Cutaneous manifestations of the acquired immunodeficiency syndrome in children

Clinical review I

III

I I

I

I

1

I

I

I

I

Cutaneous manifestations of the acquired immunodeficiency syndrome in children B. F. Straka, M.D.,* D. L. Whitaker, M.D.,* S. H. Morrison, M.D.,***.***** J. M. Oleske, M.D.,** and J. M. Grant-Kels****

Har(ord and Farmington, CT, and Newark, NJ The acquired immunodeficiency syndrome (AIDS) in children is now known to be a clinical entity separate and distinct from AIDS in adults. In this article we present a review of the recent literature describing the history, definitions, epidemiology, differential diagnosis, and immunologic and clinical features of pediatric AIDS. Special emphasis is placed on the cutaneous manifestations of human immunodeficiency virus infection in children, which, to date, have not been the subject of a comprehensive review. (J AM AC_AD DERMATOL 1988; 18:1089-1102.)

The acquired acquired immunodeficiency syndrome (AIDS) was first described in the United States in 1981, when cases of Kaposi's sarcoma and Pneumocystis carinii pneumonia were reported in previously healthy young homosexual men in New York City and Los Angeles. ~3 Additional cases were retrospectively identified back to 1978. 4 AIDS was subsequently reported in male and female intravenous drug abusers 5,6 and persons with hemophilia. 7 Transfusion-associated AIDS and heterosexual transmission of the disease were documented shortly thereafter. 8~~ In late 1983 the causative agent was isolated and is currently referred to as the human immunodeficiency virus (HIV).~H4 The first cases of pediatric AIDS were reported to the Centers for Disease Control in 1982 ~2 with

From Hartford Hospital, Department of Medicine, Hartford,* the Departments of Pediatrics** and Infectious Disease,*** University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark,** and the Department of Medicine-Division of Dermatology, University of Connecticut Health Center, Farmington.**** Reprint requests: Dr. Jane M. Grant-Kels, Chief, Division of Dermatology, Director of Dermatopathology, University of Connecticut Health Center, Farmington, CT 06032. *****Recipient of U.S. Public Health Service National Research Service Award IF32 AI 07353-01.

retrospective identification of probable cases back to 1979 or 1980. '2,ts These early reported cases occurred in children of intravenous drug-abusing or promiscuous mothers '6t8 and in infants who had received blood transfusions from HIV-infected donors, t9 AIDS in the United States has been primarily a disease of young men. 4 However, approximately 1% of all AIDS cases have occurred in children under 13 years of age. In the period between June 1, 1981, and Sept. 2, 1986, a total of 24,430 cases of AIDS were reported to the Centers for Disease Control; 345 of these cases occurred in children <13 years of age. In half of these children, a diagnosis of AIDS was made in their first year of life; in 82% the disease developed by the age of 3 years. Thus far, 65% of pediatric AIDS cases have been fatal. 2~ AIDS is a devastating disease with significant morbidity and mortality rates and with no known cure. It is estimated that > 1.5 million people have been infected with HIV in the United States; of these, > 2 5 , 0 0 0 persons have contracted AIDS, with an associated mortality rate of > 5 0 % . Scientists estimate that in 20% to 30% of individuals infected with HIV, AIDS will develop within 5 years& Since 1983 the number and percentage of 1089

1090

Journal of the American Academy of Dermatology

Straka et al

Table I. Risk factors predisposing a child to AIDS, in order of frequency* Maternal risk factors Paternal risk factors Exposure to AIDS-contaminated blood or blood products Sexual abuse *Modified from Rubinstein A, Bernstein L. Clin Immunol Immunopathol 1986;40:115-26.

women infected with the AIDS virus have increased steadily, with a concomitant rise in the number of reported pediatric AIDS cases. 22 AIDS, when first discovered, was not considered to be a disease of the pediatric population. However, views began to change when sporadic case reports describing an "AIDS-like" syndrome in children appeared in the literature. With the confirmation of HIV as the causative agent in both adult and pediatric AIDS, it was assumed that the two entities were clinically and immunologically identical. However, time and experience again proved that this is not the case. It is now known that children with AIDS suffer from striking B cell defects early in the course of the disease and thereby manifest a marked dysfunction in humoral immunity. As a result, children commonly acquire bacterial infections such as cellulitis, impetigo, skin abscesses, otitis media, sinusitis, pneumonia, and septicemia. In contrast, adults with AIDS classically show evidence of leukopenia with a decrease in absolute numbers of T helper ceils and a reversed T4/T8 (T helper/T suppressor cell) ratio. These defects account for the characteristic opportunistic infections (e.g., Pneumocystis carinii pneumonia) and unusual malignancies (e.g., Kaposi's sarcoma) associated with adult AIDS. In children, the adult type of T cell abnormalities and clinical symptoms generally occur much later in the course of the disease. In addition, certain clinical entities, such as lymphocytic interstitial pneumonitis and parotitis, occur exclusively in children, whereas Kaposi's sarcoma is rarely seen in the pediatric AIDS population. Cutaneous involvement in adult HIV infection is now recognized to be an important manifestation

of AIDS and has been discussed comprehensively in the literature. However, there are no reports to date that emphasize the dermatologic manifestations of AIDS in children. The dermatologist plays a vital role in the diagnosis, evaluation, and treatment of pediatric AIDS. Therefore this article will review what has been described and reported about AIDS in children, with special emphasis on the dermatologic clinical manifestations.

AIDS (DEFINITIONS) Since AIDS was first described, the definition has undergone considerable scrutiny and revision. Currently, it is generally accepted that once a person is infected with HIV, that individual can be placed in one of three clinical categories: (1) asymptomatic carrier state, (2) AIDS-related complex, and (3) full-blown AIDS. The Centers for Disease Control has defined each category explicitly in adults, but the boundaries are less distinct in the pediatric population. Asymptomatic carders are estimated to represent 70% to 75% of the entire adult population infected with HIV. 23These persons have a positive reaction to a serologic test for the HIV antibody but do not manifest any clinical symptoms. Although it was originally believed that all children who harbored the AIDS virus would exhibit symptoms, it is now becoming clear from clinical experience that there is a broad spectrum of disease associated with HIV infection in pediatric patients, and it includes an asymptomatic cartier state. In the second category are those with AIDSrelated complex, who represent 20% to 25% of all adults infected with the virus. 23 This diagnosis is established in adult patients by a positive reaction to a serologic test for HIV in combination with several nonspecific clinical and laboratory abnormalities. Clinical symptoms include lymphadenopathy, fever, fatigue, weight loss, diarrhea, night sweats, and oral candidiasis. Laboratory findings may show reduced numbers of helper T cells, a decreased T helper/T suppressor ratio, cutaneous anergy, and leukopenia. 2~.24 The definition also states that other causes for these abnormalities (such as malignancy or immunosuppression) must be excluded. No specific deft-

