Pediatric Aids

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PEDIATRIC AIDS Ellen Gould Chadwick, MD, and Ram Yogev, MD

EPIDEMIOLOGY

Estimates by the World Health Organization (WHO) in 1992 suggest that more than 13 million persons worldwide have been infected with HIV,l million of whom are children. 87 Eighty percent of infected women and children reside in sub-Saharan Africa where the estimated incidence of HIV infection among women of childbearing age is 2500/100,000. In the United States, women account for 12.5% of AIDS cases reported to the CDC through December 1993. 15 Although the majority of women with AIDS have been infected through intravenous drug use (IVDU), the proportion of women infected through heterosexual contact has been increasing, rising from 30% in 1987 to 39% in 1992.19 Sexual contact with males who have been infected by IVDU is a common route of heterosexual transmission, yet many women without an identified risk may have been infected heterosexually by men unrecognized to be infected or to be in high-risk groups. Among mothers giving birth to children with AIDS, heterosexually acquired infection surpassed IVDU as a risk factor in 1991.19 National HIV seroprevalence data among childbearing women show the highest incidence in New York City (1.25%), the District of Columbia (0.9%), New Jersey (0.55%), and Florida (0.54%). The estimated national seroprevalence rate in 1991 was 0.17%, reflecting approximately 7100 infected women giving birth that year. Based on a 20% to 30% perinatal transmission rate, it was estimated that 1400 to 2200 HIV-

This article is being published by special arrangement with the publisher.

From the Department of Pediatrics, Northwestern University Medical School; and the Section of Pediatric and Maternal HIV Infection, Division of Infectious Diseases, The Children's Memorial Hospital, Chicago, Illinois

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 42 • NUMBER 4 • AUGUST 1995

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infected children were born in 1991, more than three times the number of children reported with perinatally acquired AIDS in the same year. 61 These data predict further growth in the population of children with AIDS in the future, if there is no effective intervention. As of December 1993,89% of children less than 13 years of age with AIDS in the United States were infected through vertical transmission from an HIV-infected mother. 15 A diminishing minority (10%) of children were infected through receipt of contaminated blood products and/ or clotting factors, and less than 1% of cases remain under investigation. Children of racial and ethnic minority groups are disproportionally overrepresented. Whereas African-American children comprise only 15% of the childhood population in the United States, they represented 56% of cases of pediatric AIDS in 1992.18 Similarly, for Hispanic children the figures are 13% and 24%, respectively.5 Although adolescents with AIDS (ages 13 to 19 years) represent only 0.4% of United States cases, they constitute one of the fastest growing groups of newly infected persons in the country, with a 77% increase in the past 2 years. 15,76 Furthermore, considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data severely underrepresents the impact of the disease in adolescents. Based on a median incubation period of 8 to 12 years, it has been estimated that 15% to 20% of all AIDS cases were acquired between the ages of 13 and 19 years. 51 Risk factors for HIV infection vary by gender in adolescents. Whereas 45% of teenaged males with AIDS were infected by contaminated blood or blood products, only 12% of females were infected via this route.13 Half of adolescent females with AIDS were infected through heterosexual contact, and a quarter through IVDU, compared with 3% and 7%, respectively, in teenage males.13 As in the adult population, teenage males with AIDS who acquired HIV through sexual contact are more likely to have had male-to-male transmission (34%).13 The exact rate of infection in adolescents is unknown, with estimates ranging from 0.03% in military applicants to 1.2% among homeless youthsP As in the pediatric population, adolescent racial and ethnic minority populations are overrepresented, especially among females. In addition, a greater proportion of female adolescents have AIDS (male: female ratio 1.7:1) than do female adults over the age of 25 years (male:female ratio 6.7:1). Tragically, AIDS has become the sixth-leading cause of death among youth aged 15 to 24 years. 15 ETIOLOGY

The cause of AIDS is HIV. This virus is a member of the Retroviridae family and belongs to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. 23 These illnesses include visna and maedi in sheep, arthritis and encephalitis in

