Medical Care of the HIV-Infected Child

Childhood AIDS

0031-3955/91 $0.00

+ .20

Medical Care of the HIV-Infected Child Margaret H. Burroughs, MD, * and Paul J. Edelson, MDt

TRANSMISSION Children are infected with human immunodeficiency virus (HIV) by one of three routes: (1) perinatal infection, (2) transfusion of contaminated blood or blood products, or (3) sexual exposure, including sexual abuse. Transfusion-related infection has been almost entirely interrupted in this country, but children infected before 1985, when national blood screening for HIV went into effect, are still being identified. Sexual transmission, principally a problem for certain groups of adolescents, including runaways and teen-age prostitutes of both sexes, is a relatively small but growing problem. Some recent data suggest that sexual transmission resulting from abuse may be a more important route in younger children than was previously realized. 44 However, the leading mechanism of infection of children is perinatal transmission from infected women, and this risk is growing as the number of infected young women in the United States grows. As of April 1990, among 2192 cases of. pediatric acquired immunodeficiency syndrome (AIDS) collected by the Centers for Disease Control (CDC), 82% were infected perinatally, 15% by blood or blood products, and 3% were unknown or uninvestigated. 19 In New York City, where AIDS is now the leading cause of death in young women ages 18 to 45, 88% of cases are currently perinatal, 4% resulted from blood transfusion, 1% were due to sexual contacts, and 9% were unknown or uninvestigated. 70 Our understanding of the biology of perinatal HIV infection is still very limited, and the mechanism of perinatal infection is not clear. Perinatal viral infection, in general, occurs by two modes: as with rubella, infection *Clinical Fellow in Pediatric Infectious Diseases, The New York Hospital-Cornell Medical Center; and Postdoctoral Fellow, Department of Microbiology, The Rockefeller University, New York, New York tAssociate Professor, Department of Pediatrics, and Associate Professor, Department of Microbiology, Cornell University Medical College; and Associate Attending Pediatrician and Director, Division of Pediatric Infectious Diseases and Immunology, The New York Hospital-Cornell Medical Center, New York, New York

Pediatric Clinics of North America-Vol. 38, No.1, February 1991

45

46

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

can occur in utero or, as with hepatitis B, at the time of delivery when the infant is exposed to large volumes of infected fluid. In pediatric HIV disease, evidence suggests that in utero transmission occurs in at least some instances: first- and second-trimester abortuses have had virus isolated from multiple sites53. 101 and virus can be cultured from cord blood. 90 Furthermore, the placenta expresses the CD4 epitope and is a target and potential reservoir for infection with HIV.3 Given the great quantity of infected fluid the child is exposed to at delivery, the hepatitis B model is intuitively plausible. Although it is more difficult to obtain evidence for this mode, the best evidence that this route is important in HIV disease comes from case reports of mothers who were infected by postpartum transfusions and whose infants were infected via ingestion of breast milk. 110 Rates of perinatal transmission in longitudinal studies have been approximately one third, with estimates ranging from 21% to 39%.12,43.67, 76, 90 Estimates of transmission in general favor children with lower incubation periods and, thus, probably underestimate the true rate of transmission. Blanche et aP2 demonstrated that mode of delivery, weight, height, head circumference, and presence or absence of dysmorphic features did not predict which infants would subsequently prove to be infected, whereas such immunological abnormalities in the infant as elevated IgM or depressed absolute CD4 counts and CD4:CD8 ratios were closely associated with infection. A study of Zairian women suggested that mothers with absolute T4 counts less than 400 were more likely to transmit HIV, implying that more severely infected women had a higher risk of transmitting infection. 90 In a recent US series, however, women lacking a specific type of antigp120 antibody were more likely to transmit infection to their infants, whereas in these women, maternal T-cell counts or the presence of antip24 or neutralizing antibodies did not predict transmission. 43

DIAGNOSIS Clinical Presentation The mean age of diagnosis of perinatally infected children is 17 months. 85 The majority of children infected with HIV disease present with failure to thrive, hepatosplenomegaly, chronic interstitial pneumonitis, or a combination of these symptoms. 6 Infants commonly present with mucocutaneous candidiasis, failure to thrive, hepatosplenomegaly, or respiratory distress secondary to pneumocystis pneumonia (PCP), whereas toddlers may present with parotitis, generalized lymphadenopathy, recurrent bacterial infection, neurologic disease, or developmental abnormalities. 37. 78 Idiopathic thrombocytopenic purpura and certain malignancies, especially primary CNS lymphomas, are associated with HIV disease68 and should also prompt HIV testing. Although a constellation of dysmorphic characteristics was described early in the epidemic and termed HIV embryopathy, a controlled study comparing these children with children matched for race suggested that

MEDICAL CARE OF THE HIV-INFECTED CHILD

47

these features were equally prevalent in children who were not infected with HIV.81 Laboratory Findings CD4 (helper) lymphopenia with decreased absolute numbers of CD4 lymphocytes and an inverted CD4:CD8 ratio is the hallmark of HIV infection. However, children infected with HIV may have normal numbers of CD4 cells even in the face of serious bacterial infection or opportunistic infections. 63 • 78. 91 Humoral immunity is altered in HIV infection as well: B cells are activated, resulting in a polyclonal hypergammaglobulinemia that may occur very early in the course of the disease. 78 Hypogammaglobulinemia is less common in HIV disease but does occur.78 The response to new antigens is muted. 37, 55, 78 Specifically, children immunized with tetanus toxoid, diphtheria, and pneumococcal or Hib vaccine may have an impaired antibody response when compared with their uninfected peers. 10, 13, 55 In addition, in vitro lymphoproliferative response to staph A and pokeweed mitogen may be diminished. 78 Cell-mediated immunity may be less impaired in early HIV disease, but cutaneous anergy is common. 78

HN Studies HIV antibody testing, by ELISA and Western blot, is readily available in most centers, and in adults and children with transfusion-associated HIV

disease, is diagnostic of HIV infection. However, infants born to infected women acquire maternal antibody to HIV transplacentally whether or not the infants are infected. For uninfected children, the median age of seroreversion is 9 to 10 months,76, 84 although maternal antibody may persist as long as 16 months. 84 In the absence of symptoms, HIV antibody tests are not sufficient to diagnose HIV infection in infants and toddlers less than 15 months of age. In asymptomatic children with a positive antibody test, diagnosis of HIV infection may be made by detecting HIV-specific antigen (with the HIV p24 antigen ELISA), by demonstrating production of HIV specific antibody by the patient's lymphocytes in vitro, by detecting HIV-specific DNA using the polymerase chain reaction, or by demonstrating the presence of the virus itself by viral culture. None of these techniques is as yet widely available. The p24 HIV ELISA detects the presence of p24, a protein present in the core of the HIV virion. 30 Although p24 is present by ELISA in 14% to 56% of patients symptomatic with AIDS, it is rarely detected in asymptomatic patients. 14 The detection of HIV-specific DNA by polymerase chain reaction (PCR), a technique that amplifies proviral genetic material, confirms the diagnosis of HIV infection. In a preliminary study by Rogers et al,84 it proved highly specific-no infants who remained well nor any of the controls had positive tests-but the sensitivity of the test was limited. Of seven infants tested in the neonatal period who subsequently developed AIDS, five had positive tests, as did one of the eight neonates who subsequently developed symptomatic HIV infection. In the postnatal period (over 1 month of age), all 6 children who subsequently developed AIDS

48

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

had a positive test, as did 4 of 14 who subsequently developed symptoms of HIV disease. Viral culture is achieved by coculturing the patient's peripheral blood monocytes with normal peripheral blood monocytes that have been stimulated with phytohemagglutinin and interleukin-2. The culture media is assayed weekly for the presence of p24 antigen and viral reverse transcriptase; the presence of viral antigen or enzyme activity in the media is diagnostic of infection. 14 In addition, HIV infection may be diagnosed by in vitro synthesis of HIV antibody by the patient's lymphocytes. In this assay, the patient's peripheral lymphocytes are cultured. The culture supernatant is assayed for viral antibody by ELISA and Western blot. In a preliminary series, the assay identified 14 of 16 patients who met the criteria for HIV infection, as well as identifying 4 of 16 asymptomatic patients. All 22 controls and 4 seroreverters lacked HIV IgG production in vitro. 2 In general then, p24 Ag testing, viral culture, in vitro antibody production, and PCR are specific tests that when positive correctly identify patients who are infected, but in preliminary studies they lack sensitivity and thus a significant proportion of children who are infected may not be identified by these assays. Classification The classification system for pediatric HIV infection, which was developed by the CDC and revised in 1987 (Table 1), was developed for Table 1. Summary of the Classification of HIV Infection in Children Under 13 Years of Age Class P-o. Indeterminate infection Class P-1. Asymptomatic infection Subclass A. Normal immune function Subclass B. Abnormal immune function Subclass C. Immune function not tested Class P-2. Symptomatic infection Subclass Subclass Subclass Subclass