Volume 18 N u m b e r 5, Part 1 May 1988

nition for pediatric AIDS-related complex has been developed to date. In general, any child who has a positive reaction to a serologic or virologic test for HIV, but who does not fulfill the criteria for pediatric AIDS, is considered to have pediatric AIDS-related complex. This group of patients is not reported to the Centers for Disease Control. 22 Finally, full-blown AIDS encompasses approximately 5% of adults who are found to harbor the HIV. 23 The Centers for Disease Control defines adult AIDS as "a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease. ''~ The patient must also have a positive reaction to a serologic or virologic test for the AIDS virus. Pediatric AIDS is defined in exactly the same manner, except that it is necessary to exclude congenital infections and primary and secondary immunodeficiencies. Recently the Centers for Disease Control revised the definition of pediatric AIDS to state that a histologically documented lymphocytic interstitial pneumonitis occurring in a patient <13 years of age is now an acceptable criterion for diagnosis. 22.26 The reason is that lymphocytic interstitial pneumonitis has been widely described as a characteristic symptom of the pediatric population infected with HIV. M a n y authors have expressed dissatisfaction with the definition of pediatric AIDS, arguing that it does not accurately identify affected children. In general, children do not fulfill the adult criteria for AIDS with opportunistic infections and malignancies and are consequently described as having AIDS-related complex; however, the prognosis for these children is significantly worse than for adults with AIDS-related complex. 22 Rubinstein 22 believes that the original Centers for Disease Control definition therefore excluded 90% of his patient population, with the revised definition still excluding approximately 75% of his patients on their initial presentation. He believes that although the revised definition is art improvement, the diagnosis of lymphocytic interstitial pneumonitis must be documented by open lung biopsy; therefore, without a biopsy, children must be given the diagnosis of AIDS-related complex. Consequently, the current definition leads to considerable underestima-

Cutaneous manifestations of AIDS in children

1091

tion of the number of pediatric AIDS casesJ 2 Ammann 27 has proposed that the definition of pediatric AIDS be multidimensional, encompassing the areas of epidemiologic risk factors, immunologic evaluation (polyclonal hypergammaglobulinernia and T cell immunodeficiency), virologic study (antibody to AIDS retrovims), and the exclusion o f other causes of immunodeficiency. The Centers for Disease Control is therefore currently proposing a revised definition and classification scheme for pediatric AIDS.* EPIDEMIOLOGY

HIV has been described as a "fragile" virus that is not easily spread from one person to anotherJ s It has been well documented that the virus is transmitted through parenteral exposure to infected blood or blood products, through intimate sexual contact, or vertically, from mother to fetus 28 (Table I). The majority of pediatric AIDS patients are children of intravenous drug-abusing mothers or fathers or are children of bisexual fathers 4.22,29.31Maternal risk factors have been discussed at length in the literature and include intravenous drug abuse, marital or extramarital sexual relations with persons at risk for AIDS (e.g., intravenous drug abusers, bisexual men, or persons with hemophilia), Haitian or Central African heritage, promiscuity or prostitution, and exposure to contaminated blood or blood products. It is believed that the incidence of HIV infection in such women will be increasing over the coming years because of further spread of the virus through intravenous drug abuse, heterosexual contact with infected men in high-risk groups, or both. Because vertical transmission accounts for the overwhelming majority of pediatric AIDS cases (79% as of Sept. 2, 19862~ a similar rise in the number of cases of pediatric AIDS has been projectedJ 2,3~ Vertical transmission can occur in utero (transplacentally), during the birth process through exposure to contaminated blood, or postnatally.16.2o.34.35 There has been one reported case of an infant believed to have been infected through *Efird J (Centers for DiseaseControl): Personal communication, May 1987.

1092

Journal of the American Academy of Dermatology

Straka et al

breast milk from a woman who apparently acquired the disease from a postpartum transfusion, 36 and the AIDS virus has been isolated from cellfree breast milk of three asymptomatic HIV cartiers. 37 However, it is currently believed that in the majority of cases of vertical transmission, the infection is acquired in utero. 2z,3~,~9 The risk of transmission from mother to baby during pregnancy cannot be definitively assessed at this time; nevertheless, it appears to be high. Recent studies have reported transmission rates of anywhere from 33% to 6 7 % . 21'2'32'38 It is generally believed that the vast majority of these infected babies will subsequently develop AIDS and die. 2t'3z Children also acquire AIDS through blood transfusions, most often in the neonatal period. 22.40Recipients of platelet transfusions and numerous red blood cell transfusions, such as children with thalassemia, have also been reported to acquire AIDS by this route. 4t'42 Infants account for 10% of transfusion-associated AIDS cases, although they represent only 2% of the total population receiving blood transfusions. 12 Possible explanations for this discrepancy include an increased susceptibility of infants' immature immune systems to viral infection, a larger dose of virus in transfused blood relative to actual body size, and a shorter viral incubation period in infants. Iz Since tests to detect HIV antibody in donated blood were not available until 1985, rapid seroconversion in many hemophilia patients occurred before this time because of the use of plasma donated by members of other groups at high risk for AIDS.12 It has been reported that as many as 92% of all American hemophilia patients show HIV antibody positivity and that > 5 0 % of these persons have some abnormality of their immune system. Consequently, the number of AIDS cases among hemophilia patients is expected to rise dramatically over the next few years. 43 Cases of sexual abuse have also rarely been reported to lead to AIDS in children. One 10-yearold girl was found to have leukopenia with a profoundly reversed helper/suppressor cell ratio and a decrease in the absolute number of helper T lymphocytes after sexual abuse 2 years earlier by her mother's sexual partner, a known intrave-