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goats, infectious anemia in horses, and immune deficiency diseases in monkeys. The HIV genome is single-stranded RNA 9.8 Kb in size. At both ends of the genome there are identical regions (called long-terminal repeats) that contain the regulation and expression genes of HIV. The remainder of the genome includes three major sections: the gag region, which encodes the viral core proteins (Le., p24); the pol region, which produces the viral enzymes [Le., reverse transcriptase (p66), protease (pIS), integrase (pll)]; and the env region, which encodes the viral envelope proteins (Le., gp120, gp4I). Other regulatory proteins [Le., tat (pI4), rev (p27), nef (p27), vpu (pIS)] are also produced that are involved in either expression or suppression of viral replication or other stages of the life cycle. 38 The virus attaches itself to the target cell via the envelope protein gp120.55 The most common host cell-surface receptor is the CD4 molecule; however, other less common mechanisms of attachment use nonneutralizing antiviral antibodies. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (Le., macrophages, fibroblasts), thus facilitating virus transfer into the cel1. 40 The involvement of complement receptors, with or without the Fc receptor, in presenting HIV to the cell has also been suggested as a mechanism of attachment. 67 Following viral attachment, gpI20 undergoes conformational changes and gp4I interacts with the fusion receptor on the cell surface. Viral fusion with the cell membrane allows entry of viral RNA into the cell's cytoplasm. Viral DNA copies are then transcribed from the virion RNA through reverse transcriptase enzyme activity, and duplication of the DNA copies produce double-stranded circular DNA. The circular DNA is transported into the cell's nucleus where it is integrated into chromosomal DNA and referred to as the provirus. The provirus can remain dormant for extended periods. Depending on the relative expression of the viral regulatory genes (tat, rev, nef, and so on), the proviral DNA may encode production of the viral RNA genome, which in turn leads to production of viral proteins necessary for viral assembly.36 The RNA genome is then incorporated into the newly formed viral capsid. As the new virus is formed, it buds through the cell membrane and is released. Several stages in the HIV life cycle are so unusual to this virus that they are exploited as possible ways of interfering with its replication. Drugs aimed at blocking viral attachment to the CD4 receptor (Le., recombinant CD4, dextran), limiting viral replication (i.e., protease inhibitors, tat inhibitors), or inhibiting reverse-transcriptase (RT) activity (i.e., zidovudine, didanosine, zalcitabine, 2',3' / didehydro-3'-deoxythymidine, nevirapine) are only a few of the potential approaches to inhibit or eliminate HIV (see "Specific Therapy"). TRANSMISSION

Transmission of HIV-I occurs via one of three routes: intimate sexual contact, parenteral contact with blood or body fluids containing

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visible blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission, accounting for 90% of cases. Rates of transmission of HIV from mother to child vary between countries. Most large studies in the United States and Europe have documented transmission rates between 12% and 30%.2,31,32,34,79 In contrast, studies performed in Africa and Haiti have shown higher rates of transmission-between 25% and 52%.60,72 Vertical transmission of HIV can occur before (intrauterine), during (intrapartum), or after delivery (through breast-feeding). Intrauterine and intrapartum transmission are most common, but the proportions of children infected during these two periods has not been firmly established. Intrauterine transmission has been suggested by identification of HIV by culture or polymerase chain reaction (PCR) in fetal tissue as early as 10 weeks' gestation. In addition, first-trimester placental tissue from HIV-infected women has been demonstrated to contain HIV by in situ hybridization and immunocytochemistry. It is generally accepted that 30% to 50% of newborns acquire the infection in utero, as this percentage of infants has laboratory evidence of infection (positive viral culture, PCR, and/or p24 antigenemia) within the first week of life. 47 Some studies have found that viral detection soon after birth correlates with early onset of symptoms and rapid progression to AIDS, consistent with more long-standing infection during gestation. 68 Indirect data suggest that a high percentage of HIV-infected children acquire the virus intrapartum, analogous to hepatitis B transmission. First, HIV has been isolated from cervical and vaginal secretions. Second, the international registry of HIV-exposed twins found that among those discordant for HIV infection, the first-born twin was three times more likely to be infected. 37 This suggests that transmission in twin A is related to prolonged exposure to infected blood and cervical secretions in the birth canal during late gestation and delivery. Finally, the fact that 50% to 70% of infected infants do not demonstrate detectable virus until 1 to 12 weeks of age is suggestive of intrapartum transmission. 47 The least common route of vertical transmission is breast-feeding. Both free and cell-associated virus have been detected in breast milk from HIV-infected mothers. A metaanalysis of prospective studies found that the additional risk of transmission through breast-feeding in women with HIV infection before pregnancy was 14% (95% CI 7-22%).28 In contrast, in breast-feeding women who acquired HIV postnatally, the risk was 29% (95% CI 16-42%).28 This suggests that the viremia experienced by the mother during primary infection places the infant at an increased risk of infection. Thus it seems logical that women known to be HIV-infected or who are at risk for ongoing sexual or parenteral exposure to HIV should substitute infant formula for breast milk; however, the WHO recommends that in developing countries where other diseases (e.g., diarrhea, pneumonia, and malnutrition) contribute heavily to a high infant mortality rate, HIV-infected women should still be encouraged to breast-feed their infants. 86