A. Nonspecific findings B. Progressive neurologic disease C. Lymphoid interstitial pneumonitis D. Secondary infectious diseases

Category D-1. SpeCified secondary infectious diseases listed in the CDC surveillance definition for AIDS Category D-2. Recurrent serious bacterial infections Category D-3. Other specified secondary infectious diseases Subclass E. Secondary cancers Category E-1. SpeCified secondary cancers listed in the CDC surveillance definition for AIDS Category E-2. Other cancers possibly secondary to HIV infection Subclass F. Other diseases possibly secondary to HIV infection

Adapted from AIDS Program, Center for Disease Control: Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 36:225, 1987; with permission.

MEDICAL CARE OF THE HIV-INFECTED CHILD

49

epidemiologic purposes. Children are categorized as having indeterminate (P-O) , asymptomatic (P-1), or symptomatic (P-2) infection. 1 While useful in identification of infected children and in data collection, the classification system does not address severity of disease in symptomatic patients and thus is not useful in assigning prognosis. The Enrollment Visit The initial visit to a pediatric HIV clinic serves two purposes: (1) assessment of the child and his or her degree of disease and (2) discussion with the child's caretaker about the special needs and concerns of the HIVinfected child. The initial assessment includes a thorough physical examination. Particular attention to the respiratory system is appropriate, as is a thorough neurodevelopmental examination. In the child less than 15 months old with a positive HIV antibody test, p24 antigen testing, polymerase chain reaction, in vitro antibody synthesis, or viral culture may be used to confirm infection. Helper cell subsets and a complete blood count, skin testing for anergy, and immunoglobulin levels help to determine levels of immunosuppression. Infectious serologies, including cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, VDRL, and toxoplasma titers may identify both treatable illnesses and susceptibility to viral infections. Initial Areas for Advice Families coping with the new diagnosis of HIV infection need tangible advice. Because HIV is not transmitted by casual household contact, 41. 86 they can be assured that their child does not place others at risk and that he or she can attend school and participate in a free program according to his or her own capacities. Furthermore, they are under no obligation to inform others of their child's diagnosis. The chronically ill child places a burden on the whole family. Our experience strongly supports telling the child what is wrong and what we will do, at a level appropriate to the child's own concerns. Siblings also benefit from an age-appropriate explanation of their sibling's illness. Parents may find it helpful to discuss the illness with their children with the help of a physician, nurse, or social worker.

MEDICAL COMPLICATIONS Pulmonary Pulmonary disease is a prominent feature of pediatric HIV disease. Scott et al95 reported that 14% of the HIV-infected children they follow develop PCP at some time in their course and lymphoid interstitial pneumonitis (LIP) occurs in 30% of their population. Similarly, the New York City (NYC) Department of Health reports that 43% of children diagnosed with AIDS developed PCP and 24% developed LIP.70 In addition, bacterial pneumonias, including mycobacterial disease, occur with increased frequency in this population. An HIV-infected child who presents

50

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

with pulmonary symptoms, then, may have a potentially life-threatening illness that requires early diagnosis and intervention or a chronic disease requiring long-term management. Clinical presentation and laboratory data may suggest a diagnosis, but in the child who is seriously or progressively ill, an aggressive diagnostic approach, including bronchoscopy, if necessary, is warranted.

Pneumocystis carinii Pneumocystis carinii, a ubiquitous protozoan, typically causes acute disease in HIV-infected children, with associated fever, nonproductive cough, and tachypnea. Clinical evaluation reveals hypoxia with an elevated A-a gradient. 88• 99 On chest roentgenogram, diffuse interstitial changes may progress to air space filling with associated air bronchograms. 45 The diagnosis of PCP is established by identifying the characteristic cysts in respiratory secretions stained with silver methenamine or toluidine blue. To improve the sensitivity of such studies, Kovacs et al56 reported use of a monoclonal antibody for diagnosis of PCP, but there is little experience with its use in children. In most children, the diagnosis is readily made on a deep tracheal suction specimen. In older children, induced sputa may be a useful alternative in diagnosing PCP.71 However, some children require bronchoscopy and bronchoalveolar lavage to establish the diagnosis. In our clinic, lung biopsy is almost never necessary to make this diagnosis. Trimethoprim-sulfamethoxazole (TMP-SMZ) remains the drug of choice in treating PCP in pediatric HIV disease. In contrast to adult experience, adverse reactions to TMP-SMZ, including skin rashes and neutropenia, are less common. 91 The clinical response to treatment is frequently slow, with responses taking 4 to 7 days to appear. There is no evidence that replacing TMP-SMZ with pentamidine increases the rate of response; the replacement probably only makes sense when a toxic reaction requires the withdrawal of TMP-SMZ. Adverse reactions to pentamidine are common, and include hypoglycemia, pancreatitis, and renal failure. Lymphoid Interstitial Pneumonitis In contrast to PCP, lymphoid interstitial pneumonitis (LIP) typically presents as a slowly progressive pulmonary disorder, with associated cough and mild hypoxemia. Generalized lymphadenopathy and salivary gland enlargement are frequently present. Digital clubbing is a late finding. 88 On chest roentgenogram, small nodules and fine reticular densities may be present and become more prominent with time. Hilar and paratracheal adenopathy tend to be late findings. 48 Mature lymphocytes, plasma cells, and macrophages are present in bronchiolar epithelium on pathologic examination. 99 Although its course is chronic, LIP may be complicated by acute exacerbations, sometimes associated with intercurrent viral or bacterial infection. Appropriate antibiotics or antiviral agents, when warranted, and supportive care including bronchodilators or oxygen therapy are indicated for exacerbations. The role of corticosteroids in the management of LIP is still unclear.

MEDICAL CARE OF THE HIV-INFECTED CHILD

51

Tuberculosis Given the demographics of pediatric HIV disease, Mycobacterium tuberculosis is likely to be an important pathogen in HIV-infected children. Whereas tuberculosis and HIV disease are closely linked in adults, the published experience of pediatric tuberculosis associated with HIV is sparse. In adults, in whom tuberculosis most probably represents reactivation of latent disease most patients nonetheless present with chest radiographs suggestive of primary tuberculosis (that is, hilar or mediastinal lymphadenopathy with or without noncavitating infiltrates distributed over both lung fields).77 Extrapulmonary and disseminated disease occur more commonly than with non-HIV infected hosts.105 Skin testing alone is not adequate to exclude a diagnosis of tuberculosis in the immunosuppressed child. Cultures of CSF and blood should be obtained in addition to bronchial washings, to exclude disseminated disease. 21 The CDC recommends an initial regimen of isoniazid (IN H), rifampin, and pyrazinamide with the addition of ethambutol if CNS or disseminated disease is suspect or in the case of isoniazid resistance. Quadruple therapy should continue for 2 months. Thereafter, INH and rifampin should be continued for at least 9 months or 6 months after sterilization of cultures. If either INH or rifampin must be omitted from the regimen, therapy should be continued for a minimum of 18 months or 12 months following sterilization of cultures. 4 Respiratory Syncytial Virus Respiratory syncytial virus (RSV) disease appears to be surprisingly well tolerated in HIV-infected children, although severe disease can occur in children with underlying pulmonary disease. Chandwani et a123 report ten children with RSV disease, all of whom were tachypneic and febrile, but severe hypoxia and significant respiratory distress occurred only in children who had intercurrent PCP or bacterial infection. The experience in our clinic supports their observations. Although several of our patients with uncomplicated RSV disease tolerated their infections without requiring antiviral therapy, a child who had earlier had pneumocystis pneumonia had significant deterioration in her ventilatory status and required antiviral therapy. Whereas aerosolized ribavirin should be considered in the HIV-infected child with RSV infection, careful observation may obviate this need in the mildly ill child. Measles Measles appears to have a particularly virulent course in HIV-infected children. Of six HIV-infected children in whom measles were reported, four developed pneumonia and two died. One child did not develop a rash; in a second child, the rash was transient. 58. 59 We have treated a child with a highly atypical maculopapular rash in whom the diagnosis of measles could only be established by skin biopsy. Rapid diagnosis of measles pneumonia may be made by demonstration of viral antigen by fluorescent antibody and may be confirmed by a rise in serum antibody titers. Given