nous drug abuser. 34 Although sexual abuse represents an uncommon route of transmission of pediatric AIDS, the pediatric population is reported to be subjected to such behavior with startling frequency. One such encounter with an infected individual may be enough to transmit the virus. All current data suggest that horizontal transmission of AIDS through casual contact is extremely rare and is not believed to be a significant factor in the spread of the disease, z2.44,45.46 There has been only one reported case in the literature describing probable transmission of HIV from an infected child to his mother after extensive contact with his feces, urine, and other bodily secretions. ,2 IMMUNOLOGY The human immunodeficiency retrovirus shows a selective tropism and cytotoxicity for helperinducer T lymphocytes (T4), 47 with the subsequent development of abnormalities in both humoral and cellular immunity. Since the T4 lymphocyte plays a vital part in the induction and evolution of the normal immune response by other effector cells (T cells, B cells, monocytes, natural killer cells), a decrease in the number, or a disruption of the function, of these helper lymphocytes by the HIV produces a seriously altered immunity that results in significant morbidity and death. 48 In adults with AIDS or AIDS-related complex, such a decrease in T4 cell numbers coincides with functional derangements in virtually every aspect of the immune system, but particularly cell-mediated immunity. Immunologic findings include lymphopenia, a reversed T4/T8 (T helper/T suppressor cell) ratio, a decrease in the absolute number of T4 cells, poor mitogenic responses in vitro, and normal or elevated immunoglobulin l e v e l s . 44 Many children with AIDS or AIDS-related complex have immune system abnormalities similar to those seen in adult AIDS, including reversed T4/T8 ratio, poor T cell responses to mitogenic stimulation, and polyclonal hypergammaglobulinemia. 2~ However, in pediatric AIDS, B cell defects, which actually precede T cell decreases, are often the most prominent and characteristic immune defect. 29 Consequently, the hallmark of pediatric HIV infection is most often recurrent bacterial infections, with or without sepsis. 22 In

Volume 18 Number 5, Part l May I988

Cutaneous manifestations of AIDS in children

1093

Fig. 1. An IS-month-old boy with candidiasis in an unusual location on the inferolateral

aspect of the neck. Fig. 2. Hemorrhagic herpetic gingivostomatitis and clubbing of the fingers in a 24-monthold girl. Fig. 3. Herpetic whitlow on the index finger of an 18-month-old child, caused by autoinoculation as a result of severe, recalcitrant herpetic gingivostomatitis in the same child. Fig. 4. Biopsy-confirmed condyloma acuminatum in an 18-month-old girl.

contrast to adults with AIDS, children with HIV infection do not tend to exhibit lymphopenia until relatively late in the course of the disease. 2~ In addition, the total number of T4 lymphocytes in pediatric AIDS tends to remain within normal limits until end-stage disease ensues. ~6 Overall, immunologic function in pediatric AIDS, as in adult AIDS, tends to deteriorate over time? 4 DIFFERENTIAl, DIAGNOSIS IN PEDIATRIC AIDS The diagnosis of AIDS in children poses a unique problem because in pediatric AIDS, unlike adult AIDS, congenital causes as well as primary

and secondary causes of immune deficiency must be carefully excluded. Examples include adenosine deaminase deficiency, purine' nucleoside phosphorylase deficiency, DiGeorge's syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, agammaglobulinemia and hypogammaglobulinemia, combined T and B cell immunodeficiencies, graft-versus-host disease, severe malnutrition, immunosuppression, malignancy, and congenital infections. 22'49 Definitive exclusion of each o f these causes can be difficult because clinical and laboratory data may not be specific. When faced with the problem of differentiating among these immunodeficiencies, the clinician

1094

Straka et al

Journal of the American Academy of Dermatology

Fig. 5. Characteristic exanthernatous eruption on the face of a child after treatment with trimethoprim-sulfamethoxazole. Fig. 6. Diffuse erythema, or "red flush," in a child who had received no prior medications. Fig. 7. Idiopathic urticaria involving the face, neck, and trunk of an 18-month-old boy. Fig. 8. A 3-year-old girl exhibiting extremely long eyelashes that required frequent trimming. Fig. 9. Patchy alopecia primarily involving the frontal area in an 18-month-old boy. must, as always, begin with a comprehensive history and physical examination. By eliciting information regarding risk factors, time of onset of disease, presence of significant opportunistic infections or Kaposi's sarcoma, family history and medications, as well as documentation of the presence of specific dysmorphic features or neurologic defects, one may tentatively rule out many of the immunodeficiency syndromes, including ataxiatelangiectasia, Wiskott-Aldrich syndrome, malnu-

trition, immunosuppression, graft-verus-host disease, ahd severe congenital infections. Initial screening laboratory tests, such as a complete blood cell count with differential count, quantitation of immunoglobulins, and determinations of adenosine deaminase, purine nucleoside phosphorylase, and sermn calcium levels, should then be obtained. The complete blood cell count is a useful initial screening test in documenting absolute cell numbers. In addition, it can aid in

Volume 18 Number 5, Part 1 May 1988

specific diagnoses, such as the Wiscott-Aldrich syndrome, in which the presence of small platelets is a characteristic laboratory finding. Quantitation of immunoglobulin levels is valuable in that, overall, they are usually normal or decreased in most immunodeficiencies?~ It is primarily in pediatric AIDS and AIDS-related complex that a polyclonal hypergammaglobulinemia of IgG, IgM, and IgA is present. In fact, Bernstein and Rubinstein an believe that an IgG level 5 to 10 times normal with an associated increased level of IgM and igA is suggestive of AIDS. Furthermore, they state that an IgG level of >1800 mg/dl at 1 year of age, or >2300 mg/dl between 1 and 3 years of age, is extremely suggestive of AIDS.an By these criteria alone, one should miss only 8% of all pediatric AIDS cases, an Low or absent adenosine deaminase and purine nucleoside phosphorylase activity levels are diagnostic for their respective enzyme deficiencies, whereas low serum calcium levels strongly suggest DiGeorge's syndrome. When further diagnostic study is necessary, tests of T and B cell functions should be obtained. B cell studies include measurement of B cell numbers, in vitro response to B cell mitogens such as pokeweed mitogen and staphylococcal Cowan A protein, and in vitro antibody responses (both primary and secondary) to antigenic stimulation (e.g., to Epstein-Barr virus). A poor response to B cell mitogens is often the earliest immunologic abnormality seen in pediatric AIDS, and Bernstein and Rubinstein 44 have suggested that when this abnormality occurs along with polyclonal hypergammaglobulinemia, it is practically diagnostic for pediatric AIDS or AIDS-related complex. Abnormal antibody responses and absolute B cell numbers are useful in differentiating among other immunodeficiencies. T cell function studies include measurement of T cell numbers, cutaneous anergy, in vitro response to T cell mitogens such as phytohemagglutinin or concanavalin A, helper T cell numbers, and T helper/T suppressor cell ratios. These studies can be helpful in differentiating congenital infections, T cell immunodeficiencies, and early versus late pediatric AIDS or AIDS-related complex. Other laboratory tests that are more specific for the diagnosis of pediatric AIDS or AIDS-related