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Risk factors influencing the rate of vertical transmission are not yet fully defined. Multiple large prospective studies have identified several features that seem to promote transmission, including maternal p24 antigenemia and depressed CD4 count «700/ J..LL).32, 74, 79 Increased maternal CD8 counts (2':1800/ J..LL), placental membrane inflammation, delivery before 34 weeks' gestation, and breast-feeding were also associated with an increased transmission rate.28, 74 Although several studies showed an increased rate of transmission with advanced maternal disease stage or AIDS, many transmitting mothers in each series were asymptomatic. Transfusions of infected blood or blood products have accounted for 9% of pediatric AIDS cases to date. ls The period of highest risk of exposure to HIV was between 1978 and 1985, prior to the availability of HIV antibody-screened blood products. Surveys among individuals with hemophilia observed between 1985 and 1989 found that 70% with severe Factor VIII deficiency and 50% with severe Factor IX deficiency were seropositives8 ; however, since 1984 with heat treatment of Factor VIII concentrate, and since 1985, HIV antibody screening, HIV transmission has been virtually eliminated in this population. 6 Blood donor screening has dramatically reduced, but not eliminated, the risk of transfusionassociated HIV infection. The rate of HIV transmission through antibody-screened blood is estimated to be approximately 1/60,000 transfused units.u Although HIV can rarely be isolated from saliva, it is in very low titer «1 infectious particle/milliliter) and has not been implicated as a transmission vehicle. Studies of hundreds of household contacts of HIVinfected adults, children, toddlers, and infants have found that HIV has not been transmitted through nonsexual contact. To date, only two cases have been reported in which urine or feces possibly devoid of visible blood have been proposed as a possible route of HIV transmission. 16 In the pediatric population, sexual contact is an infrequent route of HIV transmission, but some cases resulting from sexual abuse have been reported. In contrast, sexual contact is a major route of transmission in the adolescent population, responsible for greater than one third of cases. PATHOGENESIS

After HIV has entered the circulation, intense viremia ensues, resulting in widespread seeding of virus to various organs, including the brain and lymphoid tissues. Most commonly, HIV selectively binds to cells expressing CD4 molecules on their surface, primarily T4 lymphocytes (CD4 cells) and cells of the monocyte-macrophage lineage. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissue containing villous Hofbauer cells, may also be infected by HIV. CD4 + lymphocytes migrate to the lymph nodes where they become activated and proliferate. This antigen-driven migration and accumulation of CD4 cells within the lymphoid tissue may contribute to