52

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

the severity of the disease and the high mortality, aerosolized ribavirin may be indicated. Varicella In the immunocompromised child, varicella may have a fulminant course with a high proportion of patients developing visceral disease. Jura et al54 reported eight children with perinatal HIV disease who developed primary varicella infection; all eight children had evidence of visceral dissemination to the lungs, liver, brain, or pancreas. The lung was frequently involved; seven of the children had evidence of pulmonary dissemination. Acyclovir was administered to seven patients; nonetheless, four developed chronic or recurrent varicella. In our experience, the incidence of visceral dissemination appears lower, but many of our children received acyclovir. 16 It is clear that the HIV -infected child is at risk for severe, and sometimes fatal, varicella infection. In addition, a syndrome of chronic varicella has been described in several HIV -infected children. 54 Given the potential for serious disease, HIV-infected children exposed to varicella should receive varicella zoster immune globulin (VZIG) within 72 hours of exposure. 27 If varicella develops in spite of prophylaxis, the child should be evaluated for evidence of systemic disease, including chest radiographs and liver function tests. Although some children will recover without intervention, the HIV-infected child with varicella should be considered an early candidate for acyclovir. Cytomegalovirus Whereas 9% of AIDS patients reported to the NYC Department of Health had evidence of disseminated cytomegalovirus infection at diagnosis, in adults CMV causes symptomatic pulmonary disease only in the presence of other bacterial or viral infection. 69 Although Krasinski et al60 report a death apparently resulting from CMV pneumonia, and Vernon et aP06 reported six children with CMV-associated respiratory failure, pediatric series defining the natural course of CMV disease in HIV -infected children are lacking. Diagnosis of CMV disease requires viral culture of more than one site, and can be further substantiated by a rise in serum antibodies. Recently, polymerase chain reaction has been used to make a diagnosis of active CMV infection. 97 Current treatment is limited to ganciclovir, a toxic drug with limited efficacy in CMV pneumonia. 40 Recurrences are frequent unless maintenance therapy is instituted. 40 Bacterial HIV-infected children are at risk for bacterial pneumonia, especially with encapsulated organisms including Streptococcus pneumoniae and Hemophilus irifluenzae as well as Staphylococcus aureus. 5 Associated bacteremia can be expected to occur frequently in immunocompromised children. Krasinski et al57 report bacteremia in 33% of patients with pneumonia. In the extremely ill child, gram-negative pneumonia may occur; as illness progresses, antibiotic coverage should include an aminoglycoside in addition to antibiotics which cover common childhood organisms.

n s n

MEDICAL CARE OF THE HIV-INFECTED CHILD

53

Gastrointestinal System Gastrointestinal complaints, including abdominal pain, recurrent diarrhea, weight loss, and failure to thrive may be prominent symptoms in HIV-infected children. Although the possible etiologies include infection, malignancy, or HIV-associated disease, malignancy is still relatively rare in HIV-infected children; infectious and HIV-associated disease more commonly cause symptoms in these children. Cryptosporidium Cryptosporidium is a coccidian protozoa that causes self-limited gastrointestinal disease in normal hosts, but in HIV-infected hosts may be associated with prolonged, profuse, watery diarrhea and weight 10ss.98 Right upper quadrant pain, vomiting, and cholestasis may indicate associated hepatobiliary disease. 33 Cryptosporidiosis is diagnosed by microscopic examination of stool specimens stained with a modified Kinyoun acid-fast stain or by using fluorescent-labeled IgG monoclonal antibody. 33.98 Intestinal biopsy may be a less sensitive means of diagnosing infection. 98 At present, there is no effective treatment of cryptosporidium, although infected children will occasionally clear the organism without treatment. If disease is protracted, the macrolide antibiotic spiramycin may diminish the severity of disease. 98

Salmonella In HIV-infected children, the course of salmonellosis has a high frequency of bacteremia. Krasinki et al57 reported that more than 40% of children in whom they documented gastrointestinal salmonellosis developed bacteremic illness, whereas Oleske et al72 reported that 75% of their patients were bacteremic. Of those who develop bacteremia, nearly half will recur, with plasmid fingerprinting suggesting persistent, not new infection. 100 Gastrointestinal symptoms may be absent or mild in face of bacteremic illness. 1OO Given the frequency of recurrent bacteremia, some clinicians suggest long-term suppressive antibiotic therapy.

Isospora beUi Patients infected with Isospora belli present with signs and symptoms similar to cryptosporidium, for example, watery, nonbloody diarrhea, crampy abdominal pain, and weight loss. Fever is not usually a prominent feature, nor is leukocytosis. Diagnosis requires identification of the oocysts in stool stained with a modified acid-fast stain. 98 I. belli responds promptly to TMP-SMZ.75 In adults, the disease recurs in 50% of patients unless longterm prophylaxis with TMP-SMZ or sulfadoxine-pyrimethamine is instituted. 75

Mycobacterium avium Complex Whereas in immunocompetent hosts, infection with Mycobacterium avium (MAl) is confined to the respiratory tract, in HIV disease MAl causes multisystem disease and is usually disseminated at the time of diagnosis. Recurrent fever, drenching night sweats, abdominal pain, and inter-

54

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

mittent diarrhea typically have their onset late in the course of HIV infection. 109 Laboratory evaluation may reveal elevated liver function tests, with alkaline phosphatase particularly elevated. MAl is the most common intrahepatic opportunistic infection. 93 MAl is readily isolated from the blood of infected patients; tissue biopsy of lymph node, bone marrow, liver, or gastrointestinal tract may yield the organism as well. 46, 109 At present, there is no effective treatment of MA142; various combinations including clofazimine, amikacin, rifabutin, and ethambutol have not been shown clearly effective. Cytomegalovirus Cytomegalovirus is associated with a diffuse colitis in HIV -infected patients, Culture of CMV from infected tissues along with histopathologic findings suggesting acute infection are required for diagnosing CMV disease. DHPG may be beneficial in gastrointestinal CMV disease. 42 Liver Although many of the HIV -associated organisms may cause hepatic disease, and a majority of HIV-infected patients will develop hepatosplenomegaly and elevated liver enzymes, symptomatic liver disease is surprisingly uncommon in HIV-infected children. Perinatal transmission represents the primary mode of transmission of hepatitis B infection in pediatric HIV disease. The mainstay of prevention then is identification of infected mothers prenatally and treatment of their infants with HBIG and hepatovax at birth, followed by two further doses of hepatovax at 1 and 6 months. 26 In adults, the course of patients who do become infected does not differ from that in the immunocompetent host, with similar proportions of patients developing chronic hepatitis. 93 Similarly, the course of hepatitis A in HIV-infected patients does not differ from immunocompetent hosts. 93 Systemic viral illnesses including Epstein-Barr virus (EBV) and CMV may cause hepatitis with elevation of transaminases. Less commonly, symptoms of right upper quadrant pain and nausea suggest gall bladder disease associated with CMV.93 When appropriate investigation of elevated serum transaminase levels is unrevealing, liver biopsy may be warranted. On biopsy, findings of giant cell transformation, CMV inclusions, Kaposi's sarcoma, diffuse lymphoplasmacytic infiltrate, granulomatous hepatitis, portal inflammation, steatosis, cholestasis, and central vein necrosis have all been described. 50 Lymphoplasmacytic infiltrate occurred in two children with LIP50; giant cell hepatitis has been described in children whose hepatitis A and Band CMV and EBV studies were negative and may represent a primary HIV-associated hepatitis. 108 Candidiasis HIV-infected children frequently develop oral thrush; successful treatment of candidiasis in these children often requires ketoconazole or clotrimazole. Dysphagia and diminished appetite in the presence of oral thrush suggest candidal esophagitis. Although diagnosis of candida} esophagitis may be made on clinical grounds, if treatment with ketoconazole fails,