Cutaneous manifestations of AIDS in children

1095

Table II. Pediatric HIV infection: Major findings in order of frequency* Chronic pneumonitis Recurrent bacterial infections and sepsis Oral thrush, persistent or recurrent Diarrhea, chronic or recurrent Lymphadenopathy (two or more sites) Hepatosplenomegaly Failure to thrive Developmental delay Encephalopathy Small for gestational age Thrombocytopenia Salivary gland enlargement Opportunistic infections Kaposi's sarcoma B cell lymphoma *From Rubinstcin A. Pediatric AIDS. Curr Probl Pediatr 1986; 16:364-409. Reproduced with permission from Year Book Medical Publishers.

complex can often be obtained. Tests for the HIV are now available. Until recently, it was believed that a serologic test for the HIV antibody should be obtained in children over 6 months of age. Viral isolation was thought to be necessary lbr infants younger than 6 months of age, because maternal antibody from passive transplacental transfer could be present in the serum of these children. 27 However, it is our experience that maternal antibody may be present in the serum of children as old as 15 months. Another reported indication of pediatric AIDS or AIDS-related complex is a decrease in thymulin levels (FTS: Fr. facteur thymique sdrique) along with an increase in thymosin levels. This is specific to AIDS because in most other congenital cellular immunodeficiencies, levels of both factors tend to be depressed. Low levels of alpha and gamma interferon have also been described in pediatric AIDS and AIDS-related complex. 4n By following these guidelines, the clinician should be able to reliably distinguish pediatric AIDS and AIDS-related complex from other immune deficiencies seen in the pediatric population. CLINICAL FEATURES Pediatric AIDS and AIDS-related complex are characterized by a series of clinically detectable disorders that share a common underlying ira-

1096

Straka et al

Table III. Cutaneous manifestations of AIDS in children Neoplastic manifestations Kaposi's sarcoma Lymphoma Infectious manifestations Candidiasis Dermatophytic infection Skin abscesses Cellulitis Folliculitis Impetigo Herpetic gingivostomatitis Herpetic whitlow Molluscum contagiosum Herpes zoster Condyloma acuminatum Others Atopic dermatitis Eczematoid rash Exanthematous rash Drug eruptions (trimethoprim-sulfamethoxazole, ampicillin) Nutritional deficiencies Urticaria Alopecia Long eyelashes

munodeficiency involving both T and B cell dysfunction. In children, the individual signs and symptoms are often nonspecific and may be seen in a variety of pediatric conditions diagnosed on the basis of clinical findings. Predominant features include failure to thrive, persistent oral Candida albicans infections, chronic pulmonary infiltrates, hepatosplenomegaly, lymphadenopathy, diarrhea, recurrent fever, eczematoid rashes, chronic irritability, and other recurrent bacterial and viral infections. 2s,33 Rubinstein 22 has described the major clinical findings in pediatric AIDS based on a study of 92 HIV-positive infants in New York (Table II). Although the majority of clinical symptoms evidenced in pediatric AIDS are similar to those found in adult AIDS, there are some important differences. Several findings that appear to be unique to the pediatric age group include pulmonary lymphoid hyperplasia, salivary gland enlargement, developmental delays, and dysmorphic craniofacial features. 22In addition, pediatric AIDS is

Journal of the American Academy of Dermatology

associated with a high prevalence of pyogenic bacterial infections such as otitis media, sinusitis, pneumonia, and septicemia caused by Haemophilus influenzae, Salmonella organisms, and Streptococcus pneumoniae. Opportunistic infections in pediatric AIDS occur late in the disease course) 1 In addition, Kaposi's sarcoma, an entity seen frequently in adult AIDS, has been described infrequently in pediatric AIDS. Finally, the clinical spectrum of pediatric AIDS is not as broad as that of adult AIDS. Among children with AIDS-related complex, morbidity and mortality rates are significant, and current data indicate that most infants affected in utero show signs and symptoms of the disease. The average age at onset of symptoms in pediatric AIDS is 51/2 to 6 months22'29; AIDS in the infant rarely results in any symptoms before 3 months of age." Cutaneous manifestations of adult AIDS The diagnosis of many of the first cases of adult AIDS was based on cutaneous manifestations of the disease. These manifestations included Kaposi's sarcoma, mollu scum contagiosum, oral candidiasis, and chronic herpesvirus infection: ~ Additional reports since 1981 have confirmed that adult AIDS patients suffer from a variety of mucocutaneous afflictions. 47,~ It has recently been reported that the majority of associated dermatologic disorders seem to occur when the number of T helper cells fails below 100 cells/mm. 3'54 Warner and Fishers2 have divided the cutaneous manifestations of AIDS in adults into three major categories: neoplastic, infectious, and "other." Many of these infectious and neoplastic manifestations are seen today almost exclusively in persons who are suffering from AIDS (e.g., Kaposi's sarcoma in a young North American man). Other disease entities, such as molluscum contagiosum, herpes simplex virus infection, and candidiasis, are not found exclusively in AIDS patients but may occur with increased severity or atypical features in such a population because of the underlying immunosuppression. Still other cutaneous manifestations, such as AIDS-associated vasculitis, are probably the result of a specific and direct reaction to the HIV itself) 2 It has been proposed by other investigators 55 that

Volume 18 Number 5, Part 1 May 1988

certain dermatoses in the adult (such as chronic acneiform folliculitis, florid neck and beard impetigo, and extensive cutaneous fungal infection) should be regarded as early warning signs of AIDS in a person belonging to a high-risk population (e.g., homosexual or intravenous drug-abusing men). Other author: 6 have suggested that the occurrence of herpes zoster in a high-risk person may represent a sign of depressed cellular immunity often associated with AIDS-related complex and AIDS. Warner and Fisher sz suggest that when a patient at high risk for AIDS has any of the aforementioned dermatologic manifestations, the clinician should suspect the possibility of underlying immunodeficiency disease. Careful cutaneous followup study is important after the diagnosis of AIDS is made, so that early treatment of a potentially fatal complication can be started: 2