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the dramatic decrease in the number of circulating CD4 cells and generalized lymphadenopathy characteristic of the acute retroviral syndrome in adults and older children. With establishment of a cellular and humoral immune response within 1 week to 3 months, the level of culturable virus from the blood declines substantially, and patients enter a phase of clinical latency, characterized by a lack of symptoms and a return of the CD4 cells to only moderately decreased levels. 49,63 The term clinical latency is a misnomer because during this period patients undergo gradual deterioration of the immune system, particularly evidenced by depletion of CD4 cells. These cells may be destroyed by multiple mechanisms: HIV-mediated single-cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus-specific immune responses, superantigen-mediated activation of T cells (rendering them more susceptible to infection with HIV), and programmed cell death (apoptosis). Recently it was demonstrated that the viral burden in the lymphoid organs is greater than that in the peripheral blood during clinical latency. As HIV virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. This action is part of the normal immune response for all antigens to facilitate optimal antigen presentation to competent immune cells; however, because the ability of HIV to replicate in T cells depends on the state of activation of the cells, the immune activation that takes place within the microenvironment of the nodes in HIV disease serves to promote infection of new CD4 cells as well as subsequent viral replication within the cells. Viral replication in monocytes, which can be productively infected yet resist killing, explains their role as reservoirs of HIV and as effectors of tissue damage in organs such as the brain. 49, 63 A group of cytokines, such as tumor necrosis factor (TNF)-a and TNF-I3, interleukin-l (IL-l), IL-3, IL-6, interferon-'Y, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colonystimulating factor, play an integral role in up-regulating HIV expression from a state of quiescent infection to active viral replication. Other cytokines such as interferon-a (lNF-a), INF-I3, and transforming growth factor-13 exert a suppressive effect on HIV replication. The interactions among these cytokines determine the concentration of viral particles in the tissues. Plasma concentrations of cytokines need not be elevated for them to exert their effect, as they are produced and act locally in the tissues. Thus, even during states of apparent immunologic quiescence, the complex interaction of cytokines sustains a constant level of viral expression, particularly in the lymph nodes. 49,63 The progression of disease is related temporally to the gradual disruption of lymph node architecture and degeneration of the follicular dendritic cell network with loss of its ability to trap HIV particles. This frees the virus to recirculate, producing the high levels of viremia seen during the later stages of disease. In addition, biologic properties of HIV also determine the rate of disease progression. For example, patients

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with low-replicating, non-syncytium-inducing HIV often have the longest symptom-free interval and prolonged survival. 49,63 . Perinatally infected infants generally demonstrate a relatively shorter period of clinical latency than do adults. It has been suggested that, if intrauterine infection coincides with the period of rapid expansion of CD4 + cells in the fetus, it could effectively infect the majority of the body's immunocompetent cells. The normal migration of these cells to the marrow, spleen, and thymus would result in efficient systemic delivery of HIV, unchecked by the immature immune system of the fetus. Thus infection would be established before the normal ontogenic development of the immune system, causing more severe impairment of immunity than HIV infection in the adult.71 CLINICAL MANIFESTATIONS

The first reports describing the natural history of perinatally acquired HIV infection were primarily retrospective series of children who had an early onset of symptoms; these reports were therefore biased toward more rapidly progressive disease. For example, in a prospective study of 172 perinatally infected children from Miami, 57% developed symptoms before 12 months of age, with a median age of 8 months at symptom onset, and 78% developed symptoms by 24 months of age.75 More recent longitudinal studies have demonstrated a bimodal distribution of disease expression, with 20% to 30% of HIV-infected children developing profound immune deficiency and AIDS-defining illnesses before the age of 1 year, and two thirds having a more slowly progressive course with greater than or equal to 5-year survival. s, 27, S1 In a series from New York City, 18% of HIV-infected children first developed clinical evidence of disease when they were older than 4 years of age, with some perinatally infected children having inapparent infection for 7 to 9 years. 64 The CDC has revised the original pediatric HIV classification system to reflect more accurately the stage of disease and prognosis and to include mutually exclusive categoriesP In the revised classification, illnesses in HIV-infected children are categorized using two parameters, clinical status and immunologic impairment (Table 1). Among the clinical categories, "Mild Signs/Symptoms" (A) includes children with nonspecific findings such as lymphadenopathy, parotitis, hepatosplenomegaly, and recurrent/persistent sinusitis or otitis media. "Moderate Signs/ Symptoms" (B) includes children with lymphocytic interstitial pneumonitis (LIP), a variety of organ-specific dysfunctions or infections or both, and "Severe Signs/Symptoms" (C) includes children with illnesses fitting the 1987 CDC definition of AIDS. In children whose HIV infection is not yet confirmed, the same clinical categories are used with a letter E (vertically exposed) placed in front of the classification, e.g., "E/N2." The immune classification is based on the absolute T-helper cell (CD4) count or the percentage of CD4 cells (CD4 %) (Table 2). If there