MEDICAL CARE OF THE HIV-INFECTED CHILD

55

endoscopic documentation of esophageal candidiasis is appropriate prior to initiation of intravenous amphotericin B. Eye As many as 20% of children with AIDS may have abnormal ophthalmoscopic examinations during the course of their illness. 31 Cotton wool spots, peripheral retinitis, CMV retinitis, macular toxoplasmosis, preseptal cellulitis, adnexal molluscum contagiosum, and esophoria were described in one series; only 25% of affected patients had ophthalmologic symptoms. 31 This experience suggests that routine ophthalmologic examinations are appropriate for HIV-infected children. Ears Children with both early and advanced HIV disease experience recurrent otitis media.' Most episodes respond well to standard therapy.24 Mycobacteria may occasionally cause otitis media and should be considered if otitis persists in spite of appropriate therapy. The severely immunocompromised child, like the neonate, may be at risk for otitis media secondary to gram-negative organisms; tympanocentesis for culture should be considered in these children. Persistent parotitis, in association with cervical adenopathy, is common in pediatric HIV disease. Xerostomia occasionally accompanies the bilateral waxing and waning swelling. Biopsy is warranted only for atypical presentations.24, 107 Oral

Oral candidiasis is discussed in the gastrointestinal section of this article. Oral hairy leukoplakia may be indistinguishable on examination but is far less common in children. Children infected with HIV develop unusually pronounced dental caries. Whether this reflects poor dental care, altered oral flora, or immune dysfunction is not clear. Regular dental services for HIV-infected children are especially important. Herpes Simplex Virus Oral ulcerations suggest herpes simplex virus, which may cause recurrent, severe, and recalcitrant disease in HIV-infected children. The morphology of herpes simplex virus lesions is not changed in the immunocompromised child. Oral acyclovir may be sufficient if oral intake is adequate; if not, intravenous drug should be administered. Hematology The peripheral blood elements, red cells, platelets, neutrophils, and lymphocytes may all be affected by HIV infection. The most common hematologic abnormality in children with HIV infection is anemia; some have reported this present in over 90% of their patients. The anemia is usually modest, with hemoglobin levels from 10.5 g/dL to 12 g/dL, and normocytic or microcytic. Probably much of the anemia is due to iron deficiency, but other nutritional deficiencies, including folate deficiency,

56

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

have not been seen by us. The anemia is rarely a clinical problem, although it may require additional care when beginning azidothymidine (AZT) therapy. Neutropenia, occurring in about 10% of patients, can be a more profound abnormality. Although most neutropenic patients have neutrophil counts of 500 to 1000/mm3, in some children levels may fall to as low as 200. Neutropenia can be exacerbated by AZT and perhaps TMP-SMZ treatment. Although neutropenia of this degree prompts considerable clinical concern, particularly with the development of fever, patients do seem to respond adequately to bacterial infection, and none of our patients, some of whom have been significantly neutropenic for as long as a year, has manifested the infectious complications associated with profound neutropenia. Thus, our clinical experience has been that the neutropenia of HIV infection is more comparable to the benign neutropenia seen in some patients with cyclic neutrophil deficiencies than with the neutropenia that develops after chemotherapy or radiation. Lymphopenia has been reported to occur in up to 30% of patients. 89 The finding often occurs late in the disease and can be progressive. 18 Its main significance is probably as a marker for advanced disease. Thrombocytopenia has probably been the most significant clinical hematologic problem for HIV-infected children. Diminished platelet levels occur in between 10% and 15% of patients and can occur at any stage of disease. Indeed, several cases have been reported of HIV infection presenting as isolated thrombocytopenia. 61 Platelet counts are usually above 45,000/mm3, but in some patients counts as low as 20,000/mm3 have been reported, and severe and fatal episodes of hemorrhage have occurred in these patients. In one study, 8 of 19 patients with thrombocytopenia had clinically Significant hemorrhages, and 3 had fatal eNS bleeds. 34 Plateletassociated antibodies have been identified in many thrombocytopenic patients, but their pathophysiologic significance for the condition is unknown. A variety of agents have been used to treat HIV-associated thrombocytopenia. In children, the most experience has been with gamma globulin and with steroids. Whereas about 40% of children with thrombocytopenia will respond initially to gamma globulin, the rises are generally not sustained, and re-treatment is often less effective. 34 Prednisone given orally has been reported to raise platelet levels in some children not responsive to gamma globulin, but the long-term benefit of this therapy is uncertain. If HIV-infected children are treated with steroids, it may be necessary to begin prophylactic INH as well, as the incidence of tuberculosis in their adult contacts is likely to be high and it may not be possible to rely on skin tests to exclude exposure. Perhaps the most promising treatment for HIV-associated thrombocytopenia is AZT. Although AZT typically reduces platelets in persons who start with normal counts, it generally raises levels in individuals with thrombocytopenia. 39 Sustained rises of from 100,000 to 400,000 platelets/ mm 3 have been reported on AZT therapy,80 but counts usually fall if the drug is withdrawn. The increase may be somewhat slower than is seen with gamma globulin, usually beginning within 2 weeks of starting treat-

MEDICAL CARE OF THE HIV-INFECTED CHILD

57

ment. 48 Thus AZT may be the most appropriate therapy for the majority of children with thrombocytopenia, but an initial dose of gamma globulin may be necessary until the AZT treatment takes effect in those children with extremely low platelet counts (below 25,000/mm 3 ) in whom the risk of intracerebral bleeding is greatest. Prognosis for HIV-associated thrombocytopenia is variable,92 but patients with isolated thrombocytopenia, even if it is profound, may have a good prognosis. Spontaneous remissions do occur, and the occurrence of thrombocytopenia does not necessarily imply advanced disease. Renal Disease Although it has been reported that as many as 40% of children with HIV infection may have abnormal Urinalyses, significant renal disease occurs in a much smaller number of patients. In one study, of 155 HIV-infected children selected for study, 12 were found to have renal disease, for a prevalence rate of 7.7%.104 This is comparable to the incidence of parenchymal renal disease complicating HIV infection in the adult. 83 In addition, a significant number of children with HIV infection will manifest renal dysfunction as a result of drug toxicities, fluid and electrolyte abnormalities, or septic complications. Perhaps the most characteristic renal complication of HIV infection is HIV -associated nephropathy.82 This disorder is characterized by heavy proteinuria, mild hypertension, and in some children the frank development of the nephrotic syndrome with hypoalbuminemia and edema. The disease has been seen in patients at all stages of HIV infection and has been the presenting form of the disease in a few children. In adults, the kidneys are typically large and highly echogenic by ultrasound examination, but similar observations have not been reported in children. The disorder is associated with a characteristic glomerular lesion of focal sclerosis and capillary "collapse. "25 In addition, Cohen 25 has emphasized tubular and interstitial lesions associated with this disease, indicating that it is really a global disorder of the kidneys rather than one limited to the glomeruli. The clinical course is often of rapidly progressing renal failure with end-stage renal disease developing in most patients within 24 months of the initial recognition of renal disease. Treatment with either steroids, in several patients,I04 or cyclosporine, in one patient,87 has not been effective. Although it initially was suggested that this disorder might reflect heroinassociated nephropathy, that is clearly excluded both by the distinct pathologic characteristics of heroin-associated nephropathy22 and by its occurrence in children and in adults who are not heroin users. The apparent concentration of cases in a few eastern centers is unexplained, however, and might suggest that HIV infection alone may not be sufficient to cause this disorder. Mesangial proliferative glomerulonephritis also has been reported in several children with proteinuria29, 104 and probably occurs about as often as HIV-associated nephropathy. The clinical presentation, with substantial proteinuria, occasional hypertension, and, in some children, development of the nephrotic syndrome, is quite similar to HIV -associated nephropathy, although it appears to occur in somewhat older children. This disorder

