evident with bright red oral mucous membranes and punctate petechial lesions of the palate. A whitish coating on the tongue frequently is present. Subsequently, edematous red papillae project through the coating, producing the so-called “white strawberry’ tongue (Fig 3). After 4 to 5 days, the coating peels away, leaving a glistening “red strawberry” tongue. The exanthem appears 12 to 48 hours after onset of the fever, starting as a blanchable fine punctate truncal eruption. The lesions have a sandpaper-like texture, and they tend to be accentuated in flexural areas and sites of pressure as the eruption generalizes. The flexural involvement may be arranged linearly, forming

FIGURE 3 Scarlet fever. ‘White strawberry” tongue red papillae projecting through a whitish of Departmental Collection, Department University of North Carolina at Chapel

is characterized by coating. (Courtesy of Dermatology, Hill.)

Pastia’s lines. The lower extremities may be spared. Facial findings include flushing and circumoral pallor, but the punctate papular eruption is usually absent. The exanthem may occur in a milder form and in such cases is sometimes called scarlatina. Postexanthematous desquamation begins as the rash fades, after 4 to 5 days. A striking exfoliation of large scales may occur on the hands, palms, fingers, and feet, as well as flexural areas. The truncal desquamation is usually extensive with a fine, branny quality. This constellation of desquamative findings is characteristic of scarlet fever, and is more marked than the limited acral desquamation seen in TSS and Kawasaki’s disease. Epidemics of scarlet fever in the early part of this century were associated with S. pyogenes strains producing pyrogenic exotoxin A.35 Milder disease in recent years has been associated with toxin types B and C.36 Although changing socioeconomic conditions and antibiotics have affected the patterns of streptococcal disease in recent decades, some authors attributed declines in rheumatic fever and more virulent scarlet fever to changes in the toxigenic profile of S. pyogenes itself.35 In the past 4 years, cases of severe streptococcal disease have reappeared, associated with the reemergence of type A, pyrogenic, exotoxin-producing streptococci.37, 38 A TSS-like illness, distinct from classic scarlet fever, consisting of multiorgan involvement, toxicity, conjunctival hyperemia, and profound hypotension, has been described. This STSLS, recently reported in a series of 20 patients from the Rocky Mountain states, differs in certain aspects from TSS.38 STLS is associated with extensive necrotizing

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streptococcal soft tissue infections, while TSS has often been associated with occult or minor focal staphylococcal infections. It appears that streptococcal pyrogenic exotoxin A shares many biologic properties with TSST-l%, 38 and is structurally homologous to staphylococcal enterotoxin B. 39These biologic similarities of exotoxin A to the TSS-associated staphylococcal toxins may help to explain the clinical similarity of STSLS to TSS. The factors that determine whether pyrogenic exotoxin A-producing streptococci lead to STSLS or classic scarlet fever, however, are more elusive. Most cases of STSLS have occurred in adults, associated with invasive streptococcal infections. Scarlet fever, on the other hand, occurs predominantly in young children, usually associated with pharyngitis. Moreover, the scarlet fever exanthem probably occurs only after previous sensitization to streptococcal exotoxins.40 No patients with STSLS had a rash typical of scarlet fever in the recent Rocky Mountain series.38 This suggests that prior exposure to exotoxin in children might protect against STSLS and predispose to scarlet fever; lack of immunity to exotoxin A in the setting of invasive streptococcal infections may predispose to STSLS. Such a situation would be analogous to the association of TSS with lack of immunity to TSST-1. Hopefully, seroepidemiologic data concerning immunity to pyrogenie exotoxin A in STSLS will be forthcoming. Ultimately, the determinants of the toxic exanthematous responses to staphylococci and streptococci are likely to include a combination of bacterial factors (toxins), endogenous mediators (cytokines) of the host, and host immunity.

Gonococcal

Infections

Infection with Neisseriu gonorrhoeae produces a spectrum of clinical manifestations, including asymptomatic and symptomatic local infections, local complicated infections, and disseminated disease. The mucocutaneous and cutaneous signs of gonococcal disease are important diagnostic clues for pediatricians who care for adolescents. Eighty-two percent of reported cases in the United States in 1987 occurred in patients aged 15 to 29 years, but the incidence among sexually active teenagers was almost double the rate for sexually active women in the 20- to 24-yearold grou~.~i, 42 Acute anterior urethritis is the most common clinical manifestation of infection in males. Dysuria, purulent urethral discharge, meatal erythema, and penile edema are the predominant findings. Proctitis and pharyngitis may also be seen in males with gonococcal infection. Asymptomatic infection of the urethra, rectum, and pharynx also occurs. In females, the endocervical canal is the primary site of urogenital

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infection, producing mucopurulent cervicitis . The rectal mucosa is infected in 35% to 50% of women with documented cervical infection.43, 44 Rectal gonorrhea is often asymptomatic in females, commonly occurs in the absence of acknowledged rectal sexual contact, and has been assumed in such cases to result from inoculation of infected endocervical secretions. Rectal gonorrhea in males, however, is often associated with overt proctitis and virtually always is associated with receptive anal intercourse. Local complications of gonococcal infection in males include epididymitis, lymphangitis, and urethral stricture, while in females salpingitis and Bartholin’s gland abscess are the most common complications. Acute salpingitis (pelvic inflammatory disease) has been estimated to occur in 10% to 20% of females with acute gonococcal infection and is the most common and significant public health problem related to gonorrhea because of both the acute syndrome and the chronic sequelae, including ectopic pregnancy and infertility.45, 46 The most distinctive dermatologic feature of gonorrhea is seen in the acute arthritis-dermatitis syndrome that characterizes disseminated gonococcal infection (DGI). This is’ the most common systemic complication of gonococcal infection, occurring in 0.5% to 3.0% of patients with untreated mucosal gonorrhea. The bacteremia in DGI may produce arthritis, tenosynovitis, and a characteristic cutaneous eruption. The skin lesions of DGI tend to be acrally located and usually number fewer than 30. The typical lesions are tender, necrotic pustules with a grayish-white center and an erythematous hale (Fig 4). A spectrum

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FIGURE 4 Disseminated gonococcal infection. A necrotic pustule with an erythematous halo is seen. (Courtesy of Departmental Collection, Department of Dermatology, University of North Carolina

at Chapel

Hill.)