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Table 1. CDC REVISED PEDIATRIC HIV CLASSIFICATIONt Clinical Categories

C

N No Signs! Symptoms

A Mild Signs! Symptoms

B Moderate Signs! Symptoms'

Severe Signs! Symptoms'

(1) No evidence of suppression

N1

A1

B1

C1

(2) Evidence of moderate suppression

N2

A2

B2

C2

(3) Severe suppression

N3

A3

B3

C3

Immune Categories

*Category C and lymphoid interstitial pneumonitis (LIP) in Category B are reportable to state and local health departments as AIDS (MMWR 36:15,1987). tChiidren whose HIV infection status is not confirmed are classified by using the above grid with a letter E (for perinatally exposed) placed before the appropriate classification code (e.g., EN2).

is a discrepancy between the CD4 count and percentage, the disease should be classified into the more severe category. Age adjustment of the absolute CD4 count is necessary because normal counts, which are relatively high in infants, decline steadily until 6 years of age, when they reach adult norms. The spectrum of clinical manifestations of HIV infection is quite variable in infants and children. In the majority, physical examination at birth is normal. Presenting symptoms may be subtle, such as failure to thrive, lymphadenopathy and hepatosplenomegaly, chronic or recurrent diarrhea, interstitital pneumonia, and persistent oral thrush, and may be distinguishable only by their persistence. Systemic and pulmonary findings are common in the United States and Europe, whereas chronic diarrhea, wasting, and severe malnutrition predominate in Africa. Recurrent bacterial infections, chronic parotid swelling, LIP, and early onset of progressive neurologic deterioration are characteristic of children with AIDS but are less common in adults. Table 2. CDC REVISED PEDIATRIC HIV CLASSIFICATION: IMMUNE CATEGORIES BASED ON CD4 COUNT OR CD4 PERCENTAGE Age Groups Immune Categories

0-11 Months 1500 25%

1-5 Years 1000 25%

6-12 Years 500 25%

(1) No evidence of suppression

2:

(2) Evidence of moderate suppression

750-1499 15-24%

500-999 15-24%

200-499 15-24%

(3) Severe suppression

< 750 < 15%

< 500 < 15%

< 200 < 15%

2:

2: 2:

2: 2:

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Infections

Recurrent bacterial infections, the result of defects in humoral immunity, are manifested primarily by pyogenic infections with encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Salmonella spp. Other pathogens may also be seen, such as Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, Moraxella catarrhalis, and other gram-negative or gram-positive organisms. The most common serious infections are bacteremia, sepsis, and pneumonia, which occur in more than 50% of HIV-infected children with bacterial infections?· 46 Meningitis, urinary tract infections, deep-seated abscesses, and bone/ joint infections occur less frequently. Milder infections, such as otitis media, sinusitis, and skin and soft tissue infections are very common, are often chronic, and may have atypical presentations. Opportunistic infections begin to occur as the CD4 count declines. In adults, these infections usually represent reactivation of a latent infection acquired early in life. In contrast, young children generally experience primary infection, and, lacking prior immunity, they have a more fulminant course of disease. This principle is best illustrated by Pneumocystis carinii pneumonia (PCP), the most common opportunistic infection in the pediatric population. The peak incidence of PCP occurs at age 3 to 6 months, with a median survival of 1 month in this age group.18.75 The classic clinical presentation of PCP includes acute onset of fever, tachypnea, dyspnea, and marked hypoxemia; however, in some children the presentation may be more indolent with hypoxemia preceding the development of clinical or roentgenographic manifestations. Chest radiograph findings include interstitial infiltrates or diffuse alveolar disease. Nodular lesions, lobar infiltrates, or effusions may occasionally be seen. Diagnosis is made by demonstration of P. carinii in fluid from bronchoalveolar lavage; rarely, an open lung biopsy is necessary. First-line therapy is trimethoprim (TMP)/sulfamethoxazole (5MZ) (15 to 20/75 to 100 mg/kg/d -7- q6h IV and then PO) with adjunctive corticosteroids for 21 days.9 Up to one third of HIV-infected children have allergic reactions to TMP /5MZ and must undergo desensitization; alternative therapy includes intravenous administration of pentamidine (4 mg/kg/d) or newer regimens such as clindamycin/primaquine or atovaquone, which have been little-used in children to date. 41 . 8o Atypical mycobacterial infection, particularly with Mycobacterium qvium-intracellulare complex (MAC), has been recognized with increasing frequency as HIV-infected children live longer. The incidence of MAC infections has recently been estimated to be 24% in children with less than 100 CD4 cells/mm3 •5o Disseminated MAC infection is characterized by fever, malaise, night sweats, and weight loss; diarrhea, anemia, and granulocytopenia are often present. Diagnosis is made by isolation of MAC from blood, bone marrow, or tissue. Although the contribution of MAC infection to mortality is not well established, it is a major contributor to morbidity. Most treatment trials have been performed in adults;