58

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

generally is not associated with the progressive deterioration of renal function, however, and seems to be associated with a better prognosis. 104 Treatment with steroids has not been effective in this condition either. Occasional cases of segmental glomerulonephritis and of "minimal change" disease also have been reported in HIV-infected children but their relationship to the underlying infection is still undetermined. Cardiovascular Disease Several reports have appeared describing cardiac involvement in HIV infection in childhood, based on clinical symptoms,102, 103 abnormallaboratory examinations,65 or autopsy results, 51 Although some authors have suggested that up to 72% of HIV-infected children have cardiac involvement, an estimate of 27% with clinically significant disease 65 seems more realistic. A similar wide range of estimates of incidence of cardiac disease appears in the adult literature. 38 Although children as young as 2 months have been described with signs of heart failure, most children with symptomatic cardiac disease have been over 1 year old, Clinically evident heart disease is more likely to occur in the child with stage P-2 (symptomatic) disease, although decreased myocardial contractility has been described in one asymptomatic child. 65 There does not appear to be any preference for one sex over the other, and cardiac disease has been described both in children infected by transfusion and those with congenital or perinatal disease. The most characteristic manifestation of HIV -associated cardiac disease is a syndrome of dilated cardiomyopathy. Whereas the cardiac silhouette on chest radiograph may appear normal, echocardiography typically identifies ventricular enlargement, with poor contractility. 103 Cardiac dysfunction in these children may be inapparent until a major cardiac stress such as severe anemia, hypoxemia, or sepsis makes it clinically evident. Echocardiographic findings of ventricular hypertrophy and dilatation, and the persistence of ventricular hypofunction even after the precipitating condition is controlled, distinguish these children from those who simply have myocardial dysfunction secondary to pulmonary or systemic pathology. Left ventricular involvement seems to occur earliest, although later biventricular, and even atrial, involvement has been described.102 Serial studies typically show progressive anatomic and functional deterioration over period of 1 to several years. These children often respond to inotropic agents, such as digitalis or dopamine, and to diuretics, although their ventricular function is generally not completely corrected with these agents,l03 Lipshultz et al65 have pointed out that many of these children have elevated afterloads, suggesting that afterload-reducing agents, in addition to diuretics, may have a role in the treatment of some of them. At autopsy, the heart is large, usually from 1.2 to 2 fold heavier than normal for age, with marked left or biventricular dilatation. There is both hypertrophy and necrosis of myocardial fibers, and a sparse, focal myocarditis. Small, usually clinically insignificant pericardial effusions, as well as pericarditis may also be present. 51 Most children with this syndrome do not die of cardiac disease, although some cases of refractory congestive heart failure have been described.

MEDICAL CARE OF THE HIV-INFECTED CHILD

59

A second variety of cardiac involvement includes rate, rhythm, and conduction abnormalities. The most common abnormality is sinus arrhythmia with wandering atrial pacemaker, but isolated atrial ectopic beats are also common. Occasionally, higher grade arrhythmias, including supraventricular tachycardia and ventricular ectopy, are seen. Lipshultz et al65 have noted that high-grade ectopy is associated with enhanced left ventricular function, elevated ventricular contractility, and decreased afterload. These children may also have abnormal heart rate and blood pressure responses. Some of these patients, particularly those with a prolonged Q-Tc, may have increased sympathetic tone associated with a sympathetic tract neuritis. 94 Children with high-grade ectopy and enhanced ventricular function may be at increased risk for sudden death, whereas those with a prolonged QTc may be more likely to develop arrhythmias with pentamidine. Postmortem examination may show vasculitis, myocarditis, or fragmentation of a conducting bundle with lobulation and fibrosis. 11 Some of these children may be candidates for artificial pacemakers. Other forms of cardiac disease reported in children with HIV infection include both nonbacterial thrombotic, or marantic, and bacterial endocarditis,l03 thickening of valvular apparatus and chordae,102 myocardial infarction,51 and coronary artery aneurysm and thrombosis. 51 The etiologies of any of these cardiac abnormalities is unclear. The consistency and unusual nature of the syndrome of dilated cardiomyopathy is suggestive that this condition might be directly due to HIV infection of the heart. Although suggestive evidence for such infection has been presented in one adult case with right ventricular dysfunction,17 similar viral studies are still lacking for pediatric cases, and obviously other recognized opportunists could just as easily be responsible. Many of the children reported with cardiac dysfunction also had significant chronic, and sometimes fatal, pulmonary disease, and much of the right heart pathology could reflect pulmonary hypertenSion and chronic hypoxemia. In a few cases, it has been suggested that cases of HIV -associated carditis might be due to myocardial infection with cytomegalovirus. Results of definitive viral studies are not reported, however, and even if CMV could be identified as infecting the myocardium, as is so often true in pulmonary infection, it need not be the only pathogen present. In fact, for many children with increased ventricular function and' reduced afterload it is not clear that there is any primary cardiac pathology, but rather that the cardiac pathophysiology may result from abnormalities in the autonomic nervous or vascular systems. It should be noted that in fact HIV infection has been documented to involve the arterial system. 52 Although the best known changes involve the cerebral vascular system, with characteristic vasculitis in the region of the basal ganglia, small and medium-sized arteries in the lungs, kidney, spleen, and intestine, as well as vessels in the heart, have also been reported to show intimal and medial fibrosis, fragmentation of elastic tissue, medial calcification, and luminal narrowing. The clinical significance of what has been termed the "distinctive arteriopathy of AIDS" still needs to be defined. Malignancy Unlike the situation in adults, in whom malignancies are rapidly becoming the leading cause of death in patients with AIDS, in children

60

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

malignancies still account for about 2% of all AIDS-related deaths. However, as survival of pediatric patients is lengthened, it is possible that malignancies will become an increasing problem for children too. B-cell lymphomas are the characteristic malignancy seen in children with AIDS. 36 This may be associated with other evidence of B-cell activation in HIV infection such as increased levels of circulating immunoglobulins and increased numbers of circulating B cells spontaneously secreting antibodies. These phenomena have generally been attributed to the impairment of T-cell suppressor function with HIV infection, but there is also some laboratory evidence that B cells may be directly stimulated by the virus. 73 Tumors have occurred in both congenitally infected and transfusionacquired cases of AIDS. Although central nervous system B-cell malignancies are the most characteristic of HIV infection,35 they may occur throughout the body. NonHodgkin's lymphomas, including Burkitt's lymphoma, have also been described in children infected with HIV, and probably occur at an increased rate. 64 Hodgkin's lymphoma mayor may not occur more frequently in HIV infection, but is not currently an accepted malignancy for the diagnosis of AIDS. Lymphomas occurring in HIV-infected patients are generally aggressive and have in the past been described as responding poorly to therapy, although a recent report suggests that some of these tumors may in fact respond to treatment. 68 We agree with these authors in their statement that "[u]ntil more data are available, the diagnosis of AIDS should not be a deterrent to treatment." Interestingly, Kaposi's sarcoma, the most common malignancy in adults with AIDS, is almost unheard of in pediatric patients. Two infants were described from the original Miami cohort,15 but no subsequent cases have been reported from this group. Another description of Kaposi's sarcoma occurring in childhood is currently in press. 28 Isolated cases of other varieties of malignancy have been reported in HIV-infected children, but the relationship between the two conditions is unclear. A child with a rhabdomyosarcoma96 and three children with multiple leiomyomata or leiomyosarcomata20 have been reported. Systemic Bacterial Infections Bacterial infections and bacteremia are prominent features of pediatric HIV disease; the NYC Department of Health reports that 18% of pediatric AIDS patients had serious bacterial infections,70 whereas Krasinski et al57 report that 24% of their patients experienced bacteremic episodes. This susceptibility probably reflects both splenic dysfunction8. 9. 79 and an impaired ability to produce antibody to novel antigens. 10. 13.55 The febrile HIVinfected child, then, deserves close attention with appropriate laboratory studies, including complete blood cell count (CBC) and blood cultures to exclude bacteremic illness. Although treatment of acute episodes of bacteremia remains standard, some children will require long-term prophylaxis. Intravenous gamma globulin has been studied for the prevention of primary and recurrent bacterial infection, but the final results are not yet available. Salmonella