of primary lesions, including macules, papules, pustules, petechiae/purpura, or bullae, may be seen. The skin findings may be accompanied by arthralgias, tenosynovitis, fever, and leukocytosis, but clinical toxicity may not be seen in all patients. Arthritis with effusions tends to be a finding in later stages of the syndrome. Disseminated gonococcal disease in newborns is not a rare event. Newborns tend to manifest polyarthritis with suppurative joints, inflammatory disease of the periarticular structures, and tenosynovitis, but cutaneous lesions are uncommon. Meningococcemia Acute meningococcemia may present as an influenzalike illness with associated fever, myalgia, arthralgia, and a prominent cutaneous eruption. Approximately two thirds of patients with acute meningococcemia or meningococcal meningitis develop skin lesions.34 The rash may consist of morbilliform macules, urticarial papules, or petechial lesions. The petechiae may be raised and have a grayish vesiculopustular center, indistinguishable from the lesions of gonococcemia. The tendency for lesions to occur in greater numbers, and on the trunk and lower extremities may help to distinguish the eruption from gonococcemia. The lesions of meningococcemia, however, can also occur in acral areas including the palms and soles, as well as mucous membranes. The differential diagnosis of the eruption also includes rickettsial disease, Henochfrom other Schonlein purpura, and purpura fulminans bacterial septicemias. Advanced and extensive lesions in meningococcemia may form large ecchymotic areas. Ischemic necrosis with sloughing may accompany overwhelming meningococcal sepsis (Fig 5). Skin lesions in meningococcemia contain organisms. Smears from characteristic petechial lesions can yield gram-negative diplococci, providing a rapid diagnostic test. Skin biopsy specimens have a characteristic histopathology with prominent vascular injury; endothelial swelling; and intraluminal microthrombi composed of fibrin, platelets, and erythrocytes. Tissue gram stains demonstrate diplococci within the vessels and thrombi. Pseudomonas Septicemia Pseudomonas aemginosa septicemia is a serious condition that usually has important cutaneous manifestations. Systemic Pseudomonas infection typically occurs in patients debilitated from malignancy, burns, malnutrition, acquired immunosuppression,~ or cystic fibrosis. Children with leukemia, being treated with immunosuppressive therapy and who are leukopenic, are especially susceptible to septicemia from Pseudomonas. Children with cystic fibrosis, on the other hand, although commonly affected by pulmonary manifestations of Pseudomonas, rarely develop sep-

FIGURE 5 Meningococcemia. Purpura fulminans: Large ecchymotic and necrotic areas are seen in a child with fulminant disease.

(Courtesy of Departmental Collection, Department of Dermatology,

University

of North

Carolina

at Chapel

Hill.)

ticemia. In some cases, the use of broad-spectrum antibiotics for other infections appears to have predisposed to superinfection with Pseudomonas. Loss of barrier function (burns, indwelling catheters) appears to explain the frequent observation that the skin is the portal of entry in Pseudomonas septicemia. The earliest skin lesions are single or multiple red macules, resembling the rose spots of typhoid fever. Primary vesicles may also occur. Lesions rapidly evolve (in hours) as enlarging areas of necrotic hemorrhagic bullae. Concentric rings of involved and uninvolved skin have been noted at the edge of expanding lesions.@’ Fully developed lesions present the clinical picture of ecthyma gangrenosum, with deeply necrotic, minimally purulent, ischemic ulcerations, often occurring in the groin, axillae, and legs (Fig 6).

Rickettsial

Infections

The rickettsial pathogens are small, nonmotile coccobacillaxy bacteria that are obligate intracellular parasites. The organisms are intracytoplasmic parasites, with the exception of rickettsia causing the spotted fever group of diseases where intranuclear multiplication also occurs. The characteristic pathologic effect of all rickettsial infections is a small-vessel vasculitis, relating to the organism’s predilection for infecting endothelial cells. Prominent cutaneous manifestations are seen in all of the human rickettsioses except Q fever. Fever and headache are classically associated with the rickettsioses. Ten species are pathogenic in humans, producing a variety of diseases, vectored by a variety of blood-sucking arthropods, including the body louse, flea, tick, and mite. The diseases include epidemic typhus, Brill-Zinsser

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F’IGURE 6 Pseudomonas septicemia. Ecthyma gangrenosum: A necrotic lesion is seen on the lower extremity. (Courtesy of Departmental Collection, Department of Dermatology, University of North Carolina at Chapel Hill.)

disease, endemic typhus, scrub typhus, trench fever, Q fever, RMSF, and rickettsialpox. The following discussion focuses on the latter two entities. Rocky Mountain Spotted Fever RMSF is the most prevalent rickettsial disease and is particularly important to pediatricians since two thirds of the cases occur in persons less than 15 years old.49 The infection is transmitted by ticks and caused by Rickettsiu rickettsii. The important tick vectors in the United States are the wood tick (Demcenfor andersoni) in the Rocky Mountain region and the dog tick (0. mriabilis) from the Great Plains to the Atlantic coast, as well as in areas of the West coast. Infections tend to occur between April and September, but have also been reported in the fall and winter. The clinical illness may appear 2 to 8 days after a tick bite, starting gradually or abruptly with a severe frontal headache and high fever (40 to 40.6”C). Fever may be persistent or fluctuate. Cutaneous findings usually appear on the second or third day of the illness (occasionally as late as the sixth day), typically starting as blanching macules of the wrists and ankles (Fig 7). Subsequently, lesions progress in character and distribution with the development of petechial and/or purpuric lesions. Lesions spread to involve the palms and soles as well as centripetally to involve the proximal extremities and trunk. The extent of the vascular injury may result in frank ulceration. Conjunctival hyperemia may be prominent, a characteristic sign that is also seen in STSS and leptospirosis. The overall clinical presentation may be confused with atypical measles or meningococcemia. A normal leukocyte count or leukopenia with thrombo-

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FIGURE 7 Rocky Mountain spotted fever. Petechial papules are seen on the wrist and palm of an infant with early disease. (Courtesy of Departmental Collection, Department of Dermatology, University of North Carolina at Chapel Hill.)