Cutaneous manifestations of pediatric AIDS A review of the recent literature reveals that cutaneous manifestations are a common occurrence in pediatric AIDS and, as in adults, can be divided into three main categories: neoplastic, infectious and "other" (Table III). In children, infections are by far the most common cutaneous manifestations of AIDS. Candidiasis (oral, cutaneous, and esophageal), herpetic gingivostomatitis, and staphylococcal skin infections (cellulitis, folliculitis, abscess, and impetigo) occur most often in this group. Neoplasms are rarely seen, whereas inflammatory exanthems are a fairly c o m m o n presenting symptom, especially in infants, and tend to occur along with a typical cluster of nonspecific symptoms such as lymphadenopathy, failure to thrive, and hepatosplenomegaly. As with adults, many children with AIDS develop a hypersensitivity-like reaction with diffuse skin eruptions when treated with trimethoprim-sulfamethoxazole (Bactrim). There are also a few reports of childhood nutritional deficiency diseases that exhibit characteristic cutaneous lesions. Neoplasms. Kaposi's sarcoma, which is seen frequently in adults with AIDS, has been described only rarely in pediatric AIDS. A June 6, 1985 review of 125 cases of pediatric AIDS revealed

Cutaneous manifestations of AIDS in children

1097

that only seven patients (5.6%) had any evidence of Kaposi's sarcoma) 7 Of 14 children with AIDS in a study group from Miami, two had histologic evidence of Kaposi's sarcoma in their lymph nodes and spleen at autopsy: 8 However, this "lymphadenopathic" form of Kaposi's sarcoma failed to reveal the characteristic cutaneous lesions typically seen in adults with AIDS. In fact, in contrast to adults with AIDS, in whom skin lesions are the most frequent presenting complaint: 9 children with AIDS who develop Kapsi's sarcoma often do not have skin lesions. In these children the tumor is usually very aggressive and has a fulminant course. ~~ If skin lesions are present, they are often discrete and can be overlooked initially. These cutaneous manifestations are commonly associated with large lesions in internal organs such as the lung, liver, lymph nodes, and intestinal tract: It is not understood at the present time why so few children with AIDS develop Kaposi's sarcoma. It has been hypothesized that cytomegalovirus infection may have a causative r o l e , 61 and many infants have not had cytomegalovirus infection. In contrast, 90% to 95% of adult AIDS patients have evidence of active cytomegalovims infection49; 94% of homosexual men and 66% of intravenous drug abusers have positive serologic characteristics of cytomegalovirus infection, s2 The development of Kaposi's sarcoma in AIDS patients may require repeated cytomegalovirus exposure, cytomegalovirus infection, or both. Since the majority of pediatric AIDS patients are less than 2 years old, such long-term, repeated cytomegalovirus exposure and infection are unlikely. .9 As with Kaposi's sarcoma, other neoplasms seen in adults with AIDS are extremely rare in the pediatric population. One case of disseminated immunoblastic lymphoma and a few cases of nonHodgkin's lymphomas have been reported in children with AIDS. 1s,62 Fungal infections. C o m m o n cutaneous infections can be manifested in atypical or severe forms in children with AIDS because of the immune suppression produced by the disease. Persistent oral and cutaneous Candida albicans infections, often resistant to conventional therapy, are extremely common in pediatric AIDS (Fig. 1). In o n e s t u d y , 63 persistent mucocutaneous Candida in-

1098

Straka et al

fection was frequent (6/8 pediatric AIDS patients) and was often the first infection that led the authors to suspect an immune deficiency disease. It is an accepted fact that Candida albicans is the major fungal agent in pediatric AIDS. 49 Moreover, persistent oral candidiasis, when it occurs without prior use of antibiotics, is thought to be a characteristic symptom of pediatric AIDS. 64 This fungal infection is often recalcitrant to the usual treatment with nystatin and gentian violet, and it is commonly recurrent on cessation of antifungal therapy. 65'66 In a study of 36 young children with AIDS or AIDS-related complex, 75 % (26 / 36) suffered from persistent mucocutaneous candidiasis. 67 Severe, widespread diaper dermatitis with truncal involvement has also been described in children with AIDS.4S Numerous other case reports of pediatric AIDS describe the occurrence of persistent Candida albicans infection involving the oral cavity, larynx, esophagus, and skirl. 19'29'57'5~'62'68'69 Treatment of oral candidiasis usually involves long-term therapy with oral nystatin, gentian violet, or ketoconazole. ~ Oral ketoconazole or intravenous amphotericin in B is recommended for the most invasive fungal infections, including Candida esophagitis. 23,64.67 Although Candida albicans is the predominant fungus infecting the pediatric AIDS patient, occasionally other fungi are implicated. A 14-monthold Haitian girl with AIDS was found to have small, discrete fiat-topped papules on her neck. Potassium hydroxide preparation and skin biopsy specimens revealed hyphal forms of a cutaneous dermatophyte infection. 7~ Bacterial infections. There is a high incidence of severe bacterial infections in the pediatric AIDS population that is a reflection and direct consequence of the underlying defective humoral immunity extant in these patients. It is known that B cell defects occur early in the course of AIDS and AIDS-related complex. Although the exact mechanism is unknown, it is hypothesized that HIV stimulates continuous B cell activation, which then renders the lymphocytes unresponsive to specific antigenic stimulation. Unable to mount an effective antibody response, the pediatric AIDS patient succumbs to recurrent bacterial infections. 71

Journal of the American Academy of Dermatology

In a study of 46 children under 6 years of age with AIDS-related complex or AIDS, 26 had had at least one episode of a serious bacterial infection. Six children suffered from cutaneous infections: four with cellulitis and two with impetigo. 7~ The authors found that most outpatient episodes of bacteremia were caused by Streptococcus pneumoniae, Haemophilus influenzae type b, or Salmonella organisms. Staphylococcal infections resulted in cellulitis, abscess formation, or impetigo. 71 Rubinstein (personal communication, March 1987) has also noted that a persistent folliculitis is commonly seen in children with AIDS and AIDS-related complex. The lesions originate as papules and subsequently progress to pustules. The folliculitis tends to recur repeatedly; cultures generally reveal Staphylococcus as the infectious organism. Other authors confirm that Staphylococcus is the most common organism infecting the skin in children with A I D S . 49 In a review of 36 cases of pediatric AIDS and AIDS-related complex, serious bacterial infections were encountered commonly. Streptococcus pneumoniae, Staphylococcus aureus, and gram-negative organisms have all caused lifethreatening infections in children with A I D S . 67 The authors of this review recommend monthly administration of parenteral immunoglobulin, which has been shown to decrease the incidence of serious bacterial and viral infections in one study group with pediatric AIDS over a 4-year period. 67 Viral infections. Viral agents associated with AIDS include cytomegalovirus, Epstein-Barr vires, herpes simplex virus, and a d e n o v i r u s . 49,64 Numerous cases of extensive or recurrent herpes lesions of the mouth, lips, and perianal areas have been reported and are thought to be the result of the underlying immunodeficiency64 (Fig. 2). Of 14 patients with pediatric AIDS in a Miami study group, three had herpetic gingivostomatitis. All three had lesions for at least 2 weeks, were acutely ill, and required hospitalization because of dehydration. 58 The first pediatric AIDS case in Switzerland involved a child who was hospitalized at 29 months of age with mucocutaneous herpes simplex virus type I infection manifested by perioral skin