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these trials suggest that combinations of at least two drugs, including clarithromycin (or azithromycin) and ethambutol, should be used. s A third drug (e.g., clofazimine, rifabutin, rifampin, ciprofloxacin, or amikacin) is often added to decrease the emergence of drug-resistant isolates. s The isolate's drug sensitivities should be ascertained and the treatment regimen adjusted accordingly. Because of the high potential for toxicity with most of these medications, surveillance for side effects should be ongoing. Oral candidiasis is the most common fungal infection seen in HIVinfected children. It progresses to involve the esophagus in approximately 20% of children; presenting symptoms include anorexia, dysphagia, vomiting, and fever?O Treatment with oral fluconazole (4 to 6 mg/ kg/d) for 14 days generally results in rapid improvement in symptoms. Intestinal cryptosporidiosis is another opportunistic infection that occurs commonly. Although a self-limiting disease in healthy hosts, it causes severe chronic diarrhea in HIV-infected children and often leads to malnutrition. Infection tends to be lifelong, especially in children with significantly depressed CD4 counts, as there is no effective therapy for this agent. Medications that have been used empirically, such as spiramycin or paromomycin, have been only partially effective. Viral infections, especially herpesvirus, pose significant problems for HIV-infected children. Herpes simplex virus causes recurrent gingivostomatitis, which may be complicated by local and distant cutaneous dissemination. Primary varicella-zoster virus (VZV) infection (chickenpox) may be severe, prolonged, and complicated by bacterial infection or visceral dissemination, including life-threatening pneumonitis.44 Recurrent, atypical, or chronic episodes of herpes zoster are often debilitating and require prolonged therapy with acyclovir; in rare instances, VZV has developed resistance to acyclovir in this setting, requiring the use of foscarneU3 Cytomegalovirus (CMV) infection occurs after severe CD4 depletion (usually
HIV invasion of the central nervous system (CNS) is thought to occur early in the course of infection. 30 Although the pathogenesis of HIV encephalopathy is unclear, several mechanisms have been proposed: direct viral infection of glial cells, endothelial cells, or possibly neurons, causing demyelination, neuronal dysfunction, or disruption of

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the blood-brain barrier; neuronal dysfunction as a result of interaction with viral envelope glycoproteins; or release of mediators (such as tumor necrosis factor, quinolinic acid, or neopterin) by infected macrophages causing impaired neuronal function or interference with metabolic pathways.39, 56, 84 Because the extent of the white matter destruction and severity of neurologic symptoms is out of proportion to the relatively small numbers of HIV-infected cells present in the CNS, it is likely that a combination of direct and indirect factors results in the encephalopathy. 39 The incidences of CNS involvement in vertically infected children is estimated to be 20% to 50%, and it may be the initial manifestation of the disease. 3o The most common presentation is progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, and impaired brain growth. Focal neurologic signs and seizures are unusual and may imply a coexisting pathologic process such as a tumor or opportunistic infection. With progression, marked apathy, motor dysfunction, spasticity, and weakness may occur, as well as loss of language and motor skills. The encephalopathy may progress intermittently with periods of deterioration followed by transiently stable plateaus. 3o Associated abnormalities identified by neuroimaging techniques include cerebral atrophy, basal ganglia calcifications, and, less frequently, leukomalacia. 30 Respiratory Tract