cytopenia may help support the diagnosis of RMSF since leukocytosis is more common in bacterial sepsis. Initial diagnosis must be made on clinical and epidemiologic grounds since there is no rapid diagnostic test. This clinical diagnosis is exceedingly difficult to make with certainty in many patients. With mortality as high as 25% without treatment,50 patients suspected to have RMSF are routinely treated prior to confirmation of diagnosis. Only 3% of patients with RMSF have the classic triad of fever, petechial skin rash, and history of a tick bite during the critical first days of illness when most patients seek medical attention.50 The skin findings are absent in 10% of patients, may occasionally start on the trunk, and may spare the palms and soles. A history of tick bite has been reported in only 60% of RMSF patients;51 this number increased to 85% of patients from a highly endemic area, but 54% of matched uninfected controls also reported tick bite in the study.52 The quickest diagnostic study is accomplished by submitting a frozen-sectioned, skin biopsy specimen to direct immunofluorescent staining of rickettsial organisms. 53 Best results are obtained when well-developed petechial lesions are sampled. An appropriately equipped laboratory with experienced microscopists can provide confirmation within 24 to 48 hours. The test is 100% specific so a positive result is diagnostic, but a negative result does not rule out RMSF since the test is only 70% sensitive.% Falsenegative results increase substantially after 48 hours of antirickettsial therapy. Serologic tests are important only as a retrospective confirmation of the clinical diagnosis since antibodies to R. rickettsii are not detectable until the

seventh day of illness or later. The indirect immunofluorescent antibody assay (IFA) is the best serologic test available.% The latex agglutination (LA) test is a simple-to-perform, commercially available alternative with good sensitivity and low cost. The We&Felix test is a nonspecific test that detects antibody reactive with certain strains of Protats bacteria, a fortuitous antigenic commonality with several rickettsial pathogens. This test has been historically important in rickettsiology, but has poor sensitivity and specificity compared with the IFA and LA tests. With the threat of significant morbidity and mortality, prompt institution of therapy is indicated if RMSF is suspected. Large numbers of patients are treated in endemic areas,55 but approximately two thirds of patients have a disease other than RMSF.52 When given in adequate dosage and early in the course of disease, ‘the tetracyclines and chloramphenicol are highly effective in treating RMSF. Intravenous chloramphenicol(100 mg/kg/24 hr up to a total dose of 3 g) is recommended for serious illness, switching to 50 mg/kg/24 hr orally as patients improve. Tetracycline (30 to 40 mg/kg/24 hr, in four divided doses) is an alternative oral therapy. The choice of antimicrobial agent is not straightforward. The Centers for Disease Control (CDC) and American Academy of Pediatrics’ recommendations for antimicrobial therapy of RMSF state that tetracycline should be avoided in children under 9 years old because of the risk of staining permanent teeth. This view has been challenged,% based on the low risk of staining with short courses of tetracycline,57 the potential serious side effects of &oramphenicol, and the emergence of human ehrlichiosis.58 This recently described rickettsial disease caused by Ehdichia canis has clinical, geographic, and seasonal features that are similar to RMSF, although cutaneous findings are less common. Current evidence suggests that tetracycline is effective for ehrlichiosis, but the efficacy of chloramphenicol in the disease is uncertain. On the other hand, in cases where N. meningiditis or Hemophilus influenzae are suspected, chloramphenicol would provide better coverage. Rickettsialpox Rickettsialpox is a benign disorder caused by Rickettsia akari that was first recognized in New York City in 1946.59 The etiologic rickettsial pathogen is related antigenicaIly to the spotted fever organisms, and shares the property of infecting both the nucleus and the cytoplasm of host cells. Unlike RMSF, however, rickettsialpox is transmitted by a mite, has a characteristic eschar at the site of the bite, has a vesiculopapular skin eruption, and produces an acute selflimited illness with no reported mortality.49 We&Felix agglutinins are not detectable in rickettsialpox. The natural cycle of disease caused by R. akari oc-

curs between the mite vector (AZZodemunyssus sunguineus) and the house mouse (Mus musntlus). Humans acquire disease when they live in proximity of infected mice, and particularly when the mouse population decreases because of reduced food supply, poison, or disease. Such conditions lead mites to seek humans as an alternative host. Most cases have been reported from New York City, but rickettsialpox probably has a worldwide distribution. The disease affects individuals of all ages without predilection for either gender. Rickettsialpox has a 9- to 14day incubation period. The mite bite typically is not noticed, but a red papule develops at the site. The papule may evolve through a vesicular stage and ultimately forms a black eschar (Fig 8). A fluctuating fever usually begins by the time an eschar has formed, ranging from 100 to 103°F (37.7 to 39.4”C) and lasting up to a week. Regional lymphadenopathy occurs near the eschar. Characteristically there is a frontal headache and other symptoms may occur, including rhinorrhea, cough, sore throat, nausea, and vomiting. The distinctive cutaneous features usually appear within several days of onset of the fever. Widely scattered asymptomatic pink-red macules develop and rapidly progress to a papular morphology. Lesions usualIy involve the face, trunk, and extremities but may occur on the mucous membranes, palms, and soles. Within 1 to 2 days, the lesions vesiculate, producing

FIGURE 8 Rickettsialpox. Black eschar is present at the site of the primary lesion. (Courtesy of Samuel Weinberg, M.D.)

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characteristic papules surmounted by vesicles. The total number of lesions ranges from less than 10 to over 100. The clinical picture may be confused with varicella, as well as infectious mononucleosis and enteroviral exanthems caused by echoviruses or coxsackie viruses. Serologic diagnosis can be made with either complement-fixation or immunofluorescent tests. Tetracycline and chloramphenicol are both effective, although in many patients with mild illness, treatment is not necessary.

Spirochetal

Infections

Congenital Syphilis In 1988, the CDC received 691 case reports of syphilis in infants less than 1 year old.60 This represented the highest number since the early 1950s when widespread penicillin usage began for treatment of syphilis in pregnancy. The trend has paralleled an increase in primary and secondary syphilis in women. Most cases of congenital syphilis have clustered among the infants of poor, urban-dwelling, black and Hispanic women in New York, California, and Florida. The demographic features have suggested that the syphilis problem relates to dramatic increases in the use of crack cocaine and the practice of trading sex with multiple partners for drugs. Fetal infection with Treponma puZZidum may occur at any time during gestation and produces multisystem pathologic conditions with varying degrees of clinical expression. Congenital syphilis is classified as early if it is discovered prior to the age of 2 years and late if it is discovered after age 2. The manifestations of early congenital syphilis resemble those of secondary syphilis in adolescents and adults. Although the signs and symptoms of early congenital syphilis may be evident at birth, many affected infants may not have obvious manifestations until the second week of life or later. The variety of manifestations can be grouped, somewhat arbitrarily, into three syndromes: cutaneous disease, a flu-like syndrome with arthralgia, and lymphadenopathy syndrome.34* 61 The cutaneous lesions of congenital syphilis may be papular, maculopapular, papulosquamous, and occasionally, bullous. An affected infant may demonstrate multiple morphologies. Lesions are typically round or oval, slowly evolving, and initially bright pink to red (Fig 9). The eruption may appear on any part of the body, but tends to affect the face, the extensor surface of extremities, and the diaper area. Over a period of 1 to 3 months, lesions become the copperybrown color typical of secondary syphilis. Ultimately, they fade to become residual areas of hyper- or hypopigmentation. Vesiculobullous hemorrhagic lesions are uncommon, but when present on the palms and soles