Volume 18 Number 5, Part 1 May 1988

lesions and severe oromucosal ulcers. The child was treated with intravenous and topical acyclovir for 2 weeks, which improved the infection, but the mucosal lesions persisted for 3 months; 7 The generally accepted therapy for herpes simplex virus infection is intravenous acyclovir for 7 to 10 days, which usually results in resolution of the mucocutaneous symptoms. 64 However, a child in New Jersey suffered from chronic herpes simplex of the chin for approximately 12 months despite three courses of intravenous acyclovir (2 weeks each) and several months of topical acyclovir. In the same child, autoinoculation with the fingers resulted in herpetic whitlow (Fig. 3). The varicella-zoster herpes virus can cause disseminated disease in pediatric AIDS patients. In one child, herpes zoster developed at the T6 dermatome and evolved into persistent eruptive, disseminated, crusted vesicular lesions requiring a treatment regimen of continuous oral acyclovir and intermittent courses of intravenous acyclovir and intravenous immunoglobulin. 54 Molluscum contagiosum has also been reported in pediatric AIDS. In healthy hosts the infection most commonly affects the trunk and anogenital regions. In contrast, in childhood AIDS, molluscum contagiosum often appears as facial papules. 52,7~ Condyloma acuminatum, a rare finding in healthy children, was a presenting symptom in an 18-month-old black girl with AIDS in New Jersey (Fig. 4). This child had no history of sexual abuse, a negative VDRL test result, and negative oral, anal, and vaginal cultures for Neisseria gonorrhoeae. Treatment with topical podophyUum resin produced no response. A biopsy of the lesion revealed papillomatosis. At 22 months of age, the child demonstrated dramatic spontaneous resolution. Because many common skin lesions with an infectious cause can occur in unusual or disseminated forms in AIDS patients, Tzanck smears, potassium hydroxide preparations, Gram stains, viral cultures, and skin biopsies may often be necessary to identify or confirm the nature of the infectious organism. Other manifestations Drug eruptions. In several patients (16% in our

Cutaneous manifestations of AIDS in children

1099

study of 50 patients) with pediatric AIDS, a delayed hypersensitivity-like skin rash has developed after treatment with trimethoprim-sulfamethoxazole, which is used commonly for the treatment and prophylaxis of Pneumocystis carinii pneumonia (Fig. 5). Rubinstein found that many children with AIDS or AIDS-related complex suffer from a macular, pruritic rash after therapy with ampicillin or trimethoprim-sulfamethoxazole (personal communication, March 1987). Others have reported that diffuse skin eruptions, fever, cytopenia, and hepatitis are frequently observed in pediatric AIDS patients who receive trimethoprimsulfamethoxazole and usually appear 8 to 10 days after initiation of such treatment. 23,64Most authors advocate stopping the drug if such a situation arises and treating the patient's underlying condition with pentamidine alone. 67 Rashes. Rashes are frequently seen in pediatric AIDS patients and are not uncommon as a presenting symptom. Of 63 children with symptomatic HIV infection seen from 1984 to 1986 in Newark, NJ, 95% had a rash at some time during this 2-year period. An exanthematous rash and fever were the only initial symptoms of pediatric AIDS in one 14-month-old child in Switzerland. 67 "Eczema-like" rashes, atopic dermatitis, and a diffuse erythematous "flush" have been observed in children with AIDS 29(Fig. 6). Secondary infection (abscess formation) is not an uncommon finding in conjunction with chronic dermatitis in these children. 23 In addition, both cold urticaria and idiopathic urticaria have been observed in pediatric AIDS patients in New Jersey (Fig. 7). Nutritional deficiencies. Children with AIDS grow poorly because of a number of factors. Episodic or chronic diarrhea certainly contributes to the failure to thrive, as does the wasting that accompanies chronic inflammation and infection. 67 Nutritional deficiency diseases have been reported in pediatric AIDS. 7~One child had verrucous, hyperpigmented lesions on the legs; a skin biopsy revealed changes compatible with pellagra, zinc deficiency, or acquired acrodermatitis enteropathica. Scurvy was diagnosed in another child after a follicular petechial eruption on the legs and bleeding of the gums were observed. In still other patients, cutaneous lesions suggestive of multiple

1100

Journal of the American Academy of Dermatology

Straka et al

combined nutritional diseases have been describedJ ~ An orofacial rash in a 14-month-old child with AIDS and a low serum zinc level resolved after oral supplementation with zinc .42 Two thirds of pediatric AIDS patients from Newark, N J, had levels of zinc at least one standard deviation below normal. It is believed that zinc deficiency is the result of malabsorption from the chronic diarrhea caused by opportunistic organisms such as Cryptosporidium and Giardia. ~2Tong et a172 recommend early, vigorous nutritional support to prevent these sequelae. Hair growth. Several children with AIDS in New Jersey have had extremely long eyelashes that required routine trimming (Fig. 8). In addition, alopecia seems to be c o m m o n among the pediatric AIDS population 73 (Fig. 9). CONCLUSION All present epidemiologic data project that the number of pediatric AIDS cases will escalate rapidly over the next several years. The general trend in incidence and geographic distribution of pediatric cases is expected to mimic that of adult AIDS. This means that the vast majority of dermatologists in the United States can expect to be involved in the diagnosis and m a n a g e m e n t of children with AIDS in the very near future. Although the disease carries a dismal prognosis and no specific treatment or cure has yet been developed, early intervention with supportive measures can often have a significant impact on the morbidity associated with the disease. To institute rapid, early treatment, the dermatologist must be aware o f the typical cutaneous lesions seen in pediatric AIDS and their protean manifestations in the pediatric AIDS population. As we have discussed, dermatologic symptoms are common; oral candidiasis, recurrent bacterial skin infections, herpetic gingivostomatitis, and various rashes are seen most often in children with AIDS. The role of the dermatologist is twofold: (1) to recognize these cutaneous manifestations as potential early warning signs o f undiagnosed cases of pediatric AIDS or AIDS-related complex and (2) to be able to intervene with appropriate therapy in the management of the cutaneous complications

of known or suspected cases of pediatric AIDS or AIDS-related complex. In this way, the dermatologist can be instrumental in ensuring that appropriate care is quickly instituted; it is hoped that morbidity can thereby be significantly reduced in these unfortunate children. REFERENCES