MEDICAL CARE OF THE HIV-INFECTED CHILD

61

bacteremia is especially likely to recur; a single episode of salmonella bacteremia should prompt consideration of long-term prophylaxis with ampicillin, amoxicillin, or TMP-SMZ.loo Cytomegalovirus Like MAl, CMV disease is frequently disseminated at the time of diagnosis. Indeed, the presentation of disseminated CMV may mirror that of MAl with recurrent fevers, weight loss, and diarrhea. The eye, heart, lungs, liver, pancreas, and colon may be infected. 46 Because viral shedding may occur in the absence of acute infection, viral culture must be confirmed by tissue biopsy demonstrating inclusion particles. CMV viremia is sufficient to diagnose disease. Although not widely available, polymerase chain reaction (PCR) has been used to demonstrate CMV infection in HIV-positive patients. 97 Additional Problems Characteristic of Infants of HIV-Infected Women Infants born to HIV-positive women, even when not infected with HIV, are at high risk for both noninfectious problems, including intrauterine drug exposure, fetal alcohol syndrome, as well as infectious problems, especially sexually transmitted diseases including syphilis, gonorrhea, and hepatitis B. With the exception of syphilis, detection and treatment of these infections does not differ from the uninfected child; serology and cultures can be used in conventional ways. Conversion of syphilis serology, however, maybe delayed32 ; a child who develops symptoms suggestive of syphilis, but whose serology is negative, should have examination of suggestive lesions or exudate with direct fluorescent antibody for treponema (DFA-TP) or Steiner stain. If the diagnosis of syphilis is confirmed, a lumbar puncture should be performed for the diagnosis of neurosyphilis 32 ; a negative CSF examination, however, does not rule out this complication. 7 The treatment of early syphilis does not differ Trom treatment of the noninfected child. In order to achieve treponemacidal CSF levels, only aqueous penicillin or procaine penicillin may be used. Benzathine penicillin is no longer an acceptable alternative. 32 Alternate regimens of amoxicillin or ceftriaxone are under investigation. 32. 47 Intrauterine exposure to alcohol and drugs may contribute to CNS disease in HIV-infected infants and children. Irritability and poor feeding suggest active withdrawal, but the range of chronic problems that may result from such exposure is still being defined. Treatment Although there is currently no cure for pediatric HIV disease, early recognition and improved medical care have changed the face of pediatric HIV disease from an acutely fatal illness to a chronic disease of childhood. Major advances have been the use of AZT and PCP prophylaxis. Immunizations HIV-infected children should receive routine childhood immunizations but require major modifications of the standard protocol (Table 2).49 Inactivated, injectable polio vaccine (Salk) should replace OPV (live or

62

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

Table 2. Recommendations for Routine Immunization of HIV-Infected ChildrenUnited States, 1988 HIV INFECTION VACCINE

DTP OPV IPV MMR Rib conjugate Pneumococcal Influenza

Known Asymptomatic

Symptomatic

yes no yes yes yes no no

yes no yes yes* yes yes yes

*Refer to text. Adnpted from Immunization Practices Advisory Committee: Immunization of children infected with human immunodeficiency virus-Supplementary ACIP statement. MMWR 37:181, 1988; with permission.

Sabin). In addition, pneumococcal vaccine is administered at 2 years; influenza vaccine at 6 months and yearly thereafter. Measles vaccine is administered to all HIV-infected children; the risk of severe disease is high58• 59 and that of vaccine-associated illness appears low. 66 In case of exposure to measles or varicella, immunoglobulin58 . 59 or VZIC,27 respectively, should be administered. Gamma Globulin Uncontrolled studies claiming improved immune function, diminished incidence of fever and bacteremia, and improved survival with monthly administration of gamma globulin 18 prompted a national multicenter, controlled study to accurately define the role of gamma globulin in the management of the HIV-infected child. Results of this study are expected shortly. We do not recommend the routine use of gamma globulin in HIVinfected children. PCP Prophylaxis PCP prophylaxis is essential for symptomatic children with depressed T-cell numbers. However, because absolute T4 cell numbers and T4:T8 ratios are not predictive of risk of pneumocystis in the first year of life63 • 91 and because the incidence of TMP-SMZ sensitivity is low in HIV-infected children,91 we recommend TMP-SMZ prophylaxis for infants less than 1 year of age, regardless of their T-cell status and for all symptomatic children older than 1 year. Those children who fail TMP-SMZ prophylaxis due to hypersensitivity have received dapsone or pentamidine. However, until the delivery system for aerosolized pentamidine can be modified to reliably deliver drug to the young child, its use in pediatric HIV disease is limited to the older, cooperative child. Nutrition Failure to thrive and poor weight gain are regular features of pediatric HIV disease and aggressive nutritional management is warranted, including monitoring of growth parameters and early dietary consultation should

MEDICAL CARE OF THE HIV-INFECTED CHILD

63

growth failure occur. If aggressive oral nutritional supplement fails, indwelling enteral tubes or parenteral nutrition may be indicated. Prognosis The prognosis for HIV-infected children appears to be dependent both on age and disease pattern at diagnosis. The mortality from perinatal HIV disease is highest in the first year of life. 57,95 Whereas Scott et al95 reported a median survival of 38 months from the diagnosis of HIV infection, children diagnosed at less than 1 year of age had a median survival of only 24.8 months. Similarly, children who developed pneumocystis pneumonia survived only 1 month after diagnosis, and those who developed encephalopathy, renal disease, or candidal esophagitis survived less than 1 year. The presenting disease patterns of recurrent bacterial infections and lymphoid interstitial pneumonitis carry a much better prognosis, with median survival of 50 and 72 months, respectively. 95 Opportunistic infections are the cause of death in more than 60% of patients. 57 The case fatality rate after diagnosis of an opportunistic infection is 85%.57 Seventy-five percent of children who develop an opportunistic infection will not survive longer than a year. 62 Krasinski et al57 noted that opportunistic infections and not HIV infection per se are the cause of death in HIV-infected children. Thus prophylaxis, early recognition, and improved treatment of opportunistic infections are likely to improve the survival of HIV-infected children.

SUMMARY Familiarity with the demographics of pediatric HIV disease and recognition of common and uncommon presentations of infection are keys to diagnosing the HIV-infected child. Subsequent management entails preventative care, including immunizations and nutritional support, as well as management of HIV-related complications.

REFERENCES 1. AIDS Program, Center for Disease Control: Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 36:225, 1987 2. Amadori A, deRossi A, Giaquinto C: In-vitro production of HIV-specific antibody in children at risk of AIDS. Lancet 1(8590):852, 1988 3. Amirhessani-Aghili N, Spector SA: Human immunodeficiency virus (HIV) infection of human placenta (abstract 974), In The American Pediatric Society and The Society for Pediatric Research Abstracts and Program Outline, Anaheim, CA, 1990, p 165A 4. American Thoracic Society: Mycobacterioses and the acquired immunodeficiency syndrome. Am Rev Respir Dis 136:492, 1987 5, Barbour DS: Acquired immunodeficiency syndrome of childhood, Pediatr Clin North Am 34:247, 1987 6. Barrett D: The clinician's guide to pediatric AIDS, Contemp Pediatr 5:24, 1988