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FIGURE 9 Congenital syphilis. Round, macular, plantar lesions are seen in a newborn. (Courtesy of Teresita A. Laude, M.D.)

are characteristic of early congenital syphilis. Such lesions may be accompanied by significant edema and induration, producing a dull red, shiny appearance, which then evolves to a flaky, desquamative state (Fig 10). Even when the desquamation has resolved elsewhere, it may persist in periungual areas of the fingers and toes. The coalescence of papules in moist, flexural areas may form warty lesions of condylomata lata. Mucous patches are pale, round mucous membrane lesions seen in approximately one third of affected infants. The mucous patches are teeming with spirochetes, and characteristically are seen in the mouth and on the lips. Extensive, exudative lesions may grow toward and beyond the mucocutaneous junction, leading to the formation of moist periorificial, fissured, radiating furrows called rhagades. The flu-like syndrome of early congenital syphilis includes the highly characteristic finding of rhinitis (snuffles), often the first sign detected, and the result of nasal mucosal ulceration. A thick, purulent, sometimes blood-tinged discharge is produced and teems with spirochetes. The rhinitis usually appears between the second and sixth weeks after birth. A pharyngitis associated with a weak, hoarse cry may be seen, along with lacrimation secondary to syphilitic iritis. Central nervous system involvement may produce signs and symptoms of meningoencephalitis. Osteochondritis of the long bones can produce generalized arthralgia (pseudoparalysis of Parrot). Periostitis may affect the long bones and the skull; midtibial periostitis results in anterior bowing or saber shin. Early congenital syphilis may be accompanied by generalized lymphadenopathy and hepatosplenomegaly. Severely affected infants may demonstrate jaundice, anemia, and large numbers of circulating

FIGURE 10 Congenital syphilis. Peeling of the palms is seen in a l-weekold infant. (Courtesy of Teresita A. Laude, M.D.)

nucleated erythrocytes. Such findings associated with palpable epitrochlear lymph nodes should strongly suggest the diagnosis of syphilis in an infant. The findings of late congenital syphilis include frontal bossing (due to localized periostitis of frontal and parietal bones), short maxilla, and high palatal arch. Additional findings that may be seen comprise Hutchinson’s triad: interstitial keratitis; eighth nerve deafness; and Hutchinson’s teeth, a barrel-shaped or peg-shaped anomaly of the upper central incisors of the permanent dentition. The sixth-year molars that develop at the same time as the upper central incisors may have a dome shape, with numerous small cusps forming the characteristic mulberry molars of late congenital syphilis. The end result of untreated syphilitic rhinitis is the saddle-nose deformity. Finally, painless synovitis and knee swelling characterize the rare finding of Clutton’s joint. Penicillin is the treatment of choice for congenital syphilis. Accepted regimens include aqueous penicillin G (50,000 units/kg administered intravenously every 8 to 12 hours), or procaine penicillin G (50,000 units/ kg administered intramuscularly daily) for 10 to 14 days.@ Alternative regimens and treatment guidelines for pregnant women have been reviewed recently.63, 64 Lyme Disease

Lyme disease is a systemic infection caused by the spirochete Bow&z burgdorferi. The disorder is transmitted by a variety of ticks, and is now reported to occur indigenously in 43 states. 65 Lyme disease is most com-

mon in the Northeast (New York, New Jersey, Connecticut, Pennsylvania, Rhode Island, Massachusetts), North Central region (Wisconsin, Minnesota), and California. Because the early treatment of Lyme disease may avert the development of rheumatologic, neurologic, and cardiac complications, it is extremely important to recognize the cutaneous manifestations that may occur at the onset of infection. Erythema migrans occurs at the site of the original tick bite (Fig 11). The lesion begins as a small redmacule and expands centrifugally to a diameter ranging from 2 to 68 cm, with a median of 15 cm. There are two general forms: (1) an erythematous patch with varying intensities of redness, and a central red macule; and (2) a papule surrounded by an area of clearing and then by a larger erythematous ring.66 The lesion may be entirely flat or slightly elevated, and there may be minimal scale. The lesion of erytheme migrans (ECM) feels warm to the touch, and the patient may complain of either a burning or an itching sensation. Twenty-five percent of patients develop multiple skin lesions. These may present as additional rings (Fig 12) or as linear plaques. Generalized urticaria or a maculopapular eruption may also occur during the course of erythema migrans. Erythema migrans, which is part of stage I Lyme disease, may be accompanied by malaise, fever, lethargy, nausea, and regional lymphadenopathy.67 Examination of a biopsy specimen of an erythema migrans lesion reveals a superficial and deep perivascular infiltrate that is composed of lymphocytes and some plasma cells. In some cases, the presence of

FIGURE, 11 Lyme disease. Erythema migrans: Central punctum with an area of expanding erythema is on the shoulder. (Courtesy of Departmental Collection, Department of Dermatology, University of North Carolina at Chapel Hill.)

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FIGURE 12 Lyme disease. Multiple annular lesions are seen. (Courtesy of Samuel Weinberg, M.D.)

spirochetal organisms, especially in the subepidermal zone, can be demonstrated by Warthin-Starry and Steiner silver impregnation stains. However, biopsy of a lesion is not a reliable means of confirming the diagnosis of Lyme disease. Unfortunately, both enzyme-linked immunosorbent assay (ELISA) and indirect IFA results are usually negative at this stage of illness and are of little help in diagnosis. The incidence of a positive results on serologic study increases significantly after 5 weeks of illness.@ One recommended treatment for Lyme disease in its first stage in children under the age of 8 consists of amoxicillin or penicillin (250 mg three times a day, or 20 mglkglday for 10 to 30 days, depending on the clinical course). In the child who is allergic to penicillin, erythromycin (250 mg three times a day, or 20 mglkgl day) is an effective alternative.(j7 In older children and adolescents, tetracycline, 250 mg four times a day for 10 to 30 days, is recommended. Stage II or disseminated Lyme disease occurs several weeks to months after initial infection. Fatigue and migratory musculoskeletal pain are commonly seen. A wide variety of other complications include encephalitis, atrioventricular block, and asymmetric, oligoarticular arthritis.