1. Gottlieb MS, Sehroff R, Schanker HM, et al. Pneumocystis carlnii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired immunodeficiency. N Engl J Med 1981;305: 1425-1421. 2. Hymes KB, Cheung T, Greene JB, et al. Kaposi's sarcoma in homosexual men: report of eight cases. Lancet 1981;2:598-600. 3. Kaposi's sarcoma and pneumocystis pneumonia among homosexual men--New York City and California. MMWR 1981;30:305-8. 4. Selwyn PA. AIDS: What is now known. I. History and immunovirology. Hosp Pract (Off) 1986;21:67-82. 5. Moll B, Emeson EE, Small CB, Friedland GH, Klein RS, Spigland I. Inverted ratio of inducer to suppressor T-lymphocyte subsets in drug abusers with opportunistic infections. Clin Immunol Immunopathol 1982;25:41723. 6. Jaffe HW, Bregman DJ, Selik RM. Acquired immune deficiency syndrome in the United States: the first 1,000 cases. J Infect Dis 1983;148:339-45. 7. Davis KC, Horsburgh CR, Hasiba V, Schockert AL, Kirkpatrick CH. Acquired immunodeficiency syndrome in a patient with hemophilia. Ann Intern Med 1983; 98:284-6. 8. Curran JW, Lawrence DN, Jaffe H, et al. Acquired immunodeficiencysyndrome (AIDS) associated with transfusions. N Engl J Med 1984;310:69-75. 9. Harris C, Small CB, Klein RS, et al. Immunodeficiency in female sexual partners of men with the acquired immunodeficiency syndrome. N Engl J Med 1983;308: 1181-4. 10. Redfield RR, Markham PD, Salahuddin SZ, et al. Frequent transmission of HTLV-III among spouses of patients with AIDS-related complex and AIDS. JAMA 1985;253:1571-3. 11. Gallo RC, Satin PS, Gelmann EP, et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome. Science 1983;220:865-7. 12. Selwyn PA. AIDS: what is now known. II. Epidemiology. Hosp Pract (Off) 1986;21:127-39. 13. Epstein LG, Goudsmit J, Paul DA, et al. Expression of human immunodeficiency virus in cerebrospinal fluid of children with progressive encephalopathy. Ann Neurol 1987;21:397-401. 14. Coffin J, Hasse A, Levy JA, et al. Human immunodeficiency viruses [letter]. Science 1986;232:697. 15. Rogers MF. AIDS in children: a review of the clinical, epidemiologic and public health aspects. Pediatr Infect Dis 1986;4:230-6.

Volume 18 Number 5, Part 1 May 1988

16. Rubinstein A, Sicklick M, Gupta A, et al. Acquired immunodeficiency with reversed T4/T8 ratios in infants born to promiscuous and drug-addicted mothers. JAMA 1983;249:2350-6. 17. Rubinstein A. Acquired immunodeficiency syndrome in infants. Am J Dis Child 1983;137:825-7. 18. Oleske J, Minnetor A, Cooper R, et al. Immune deficiency syndrome in children. JAMA 1983;249:2345-9. 19. Ammann AJ, Wara DW, Dritz S. Acquired immunodeficiency in an infant: possible transmission by means of blood products. Lancet 1983;1:956-8. 20. Immunization of children infected with human Tlymphotropic virus type II/lymphadenopathy-associated virus. JAMA 1986;256:2477-83. 21. Surgeon General's report on acquired immune deficiency syndrome. JAMA 1986;256:2784-9. 22. Rubinstein A. Pediatric AIDS. Curr Probl Pediatr 1986; 16:361-409. 23. Sheperd FA, Fanning MM, Duperval R, et al. A guide to the investigation and treatment of patients with AIDS and AIDS-related disorders. Can Med Assoc J 1986; 134:999-1008. 24. Farthing CF, Brown SE, Staughton RCD, Cream JJ, Muhleman M. A colour atlas of AIDS. London: Wolfe Medical Publications, 1986. 25. Update on acquired immune deficiency syndrome (AIDS)--United States. MMWR 1982;31:507-14. 26. Update: acquired immunodeficiency syndrome (AIDS)--United States. MMWR 1984;32:688-91. 27. Ammann AJ. The acquired immunodeficiency syndrome in infants and children. Ann Intern Med 1985;103: 734-7. 28. Feder HM, Schmidt P. AIDS in a child: the family physician's role. Am Fam Physician 1986;34:114-8. 29. Rubenstein A, Bernstein L. The epidemiology of pediatric acquired immunodeficiency syndrome. Clin Immunol Immunopathol 1986;40:115-21. 30. Lampert R, Milberg J, O'Donnell R, Kirstal A, Thomas P. Life table analysis of children with acquired immunodeficiency syndrome. Pediatr Infect Dis 1986;5: 374-5. 31. Update: acquired immunodeficiency syndrome-United States. MMWR 1985;34:245-8. 32. Pinching AJ, Jeffries DJ. AIDS and HTLV-III/LAV infection: consequences for obstetrics and perinatal medicine. Br J Obstet Gynaecol 1985;92:1211-7. 33. HTLV-III chronicle. Abbott Park, IL: Abbott Diagnostics Educational Services, summer 1986, pp. I-8. 34. Liederman BA, Grimm KT. A child with HIV infection. JAMA 1986;256:3904. 35. Thomas PA, Jaffe HN, Spira TJ, et al. Unexplained immunodeficiency in children: a surveillance report. JAMA 1984;262:639-44. 36. Ziegler JB, Cooper DA, Johnson RO, Gold J. Postnatal transmission of AIDS-associated retrovirus from mother to infant. Lancet 1985;1:896-8. 37. Thiry L, Sprecher-Goldberger S, Janckheir T, et al. Isolation of AIDS virus from cell-free breast milk of three healthy virus carriers. Lancet 1985;2:891-2. 38. Quaggin A. Get prepared for more cases of AIDS during pregnancy. Can Med Assoc J 1987;136:192-3.