64

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

7. Beck-Sague C, Alexander ER: Failure of benzathine penicillin G treatment in early congenital syphilis. Pediatr Infect Dis J 6:1061, 1987 8. Bender BS, Frank MM, Lawley TJ, et al: Defective reticuloendothelial system Fc receptor function in patients with acquired immunodeficiency syndrome. J Infect Dis 152:409, 1988 9. Bender BS, Davidson BL, Kline R, et al: Role of the mononuclear phagocyte system in the immunopathogenesis of human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Rev Infect Dis 10:1142, 1988 10. Bernstein L, Ochs H, Wedgwood R, et al: Defective humoral immunity in pediatric acquired immunodeficiency syndrome. J Pediatr 107:352, 1985 11. Bharati S, Joshi VV, Connor EM, et al: Conduction system in children with acquired immunodeficiency syndrome. Chest 96:406, 1989 12. Blanche S, Rouzioux C, Moscato M, et al: A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N Engl J Med 320:1643, 1989 13. Borkowsky W, Steele C, Grubman S, et al: Antibody responses to bacterial toxoids in children infected with human immunodeficiency virus. J Pediatr 110:563, 1987 14. Bremer J, Hollinger F: Pediatric HIV infection and AIDS: Diagnostic tests. Semin Pediatr Infect Dis 1:27, 1990 15. Buck BE, Scott GB, Valdes-Dapena M, et al: Kaposi sarcoma in two infants with acquired immune defiCiency syndrome. J Pediatr 103:911, 1983 16. Burroughs MH, Hinds GA, Marshall F, et al: Immunity to varicella in HIV infected children. In Fifth Annual Pediatric AIDS Conference Abstracts, Los Angeles, 1989, p 12 17. Calabrese LH, Proffitt MR, Yen-Lieberman B: Congestive cardiomyopathy and illness related to the acquired immunodeficiency syndrome (AIDS) associated with isolation of retrovirus from myocardium. Ann Intern Med 107:691, 1987 18. Calvelli T, Rubinstein A: Intravenous gamma globulin in infant acquired immune deficiency syndrome. Pediatr Infect Dis J 5:S207, 1986 19. Center for Disease Control: HIV/AIDS Surveillance Report. April, 1990 20. Chadwick EG, Connor EJ, Hanson IC, et al: Tumors of smooth muscle origin in HIVinfected children. JAMA 263:3182, 1990 21. Chaisson R, Slutkin G: Tuberculosis and human immunodeficiency virus infection. J Infect Dis 159:96, 1989 22. Chander P, Soni A, Suri A, et al: Renal ultrastructural markers in AIDS-associated nephropathy. Am J Pathol 126:513, 1987 23. Chandwani S, Borkowsky W, Krasinski K, et al: Respiratory syncytial virus infection in human immunodeficiency virus-infected children. J Pediatr 117:251, 1990 24. Chanock S, McIntosh K: Pediatric infection with the human immunodeficiency virus: Issues for the otorhinolaryngologist. Otolaryngol Clin North Am 22:637, 1989 25. Cohen AH, Nast CC: HIV-associated nephropathy: A unique combined glomerular, tubular and interstitial lesion. Mod Pathol1:87, 1988 26. Committee on Infectious Diseases, American Academy of Pediatrics: Hepatitis B. In Peter G, Hall C, Lepow M, et al (eds): Report of the Committee on Infectious Diseases, ed 21 (The Red Book). Elk Grove Village, American Academy of Pediatrics, 1988, p 217 27. Committee on Infectious Diseases, American Academy of Pediatrics: Varicella-Zoster infections. In Peter G, Hall C, Lepow M, et al (eds): Report of the Committee on Infectious Diseases, ed 21 (The Red Book). Elk Grove Village, American Academy of Pediatrics, 1988, p 456 28. Connor E, Boccon-Gibod L, Joshi V, et al: Cutaneous acquired immunodeficiency syndrome-associated Kaposi's sarcoma in pediatric patients. Arch Derm 126:791, 1990 29. Connor E, Gupta S, Joshi V, et al: Acquired immunodeficiency syndrome-associated renal disease in children. J Pediatr 113:39, 1988 30. Demmler G, Taber L: Virology of HIV-1. Semin Pediatr Infect Dis 1:17, 1990 31. Dennehy P, Warman R, Flynn J, et al: Ocular manifestations in pediatric patients with acquired immunodeficiency syndrome. Arch Ophthalmol 107:978, 1989 32. Division of Sexually Transmitted Diseases, Center for Prevention Services: AIDS Program and Sexually Transmitted Disease Laboratory Program, Center for Infectious Diseases, CDC: Recommendations for diagnosing and treating syphilis in HIV-infected patients. MMWR 37:600, 607, 1988

MEDICAL CARE OF THE HIV-INFECTED CHILD

65

33. Doyle M, Pickering L: Gastrointestinal tract infections in children with AIDS. Semin Pediatr Infect Dis 1:64, 1990 34. Ellaurie M, Burns E, Bernstein'L, et al: Thrombocytopenia and human immunodeficiency virus in children. Pediatrics 82:905, 1988 35. Epstein LG, DiCarlo FJ, Joshi W, et al: Primary lymphoma of the central nervous system in children with acquired immunodeficiency syndrome. Pediatrics 82:355, 1988 36. Falaey JL, Oho-Amaize E: Acquired immunodeficiency syndrome (AIDS) and neoplasia. Am J Pediatr Hematol Oncol 9:193, 1987 37. Falloon J, Eddy J, Weiner L, et al: Human immunodeficiency virus infection in children. J Pediatr 114:1, 1989 38. Fink L, Reichek N, St John Sutton M, et al: Cardiac abnormalities in acquired immune deficiency syndrome. Am J Cardiol 54:1161, 1984 39. Flegg pJ, Jones ME, MacCallum LR, et al: Effect of zidovudine on platelet count. Br Med J 298:1074, 1989 40. Frank I, Friedman H: Progress in the treatment of cytomegalovirus pneumonia. Ann Intern Med 109:769, 1988 41. Friedland GH, Klein RS: Transmission of the human immunodeficiency virus. N Engl J Med 317:1125, 1987 42. Glatt A, Chirgwin K, Landesman S: Treatment of infections associated with human immunodeficiency virus. N Engl J Med 318:1439, 1988 ' 43. Goedert J, Mendez H, Drummond M, et al: Mother to infant transmission of human immunodeficiency virus type 1: Association with prematurity or low ariti-gpI20. Lancet 2(8676):1351, 1989 44. Gutman LT, St. Claire KK, Weedy C, et al: The epidemiologic intersection in children of sexual abuse and AIDS (abstract 1015). In The American Pediatric Society and The Society for Pediatric Research Abstracts and Program Outline, Analaeim, CA, 1990, P 172A 45. Haney P, Yale-Loehr A, Nussbaum A, et al: Imaging of infants and children with AIDS. Am J RoentgenoI152:1033, 1989 46. Hanson I, Kaplan S: Opportunistic infections. Semin Pediatr Infect Dis 1:31, 1990 47. Hook E: Syphilis and HIV infection. J Infect Dis 160:530, 1989 48. Hymes K, Greene J, Karpatkin S: The effect of azidothymidine on HIV-related thrombocytopenia. N Engl J Med 318:516, 1988 49. Immunization Practices Advisory Committee: Immunization of children infected with human immunodeficiency virus-Supplementary ACIP statement. MMWR 37:181, 1988 50. Jonas MM, Roldan EO, Lyons HJ, et al: Histopathologic features of the liver in pediatric acquired immune deficiency syndrome. J Pediatr Gastroenterol Nutr 9:73, 1989 51. Joshi W, Gadol C, Connor E, et al: Dilated cardiomyopathy in children with acquired immunodeficiency syndrome: A pathologic study of five cases. Hum Pathol 19:69, 1988 52. Joshi W, Pawel B, Connor E, et al: Arteriopathy in children with acquired immune deficiency syndrome. Pediatr Pathol 7:261, 1987 53. Jovaisas E, Koch M, Schafer A, et al: LAVlHTLVIII in 20 week fetus. Lancet 2:1129, 1985 54. Jura E, Chadwick E, Josephs S, et al: Varicella-zoster virus infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 8:586, 1989 55. Kamani N, Lightman H, Leiderman I, et al: Pediatric acquired immunodeficiency syndrome-related complex: Clinical and immunological features. Pediatr Infect Dis J:383, 1988 56. Kovacs J, Ng V, Masur H, et al: Diagnosis of Pneurrwcystis carinii pneumonia: Improved detection in sputum with use of monoclonal antibodies. N Engl J Med 318:589, 1988 57. Krasinski K, Borkowsky W, Bonk S, et al: Bacterial infection in human immunodeficiency virus-infected children. Pediatr Infect Dis J 7:323, 1988 58. Krasinski K, Borkowsky W: Measles and measles immunity in children infected with human immunodeficiency virus. JAMA 261:2512, 1989 59. Krasinski K, Borkowsky W, Chandwani S, et al: Measles in HIV-infected children, United States. MMWR 37:183, 1988 60. Krasinski K, Borkowsky W, Holzman R, et al: Prognosis of human immunodeficiency virus infection in infants and children. Pediatr Infect Dis J 8:216, 1989

66

MARGARET

H.

BURROUGHS AND PAUL

J.