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Skin lesions commonly occur in patients with stage II Lyme disease, but are not specific. Annular lesions, malar rash, and diffuse erythema or urticaria have all been reported. Most patients with stage II Lyme disease have serologic evidence of infection. However, a number of factors complicate the interpretation of these results. Problems include a high degree of interlaboratory variability, and a significant incidence of background seropositivity among healthy individuals in endemic areas. Causes of false-positive serologic results for Lyme disease include other spirochetal diseases, such as yaws, pinta, and relapsing fever, as well as rheumatoid arthritis, systemic lupus erythematosus, infectious mononucleosis, RMSF, and mumps meningitis.69-71 Stage III or persistent Lyme disease is characterized by chronic arthritis, and may be accompanied by syndromes of the central and peripheral nervous systerns. Acrodermatitis chronica atrophicans is a unique skin disease that may evolve after long-term Borreh infection. This disorder, which appears to be most common in Europe but has been observed in the United States, is characterized by areas of erythema and atrophy of the skin of the extremities.n, 73 The treatment of the late stages of Lyme disease is the subject of extensive study. Current choices of antibiotic therapy include ceftriaxone, penicillin G, and amoxicillin with probenecid.67

Viral Infections A wide variety of viral illnesses in children are associated with mucocutaneous eruptions. In some of these disorders, such as chickenpox and fifth disease, the appearance of the rash is so unique that it is the major criterion for diagnosis. In other viral infections, including a number of the enteroviruses, the appearance of the rash may not be as helpful in establishing a precise viral etiology. The following discussion focuses on some of the most distinctive cutaneous manifestations of the systemic viral infections in children. Erythema Infectiosum (Fifth Disease) Erythema infectiosum is a common childhood eruption that has several distinctive clinical aspects.7476 The most characteristic feature is the rapid appearance of facial erythema, which is typically bright red and macular, and favors the malar surface. The so-called “slapped cheek” appearance of erythema infectiosum is accentuated by the sparing of the orbit, nasal bridge, and skin around the mouth. A rash involving other skin surfaces may evolve simultaneously with or several days after the facial eruption. Macular or morbilliform erythema, with or without pruritus, may involve any anatomic location,

including the palms and soles. Most commonly, the eruption is limited to the extensor surface of the extremities and the buttocks. Over a period of several days, the rash may take on a lacy or reticular pattern, which, when present, is virtually pathognomonic of fifth disease (Fig 13). In rare cases, the reticular eruption may occur without the presence of facial erythema. The tendency for the rash to flare in response to certain physical stimuli is very common in fifth disease, and may aid significantly in the diagnosis of this disorder. Particularly, exposure to heat and/or sunlight may bring out the rash, and the reappearance of skin lesions after a warm bath is particularly characteristic. Fifth disease is occasionally preceded by a mild prodromal syndrome of low-grade fever, malaise, sore throat, and coryza. For most children, however, it is a completely benign illness and resolves spontaneously over a period of 1 to 2 weeks. However, in some patients, the rash may recur periodically for a period of a month or longer before it disappears completely. Fifth disease derives its unusual name from the assignment of numbers to the childhood exanthems. L. Cheinisse of Paris assigned the number 5 to erythema infectiosum in 1905.77 The cause of fifth disease is now known to be human parvovirus B19.78 B19 infection, which is often asymptomatic, is most common among school-age children and is probably spread by respiratory secretions. The incubation period is usually 4 to 14 days, but may occasionally be as long as 3 weeks. B19 infection often occurs in epidemics, which start in the late winter and spring and last 2 to 6 months. Fifty percent of adults have serologic evidence of prior infection.76 B19 infection in adults may also cause a macular and reticular erythematous eruption, and may result

in a symmetric polyarthropathy involving the hands, feet, and knees.79 B19 infection is now also implicated in the etiology of aplastic crises in patients with underlying hemolytic anemias. 80, s1 In addition, B19 infection during pregnancy may result in fetal hydrops and stillbirth.82 Children with erythema infectiosum are no longer infectious, do not represent a risk to pregnant women, and may attend school or day care.83 Roseola (Exanthem

Hand-Foot-And-Mouth

FIGURE13 Fifth disease. Reticulated erythema may be accentuated by bathing.

over the lower extremities

Subitum)

Roseola is an extremely common childhood illness that occurs in approximately 30% of all children. It is seen most commonly between the ages of 6 months and 3 years. The disease is characterized by the acute onset of high fever (38” to 40”(Z), which usually lasts for 2 to 4 days.@, @ The fever tends to be higher late in the day, and except for mild irritability in the presence of high fever, the child is otherwise well. The resolution of the fever is typically accompanied by the development of a generalized rash. The eruption of roseola may begin up to several days after the temperature returns to normal and lasts 1 to 2 days. The eruption favors the head and trunk, and consists of numerous rose-pink irregular macules and maculopapules 2 to 3 mm in diameter. Pruritus and desquamation are absent. In rare cases, the rash of roseola may last for only several hours. Roseola is now known to be caused by human herpesvirus 6. 86 This virus can be isolated from the peripheral blood mononuclear cells of most patients during the course of their illness, and a rise in antibody titers can be documented.87 In several infants, human herpesvirus 6 appeared to be responsible for an acute febrile illness that was not accompanied by rash.88 A recent study showed that human herpesvirus 6 can be isolated from the saliva of more than 85% of healthy adults. 89 The periodic shedding of virus in saliva appears to be the most probable source of childhood infection with human herpesvirus 6. Disease

Hand-foot-and-mouth disease is a viral exanthem that is most commonly caused by coxsackie A16, but may also be due to a number of other coxsackieviruses and enteroviruses.gOt 91 The disease occurs most commonly in the spring and fall, and is characterized by the evolution of vesicles and small ulcers on the tongue and buccal mucosa. The palate, tonsils, and uvula may also be involved and may lead to oral discomfort and difficulty in swallowing. In most children, the enanthem is accompanied by oval, gray vesicles and superficial erosions that range from 2 to 6 mm in diameter. These lesions are usually concentrated on the palms and soles, and favor the lateral surfaces (Fig 14). The palm and sole lesions may be tender or painful. In younger children, lesions commonly occur on the

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become confluent, especially on the extensor surfaces of the extremities.94 Although the cutaneous eruption associated with infectious mononucleosis may be severe, there is no aspect that is completely distinctive. For this reason, the diagnosis must be based on the presence of the varied clinical features listed above, along with associated laboratory findings. The presence of an atypical lymphocytosis is particularly helpful. The rapid mono-spot heterophile test is of little value in children under the age of 4 years, and Epstein-Barr virus-specific antibodies must be measured in these patients.95 Rubella

FIGURE

14

Hand-foot-and-mouth

disease. Oval plantar blisters are seen.