Cutaneous manifestations of AIDS in children

1101

39. Jovaisas E, Koch MA, Schafer A, Stauber M, Lowenthal D. LAV/HTLV-III in 20-week fetus. Lancet 1985; 2:1129. 40. Wykoff RF, Pearl ER, Saulsbury FT. Immunologic dysfunction in infants infected through transfusion with HTLV-III. N Engl J Med 1986;312:294-6. 41. Paul R, Dobkin D, Maurer H, Noah Z, Yogev R. Acquired immunodeficiency syndrome in a thalassemic child. Pediatr Infect Dis 1986;5:274-6. 42. Ammann AJ, Cowan MJ, Wara DW, et al. Acquired immunodeficiency in an infant: possible transmission by means of blood products. Lancet 1983;1:956-8. 43. Wykoff R. Children and transfusion related AIDS. J La State Med Soc 1985;137:65-8. 44. Bemstein LJ, Rubinstein A. Acquired immunodeficiency syndrome in infants and children. Prog Allergy 1986; 37:194-206. 45. Kaplan JE, Oleske JM, Getchell JP, et al. Evidence against transmission of human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-III/LAV) in families of children with the acquired immunodeficiency syndrome. Pediatr Infect Dis 1985;4:468-71. 46. Friedland GH, Saltzman BR, Rogers MF, et al. Lack of transmission of HTLV-III/LAV infection to household contacts of patient with AIDS or AIDS-related complex with oral candidiasis. N Engl J Med 1986; 314:344-9. 47. Muggia FM, Lonberg M. Kaposi's sarcoma and AIDS. Med Clin North Am 1986;70:139-54. 48. Bowen DL, Lane HC, Favci AS. Immunopathogenesis of the acquired immunodefieiency syndrome. Ann Intern Med 1985;103:704-9. 49. Ammann A J, Wara DW, Cowan MJ. Pediatric acquired immunodeficiency syndrome. Ann NY Acad Sci 1984; 437:340-9. 50. Rosen FS, Wedgwood RJ, Eibl M, et al. Primary immunodeficiency disease: a report of a world health organization scientific group. Clin Immunol Immunopathol 1986;40:166-96. 51. Church JA, Allen JR, Stiehon ER. New scarlet letter(s), pediatric AIDS. Pediatrics 1986;77:423-7. 52. Warner LC, Fisher BK. Cutaneous manifestations of the acquired immunodeficiency syndrome. Int J Dermatol 1986;25:337-50. 53. Selwyn PA. AIDS: what is now known. III. Clinical aspects. Hosp Pract (Off) Sept 1986;21:119-53. 54. Kaplan MH, Sadick N, McNutt NS, Meltzer M, Sarngadharan MG, Pahwa S. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J AM ACADDERMATOL1987;16:485-506. 55. Muhlemann MF, Anderson MG, Paradinas FJ. Early warning skin signs in AIDS and persistent generalized lymphadenopathy. Br .1 Dermatol 1986;114:419-24. 56. Friedman-Kien AE, Lafleur FL, Gendler E, et al. Herpes zoster: a possible early clinical sign for development of acquired immunodeficiency syndrome in high-risk individuals. J AM ACADDERMATOL1986;14:1023-8. 57. Schaad VB, Morell A, Vogt M. Acquired immunodeficiency syndrome (AIDS) in pediatric patients. Helv Paediatr Acta 1985;40:249-60. 58. Scott GB, Buck BE, Leterman JG, Bloom FL, Parks

1102

59. 60. 61. 62. 63. 64. 65.

Straka et al

WP. Acquired immunodeficiency syndrome in infants. N Engl J Med 1984;310:76-81. Leslie W, Templeton A, Braun D. Kaposi's sarcoma in the acquired immune deficiency syndrome. Med Pediatr Oncol 1984;12:336-42. Buck BE, Scott GB, Valdes-Dapena M, Parks WP. Kaposi's sarcoma in two infants with acquired immune deficiency syndrome..l Pediatr 1983;103:911-3. Gelmann EP. New concepts in Kaposi's sarcoma: the acquired immunodeficiency syndrome: an update. Ann Intern Med 1985;102:800-13. Pahwa S, Fikrig S, Kaplan M, Kahn E, Pahwa R. Expressions of HTLV-III infection in a pediatric population. Adv Med Biol 1985;187:45-51. Lauzon D, Delage G, Brochu P, et al. Pathogens in children with severe combined immune deficiency disease of AIDS. Can Med Assoc J 1986;135:33-8. Berkowitz CD. AIDS and parasitic infections, including Pneumocystis carinii and Cryptosporidium. Pediatr Clin North Am 1985;32:933-52. Parks WP, Scott GB. Pediatric AIDS: a disease spectrum causally associated with HTLV-III infection. Cancer Res 1985 ;45:4659-61.

Journal of the American Academy of Dermatology

66. Ragni MV, Urbach AH, Kierran S, et al. Acquired immunodeficiency syndrome in the child of a hemophiliac. Lancet 1985;1:133-5. 67. Shannon KM, Ammann AJ. Acquired immune deficiency syndrome in childhood. J Pediatr 1985;106:332-42. 68. Bernstein LJ, Ochs HD, Wedgwood RJ, Rubinstein A. Defective humoral immunity in pediatric acquired immune deficiency syndrome. J Pediatr 1985;107:352-7. 69. Berkowitz CD, Seidel JS. Spontaneous resolution of cryptosporidiosis in a child with acquired immunodeficiency syndrome. Am J Dis Child 1985;139:967. 70. Penneys NS, Hicks B. Unusual cutaneus lesions associated with acquired immunodeficiency syndrome. J AM AC.AD DERMATOL1985;13:845-52. 71. Bernstein LJ, Krieger BZ, Novick B, Sicklide MJ, Rubinstein A. Bacterial infection in the acquired immunodeficiency syndrome of children. Pediatr Infect Dis 1985;4:472-5. 72. Tong TK, Andrew LR, Albert A, Mickell J J. Childhood acquired immune deficiency syndrome manifesting as acrodermatitis enteropathica. J Pediatr 1986; 108:426-8. 73. Barbour SD. Acquired immunodeficiency syndrome of childhood. Pediatr Clin North Am 1987;34:247-65.

BOUND VOLUMES AVAILABLE TO SUBSCRIBERS

Bound volumes of the JOURNALOFTHEAMERICANACADEMYOFDERMATOLOGYare available to subscribers (only) for the 1988 issues from'the Publisher at a cost of $49.00 ($62.00 international) for volume 18 (January-June) and volume 19 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment nlust accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.