EDELSON

61. Labrune P, Blanche S, Catherine N, et al: Human immunodeficiency virus-associated thrombocytopenia in infants. Acta Paediatr Scand 78:811, 1989 62. Lampert R, Milberg J, O'Donnell R, et al: Life table analysis of children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 5:374, 19$6 63. Leibovitz E, Rigaud M, Chandwani S, et al: CD-4 T-cell count are not predictive of acquiring Pneumocystis carinii pneumonitis in HIV-infected children (abstract 1043). In The American Pediatric Society and The Society for Pediatric Research Abstracts and Program Outline, Anaheim, CA, 1990, P 176A 64. Levine AM: Non-Hodgkin lymphomas and other malignancies in the acquired immune deficiency syndrome. Semin Oncol 14:34, 1987 65. Lipshultz SE, Chanock S, Sanders SP, et al: Cardiovascular manifestations of human immunodeficiency virus infection in infants and children. Am J Cardiol 63:1489, 1989 66. McLaughlin M, Thomas P, Onorato I, et al: Live virus vaccines in human immunodeficiency virus-infected children: A retrospective survey. Pediatrics 82:229, 1988 67. Mok JQ, Giaquinto C, DeRossi A, et al: Infants born to mothers seropositive for human immunodeficiency virus. Preliminary findings from a multicentre European study. Lancet 1:1164, 1987 68. Montalvo F, Casanova R, Clavell L: Treatment outcome in children with malignancies associated with human immunodeficiency virus infection. J Pediatr 5:735, 1990 69. Murray J, Garay S, Hopewell P, et al: Pulmonary complications of the acquired immunodeficiency syndrome: An update. Am Rev Respir Dis 135:504, 1987 70. New York City Department of Health AIDS Surveillance Unit: AIDS surveillance update, April 25, 1990 71. Ognibene FP, Gill VJ, Pizzo PA, et al: Induced sputum to diagnose Pneumocystis carinii pneumonia in immunosuppressed pediatric patients. J Pediatr 115:430, 1989 72. Oleske J, Minnefor A, Cooper R, et al: Immune deficiency syndrome in children. JAM A 249:2345, 1983 73. Pahwa S, Pahwa R, Saxinger C, et al: Influence of the human T lymphotropic virus/LAV on functions of human lymphocytes: Evidence for immunosuppressive effect on polyclonal B cell. Proc Natl Acad Sci USA 82:8198, 1985 74. Pahwa S: Human immunodeficiency virus infection in children: Nature of immunodeficiency, clinical spectrum and management. Pediatr Infect Dis J 7:561, 1988 75. Pape J, Verdier R, Johnson W: Treatment and prophylaxis of Isospora belli infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:1044, 1989 76. Peckham CS, Senturia YD, Ades AE, et al: Mother-to-child transmission of HIV infection: The European Collaborative Study. Lancet 2(8619):1039, 1988 77. Pitchenik A, Fertel D, Bloch A: Mycobacterial disease: Epidemiology, diagnosis, treatment and prevention. Clin Chest Med 9:425, 1988 78. Pizzo P, Eddy J, Falloon J: Acquired immune deficiency syndrome in children. Am J Med 85(suppl 2A):195, 1988 79. Pollack H, Noel GJ, Fikrig S, et al: Ability of RBC pocked counts to identify mv + children who are at risk for bacterial sepsis (abstract). First International Conference on AIDS in Children, Adolescents, and Heterosexual Adults, Atlanta, 1987 80. Pottage J, Benson C, Spear J, et al: Treatment of human immunodeficiency virusrelated thrombocytopenia with zidovudine. JAMA 260:3045, 1988 81. Qazi Q, Sheikh T, Fikrig S: Lack of evidence for craniofacial dysmorphism in perinatal human immunodeficiency virus infection. J Pediatr 117:7, 1988 82. Rao TK, Filippone EJ, Nicastri AD, et al: Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 310:669, 1984 83. Rao TKS, Freidman EA, Nicastri AD: The types of renal disease in the acquired immune deficiency syndrome. N Engl J Med 316:1062, 1987 84. Rogers M, Ou C, Rayfield M, et al: Use of the polymerase chain reaction for early detection of the proviral sequences of human immunodeficiency virus in infants born to seropositive mothers. N Engl J Med 320:1649, 1989 85. Rogers M, Thomas P, Starcher E, et al: Acquired immunodeficiency syndrome in children: Report of the Centers for Disease Control national surveillance, 1982 to 1985. Pediatrics 79:1008, 1987 86. Rogers MF, White CR, Sanders R, et al: Lack of transmission of human immunodeficiency virus from infected children to their household contacts. Pediatrics 85:210, 1990

MEDICAL CARE OF THE HIV-INFECTED CHILD

67

87. Rousseau E, Russo P, Lapointe N, et al: Renal complications of acquired immune deficiency syndrome in children. Am J Kidney Dis 11:48, 1988 88. Rubinstein A, Morecki R, Silverman B, et al: Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex. J Pediatr 108:498, 1986 89. Ryan B, Connor E, Minnefor A, et al: Human immunodeficiency virus infection in children. Hematol Oncol Clin North Am 1:381, 1987 90. Ryder R, Nsa W, Hassig S, et al: Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N Engl J Med 320:1637, 1989 91. Sanders-Laufer D, Burroughs M, Marshall F, et al: Pneumocystis carinii pneumonia (PCP) in "low risk" HIV-infected children (abstract 1080). In The American Pediatric Society and The Society for Pediatric Research Abstracts and Program Outline, Analteim, CA, 1990, P 183A 92. Saulsbury TJ, Boyle RJ, WykoffRF, et al: Thrombocytopenia as the presenting manifestation of human T-lymphotropic virus type III infection in infants. J Pediatr 109:30, 1986 93. Schneiderman D: Hepatobiliary abnormalities of AIDS. Gastroenterol Clin North Am 17:615, 1988 94. Schwartz PJ: Idiopathic long QT syndrome: Progress and questions. Am Heart J 109:399, 1985 . 95. Scott G, Hutto C, Makuch R, et al: Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. N Engl J Med 321:1791, 1989 96. Scully RE, Mark EJ, McNeely BBU: Case records of the Massachusetts General Hospital. N Engl J Med 314:629, 1984 97. Shibata D, Martin WJ, Appleman MD, et al: Detection of cytomegalovirus DNA in peripheral blood of patients infected with human immunodeficiency virus. J Infect Dis 158:1185, 1988 98. Soave R, Johnson W: Cryptosporidium and Isospora belli infections. J Infect Dis 157:225, 1988 99. Sotomayer J, Douglas S, Wilmott R: Pulmonary manifestations of immune deficiency diseases. Pediatr Pulmonol 6:275, 1989 100. Sperber S, Schleupner C: Salmonellosis during infection with human immunodeficiency virus. Rev Infect Dis 9:925, 1987 101. Sprecher S. Soumenkoff G, Puissant F, et al: Vertical transmission of HIV in 15 week fetus. Lancet 2:288, 1986 102. Strauss J, Abitbol C, Zilleruelo G, et al: Renal disease in children with the acquired immune deficiency syndrome. N Engl J Med 321:625, 1989 103. Steinherz LJ, Brochstein JA, Robin J: Cardiac involvement in congenital acquired immunodeficiency syndrome. Am J Dis Child 140:1241, 1988 104. Stewart JM, Kaul A, Gromisch DS, et al: Symptomatic cardiac dysfunction in children with human immunodeficiency virus infection. Am Heart J 117:140, 1989 105. Sunderman G, McDonald R, Maniatis T, et al: Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS). JAMA 256:362, 1986 106. Vernon D, Holzman B, Lewis P, et al: Respiratory failure in children with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome-related complex. Pediatrics 82:223, 1988 107. Williams M: Head and neck findings in pediatric acquired immune deficiency syndrome. Laryngoscope 97:713, 1987 108. Witzleben CL, Marshall GS, Wenner W, et al: HIV as a cause of giant cell hepatitis. Hum Pathol19:603, 1988 109. Young L: Mycobacterium avium complex infection. J Infect Dis 157:863, 1988 110. Ziegler J, Cooper D, Johnson R, et al: Postnatal transmission of AIDS-associated retrovirus from mother to infant. Lancet 2:891, 1985

Address reprint requests to Margaret H. Burroughs, MD The Rockefeller University 1230 York Avenue New York, NY 10021