(From Prose NS: Mediguide

Demzatol 1987; 2:1-5.

Used by

permission.)

buttocks. Papular and vesicular lesions on the face and trunk sometimes occur. Except for a brief prodrome of low-grade fever and malaise, hand-foot-and-mouth disease is a mild selflimited illness of no major consequence. The diagnosis is made solely on clinical grounds, and no treatment is required. Epstein-Barr

Virus Infection

Epstein-Barr infectious mononucleosis is most often characterized by fever, lymphadenopathy, pharyngitis, and hepatosplenomegaly. A rash, which may be maculopapular, petechial, papulovesicular, or erythema multiforme-like, occurs in approximately 25% of children.92 Eyelid and facial edema may also be seen. Cutaneous involvement appears to be more common in children under the age of 4 years. In addition, the development of a characteristic drug eruption following the administration of ampicillin is well documented in patients with active infectious mononucleosis.93 The rash begins 1 to 2 days after the course of antibiotic is begun, and consists of erythematous maculopapules that spread from the trunk to the face and the extremities. The lesions may

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The incidence of disease due to infection with rubella virus, an RNA virus of the togaviridae family, has decreased markedly since the widespread availability of a live attenuated vaccine. The susceptibility of children who have not been vaccinated remains a significant public health problem, and the clinician who cares for children must be aware of the characteristic clinical findings in this disease.M, 94 The prodrome, which occurs more commonly in adolescents and young adults, consists of malaise, fever, sore throat, headache, and eye pain. The eruption begins as discrete macules and papules, and progresses to a confluent, morbilliform appearance. It begins on the head and neck, and goes on to involve the trunk and extremities over a period of 1 to 2 days. The minute red petechiae or macules that may occur on the uvula or soft palate are termed Forschheimer’s spots. The total duration of the nonpruritic skin disease is usually about 3 days. The associated presence of posterior auricular and suboccipital lymph node enlargement is a particularly helpful clinical sign. The cutaneous manifestations of congenital rubella do not resemble those seen in the childhood form of the disease. The most characteristic lesions are areas of bluish to purple discoloration of varying sizes, termed “blueberry muffin” spots. These lesions, which are present at birth or shortly thereafter, are sites of extramedullary hematopoiesis.96 Examination of a biopsied area of involvement reveals numerous normoblasts concentrated around sweat glands, sebaceous glands, and hair follicles. Blueberry muffin lesions favor the trunk, neck, and scalp, and resolve spontaneously over a period of several weeks. Involvement of the skin is usually part of a complex of findings including microcephaly, intrauterine growth retardation, and a variety of visceral abnormalities. Children with congenital rubella infection may go on to develop a number of other findings during early childhood. These include a morbilliform eruption that is similar to that seen in childhood rubella and necrosis of the inner enamel epithelium of the teeth.97

Measles Although measles is far less common than in the prevaccination era, it remains a significant public health. problem throughout the United States. Epidemics among preschool children tend to occur in inner-city areas among children of lower socioeconomic groups, and are largely due to lack of vaccination among these children.98 Outbreaks among highly vaccinated, school-age children and college students also occur; these are attributed to a number of factors, including vaccination prior to the age of 15 months. The incubation period for measles, which is caused by an RNA virus of the paramyxovirus group, is 10 to 12 days. The evolution of cutaneous disease usually follows 3 to 4 days of cough, coryza, fever, malaise, and conjunctivitis. Koplik’s spots, a characteristic enanthem that involves the buccal mucosa, gums, and lips, precede the rash by 1 to 2 days. These lesions, which may be quite numerous, are punctate blue-white spots with an erythematous halo. The exanthem of measles has a characteristic appearance, consisting of purplish-red macules and papules, which tend toward confluence. The morbilliform eruption begins on the forehead and upper neck, and spreads to involve the upper extremities, trunk, and lower extremities over a period of 1 to 2 days (Fig 15). The peak of systemic symptoms correlates with the second or third day of the eruption, and the resolution of symptoms with the fading of rash from head to toe. Although measles is a self-limited illness, it may be accompanied by a number of complications, including bacterial infection (e.g., pneumonia), postinfectious encephalomyelitis, and subacute sclerosing panencephalitis. Atypical measles occurs when patients who received killed measles vaccine (used in the United States between 1963 and 1967) are infected with natural measles virus.lm High fever, cough, and myalgias are accompanied by a characteristic rash. The eruption begins on the distal extremities, and spreads over a 3to 5-day period to involve the entire skin surface. Lesions are maculopapular and erythematous early in the disease, and progress to vesicles, petechiae, and palpable purpura (Fig 16). Periorbital and pedal edema is sometimes noted. Pneumonia is the most frequent complication of atypical measles. In some cases, atypical measles may be difficult to differentiate from RMSF.

Cytomegalovirus

Infection

Cytomegalovirus (CMV) is the most common cause of viral infection in the newborn. In 90% of children, the disorder is asymptomatic. la1 Newborns with clinical evidence of CMV infection at birth are at risk for a

FIGURE 15 Measles. Confluent macules and papules involve trunk. (Courtesy of Dr. Bernice Krafchik)

the face and

variety of severe neurologic defects. These patients may present with hepatosplenomegaly, jaundice, and microcephaly. In addition, a variety of cutaneous findings have been noted in children with this disorder. Petechiae and purpura are a result of the moderate to severe thrombocytopenia associated with congenital CMV infection. A blue to purple papulonodular eruption, identical in morphology and distribution to the “blueberry muffin” lesions of congenital rubella, may also occur (Fig 17). These areas of involvement are sites of dermal erythropoiesis. Rarely, congenital CMY infection may present with either vesicles mimicking herpes simplex, or with cutaneous vasculitis.io2, lo3 An acute febrile illness associated with fever, leukocytosis, and abnormal liver function may result from CMV infection in children and young adults. A maculopapular or morbilliform eruption has been observed during the course of this self-limited illness.lM

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FIGURE16 Atypical measles. Pete&al eruption is seen on the lower extremities. (Courtesy of Samuel Weinberg; M.D.)

Herpes-Simplex

Infection

Infection with herpes simplex is encountered by the most individuals at some time during childhood. For most, this infection consists of herpetic gingivostomatitis, which may be followed by recurrent mild episodes of viral reactivation on or near the lips, or on other skin surfaces. Herpes simplex is associated with severe systemic illness in the case of intrauterine and neonatal infection, and in children with eczema herpeticum. Intrauterine exposure to herpes simplex virus may occur as a result of either primary or recurrent maternal herpes infection. Intrauterine infection, which is quite rare, may result in chorioretinitis, microcephaly, hydranencephaly, and microphthalmia.105 Dermatologic findings are present in almost all patients with intrauterine herpes simplex infection. Characteristic lesions are extensive vesicles and bullae, and widespread scarring may be present at birth. A new-

106

born with intrauterine herpes simplex infection and extensive calcification of the skin and soft tissue has been described.lo6 The presence of widespread blistering and scarring helps to distinguish between this disease and entities such as congenital rubella, varicella-zoster, and CMV infection. Intrauterine herpes simplex infection is not known to occur during a particular stage in pregnancy, and the relation of disease severity to maternal antibody status is not known. In children with characteristic skin lesions, cultures should be grown for evidence of herpes simplex virus. Because disseminated infection may occur, appropriate antiviral therapy is indicated. Neonatal herpes simplex infection is a lifethreatening disorder that may be responsible for severe neurologic impairment. The tendency for delay between the appearance of skin lesions and the initiation of antiviral therapy has been well documented.107 Because subtle cutaneous lesions may represent an opportunity for therapeutic intervention and the prevention of severe disease, a thorough knowledge of these skin findings is critical for all health providers who care for newborns. Mucocutaneous lesions are the first sign of illness in approximately 30% of newborns, and develop during the course of illness in an additional 50%.lo7 The diagnostic hallmark is grouped vesicles on an erythematous base (Fig 18), which progress to erosions and crusts over a period of several days. Lesions commonly occur on the scalp, and may first be noted at the sites of monitoring electrodes. Poor healing at these sites may be the sole early manifestation of neonatal herpes simplex infection. In a breech delivery, initial involvement may be noted on the buttocks or legs. Large areas of skin denudation, mimicking epidermolysis bullosa,

Current Problems in Pediatrics I March 1991

FIGURE17 Congenital cytomegalovirus infection. Purple nodules are the sites of dermal erythropoiesis. (Courtesy of Dr. Bemice Krafchik)

FIGURE 18 Neonatal herpes simplex. Clustered vesicles are on the abdomen of an infant. (Courtesy of Teresita A. Laude, M.D.)

have been seen in several infants with neonatal herpes simplex.lo8 Oral involvement occurs in approximately 30% of children.im Significant new information is available on the epidemiology of herpes simplex infection in the newborn. The children of women with a history of recurrent genital herpes simplex, or with serologic evidence of prior infection, are at very low risk of developing infection.‘la, l*l By contrast, the children of women who acquire herpes simplex infection during pregnancy are at high risk for perinatal infection.‘12 Attempts to identify children at risk for perinatal exposure to herpes simplex virus have been largely unsuccessful. In one study, only 7% of women shedding virus at the time of delivery had a history of genital herpes.lll In addition, maternal cultures obtained during the 4 to 6 weeks prior to delivery do not predict the infant’s risk of exposure at delivery.l13 Therefore, the clinician must maintain a high index of suspicion for herpes simplex infection in the new-

born with vesicular skin lesions, or with signs of sepsis. If lesions are present, Tzanck preparation should be performed by scraping the base of an intact vesicle and placing it on a slide. The slide is stained with toluidine blue 0.1% for 15 seconds, or with Giemsa, Wright’s, or methylene blue stains.ii4 A positive preparation reveals large, multinucleated giant cells. When neonatal herpes simplex infection is suspected, cultures of the throat, urine, cerebrospinal fluid, skin, conjunctiva, and stool should also be obtained. Both isolation and intravenous antiviral therapy should be instituted while awaiting culture results. Treatment with intravenous acyclovir has replaced systemic vidarabine in almost all centers. The development of severe generalized herpes simplex virus infection in patients with underlying skin disease is termed eczema herpeticum or Kaposi’s varicelliform eruption. Most children who develop this disorder have a history of significant atopic dermatitis, and inoculate virus into areas of damaged skin. A mild defect in cell-mediated immunity among children with atopic dermatitis may contribute to the evolution of this process. Eczema herpeticum is characterized by the rapid onset of fever and a generalized vesicular eruption. Vesicles tend to involve areas of pre-existing skin disease (Fig 19), although there may be slight extension to previously normal skin. The vesicles enlarge and coalesce over a period of 4 to 7 days, and then form a crust and heal. The advent of antiviral therapy, particularly with acyclovir, has markedly decreased the morbidity and mortality associated with eczema herpeticum.li5, 116 Optimal treatment consists of intravenous acyclovir at a dose of 250 mg/m2 every 8 hours for 7 days. If rapid

FIGURE 19 Eczema herpeticum. Involvement is concentrated in areas of prior atopic dermatitis.

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resolution occurs, therapy may be completed acyclovir on an outpatient basis.

with oral

Varicella-Zoster Virus Infection Varicella is an extremely common systemic illness that is familiar to all practitioners who care for children. The characteristic eruption consists of crops of numerous, small, discrete vesicles, each with a l- to 2-mm surrounding area of erythema. The eruption usually begins on the scalp, face, and trunk, and spreads to the extremities over a period of several days. The presence of lesions in different stages of evolution, and of mild constitutional symptoms helps to differentiate chickenpox from other vesiculobullous disorders of childhood. Several atypical cutaneous manifestations of chickenpox are worth noting. Bullous lesions are sometimes associated with superinfection with S. aureus, but they may also occur due to varicella-zoster infection alone.li7 Children with thrombocytopenia may develop hemorrhagic lesions during the course of their illness.li* The lesions of varicella may localize to areas of sunburned or suntanned skin.l19 The continued development of new lesions several weeks after the onset of illness may be an indication of depressed immune function. Progressive varicella occurs in children under treatment for malignancy, and in children with congenital or acquired immune deficiencies.i20 Varicella-zoster infection in the newborn is a significant cause of morbidity and mortality. Infants born to women who develop varicella within 5 days before delivery to 2 days after delivery are known to be at risk for serious or fatal infection.lzl Disseminated varicella has been reported in full-term infants up to 15 days old. * The skin lesions in neonatal varicella-zoster infection are identical in morphology to those seen in children with routine chickenpox. However, the lesions may be extremely numerous and develop rapidly and simultaneously over the face, trunk, and extremities. Intrauterine infection with varicella-zoster occurs following first-trimester exposure in less than 5% of infants. *23 Features of congenital varicella syndrome include low birth weight, cataracts, and severe central nervous system dysfunction.12P126 Skin involvement, consisting of congenital areas of ulceration or scarring, is extremely characteristic. The lesions most commonly occur in a dermatomal distribution, and may be associated with hypoplasia of the same limb. Papular Acrodermatitis of Childhood (Gianotti-Crosti Syndrome) Papular acrodermatitis of childhood (PAC) was originally described by Gianotti in 1955 and Crosti and Gianotti in 1956.127, 128 This skin disorder presents

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with symmetric, flat-topped erythematous or fleshcolored papules that involve the face, buttocks, and extremities (Fig 20). The lesions tend to be very firm to the touch, and may become confluent on the cheeks, elbows, and knees. Pruritus may be severe or completely absent. The diagnosis of PAC is based on the typical appearance and distribution of the skin lesion. Skin biopsy of a lesion is nonspecific and reveals a perivascular lymphocytic and histiocytic infiltrate in the mid and upper dermis. 129 PAC was originally described in a group of children with lymphadenopathy, mild hepatomegaly, and acute anicteric hepatitis, associated with the presence of hepatitis B surface antigen subtype ayw. Several subsequent series, in both Europe and Japan,

FIGURE

20

Pap&r acrodermatitis of childhood. Firm papules on the extensor

surfaces

of arms and legs are characteristic.

also revealed an association between PAC and mild hepatitis B infection.130, 13i It is now widely recognized that an eruption that is either similar or identical to the original PAC may occur without hepatitis B infection. PAC has been described in association with a variety of viral infections, including respiratory syncytial virus; coxsackieviruses A-16, B-4, and B-5; echovirus type 7 and 9; CMV; and hepatitis A. *32-135In one series, 7 of 13 children had serologic evidence of concurrent EpsteinBarr virus infection.lX This particular association was subsequently confirmed by others.137 In our own experience, Epstein-Barr virus is a particularly common cause of PAC. PAC is a benign and self-limited disorder that resolves spontaneously with the underlying viral illness. Children with the characteristic eruption should be evaluated for liver function abnormalities and for serologic evidence of hepatitis B infection. Serologic testing for Epstein-Barr virus infection is also advisable when there is additional clinical evidence to suggest this possibility. Human Immunodeficiency Type 1 Infection

Virus

More than 2,464 cases of HIV-l infection in children have been reported to the CDC.138 The majority of children become infected with this virus by perinatal transmission from an infected mother; smaller groups are the recipients of contaminated blood products or clotting factors. Pediatric HIV-l infection may present with a variety of features. The most common clinical manifestations are lymphadenopathy, neurologic dysfunction, failure to thrive, lymphoid interstitial pneumonitis, and a wide variety of opportunistic infections.139, 140 Cutaneous disease is a prominent feature in many children with HIV-l infection, and may be a presenting sign of infection in some children.i41 There is no single cutaneous disorder that is pathognomonic for infection with HIV-l. A papulosquamous eruption has been observed in young adults during acute HIV infection; to date, this skin disease has not been observed in children. As a general principle, the mucocutaneous disorders seen in association with HIV infection are infectious and inflammatory processes that are distinguished by their severity, poor response to therapy, and tendency to recur. Candidiasis is by far the most common mucocutaneous manifestation. Children frequently develop severe oral thrush; the white to yellow plaques are typical in morphology, but may involve large areas of the tongue and oral mucosa.142 Therapy with oral nystatin or miconazole is beneficial early in the course of the HIV-related illness, but systemic therapy with agents like ketoconazole may be required as immune

status deteriorates and esophageal involvement occurs. Recalcitrant candidal infections of the diaper area and neck folds may develop. In addition, chronic candidal infection of the proximal nail folds may lead to severe nail dystrophy. Fungal and bacterial infections may be particularly severe in the HIV-l-infected child. We have encountered children with recalcitrant tinea capitis and with cellulitis and ecthyma due to S. uuras and H. influenzae. Children with acquired immunodeficiency syndrome (AIDS) may develop severe and recurrent herpetic gingivostomatitis. Herpes infections of the fingers (herpetic whitlow) and of other body areas may also occur.143 Persistent ulcerative lesions in any child with HIV-l infection should be cultured for this organism, and therapy with intravenous acyclovir should be instituted when appropriate. Herpes zoster, which is relatively rare in the healthy child, appears with some frequency in children with HIV-related disease. Blisters and erosions occur in a typical dermatomal distribution; the lesions may be exceptionally painful and have a higher tendency toward scarring than in the otherwise healthy child. A unique form of chronic cutaneous infection with varicella-zoster virus has been described in children with HIV-l infection.144, 145The lesions, which may be several or numerous, are ulcerated nodules or plaques with surrounding hyperkeratosis. Poor response to acyclovir in this disorder may be indicative of the development of a varicella-zoster strain that is resistant to this drug. Molluscum confagiosum and widespread verruuz vulguns and flat warts are additional viral skin infections that are seen in association with HIV-l infection. In some cases, the occurrence of hundreds of lesions over large areas makes treatment extremely difficult. Response to systemic therapy with zidovudine (AZT) is noted in some of these disorders. As in other immune disorders, scabies may present with numerous erythematous and crusted lesions involving the trunk and extremities. So-called “Norwegian scabies” may mimic other eczematous skin conditions and is extremely contagious to both family members and health personnel. 146,147 Inflammatory disorders that are worsened by the presence of HIV-l infection include seborrheic dermatitis, atopic dermatitis, and psoriasis. Vasculitis mimicking Henoch-Schonlein purpura, and drug eruptions (usually secondary to trimethoprim-sulfamethoxazole) are additional hallmarks of the disease.i4s-lw Cutaneous Kaposi’s sarcoma, which is a hallmark of HIV-l infection among homosexual men, is extremely rare in children with AIDS. There are only several case reports of Kaposi’s sarcoma of the lymph nodes or skin in children ranging from 6 weeks to 11 years old.isi-154

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