Recurrent upper respiratory tract infections such as otitis media and sinusitis are common. Although the etiologic agents are usually the same as those in normal children, unusual pathogens, such as P. aeruginasa and anaerobes, may be present in chronic infections and result in complications such as mastoiditis. LIP is the most common chronic lower respiratory tract abnormality, occurring in one third of children with AIDS. LIP is a chronic interstitial process with nodular lymphoid hyperplasia in the bronchial and bronchiolar epithelium that often leads to progressive alveolar-capillary block over months to years. Its characteristic persistent diffuse reticulonodular pattern on chest radiograph examination allows a presumptive diagnosis to be made radiologically before the onset of symptoms in most instances. Clinically there is insidious onset of tachypnea, cough, and mild-to-moderate hypoxemia with normal auscultatory findings or minimal rales. Progressive disease may be accompanied by digital clubbing and symptomatic hypoxemia, which usually resolves with oral corticosteroid therapy. The etiology of LIP is not well established, although several studies suggest LIP is associated with a primary EBV infection in the setting of HIV infection. EBV capsid antibody titers are typically elevated, and EBV DNA has been found in lung tissue of children with LIP but not in those with opportunistic infections such as CMV or PCP.! Infectious complications of the lung are common, affecting most

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HIV-infected children at some point. Bacterial pneumonias occur frequently. S. pneumoniae is the most common pathogen, but gram-negative bacteria may also be problematic; P. aeruginosa pneumonia is often associated with acute respiratory failure and death. 83 PCP is the most common opportunistic infection; but other pathogens include CMV, Aspergillus, Cryptococcus, and Histoplasma. Infection with common respiratory viruses, including respiratory syncytial virus, parainfluenza, influenza, and adenovirus, may occur simultaneously and have a protracted course. Pulmonary and extrapulmonary tuberculosis has been reported with increasing frequency in HIV-infected children, although it is considerably more common in HIV-infected adults. Cardiovascular System

The incidence of cardiac manifestations in HIV infection has not been assessed accurately, but approximately 20% of HIV-infected children have some cardiac involvement. 45 The pathogenesis of cardiomyopathy may be multifactorial, including pulmonary insufficiency, anemia, nutritional deficiencies (e.g., selenium), specific viral infections such as CMV, immunologic disturbances, and drug toxicities. Pathologic findings are variable; lymphocytic infiltrates, nonspecific focal myocardial degeneration with cytoplasmic vacuolization, interstitial edema, and hypertrophy of myocardial fibers have been described. 43,52 Left ventricular dysfunction appears to be the most common cardiac manifestation. Other manifestations include congestive heart failure (CHF), dilated cardiomyopathy, arrhythmias, and rarely, pericardial effusion and coronary arteriopathy. Gallop rhythm with tachypnea probably is the best clinical indicator of CHF in HIV-infected children. Electrocardiogram (ECG) and echocardiography are helpful in assessing cardiac function before the onset of clinical symptoms. Gastrointestinal and Hepatobiliary Tract

The gastrointestinal (GI) tract is commonly involved in HIV infection. AIDS enteropathy, a syndrome of malabsorption with partial villous atrophy not associated with a specific pathogen, has been postulated to be a result of direct HIV infection of the gut. In addition, a variety of pathogens characteristically cause GI disease, including bacteria (Salmonella, nontuberculous mycobacteria, Campylobacter), protozoa (Cryptosporidium, Microsporidia, Isospora, Giardia), viruses (CMV, rotavirus), and fungi (Candida).77 Infections may be localized or disseminated and may affect any part of the GI tract from the oropharynx to the rectum. 77 The most common symptoms of GI disease are chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia, and failure to thrive (FTT). The "wasting syndrome," a loss of more than 10% of body weight, is not as common as FIT in pediatric patients.

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Chronic liver inflammation evidenced by fluctuating serum levels of transaminases with or without cholestasis is relatively common, often without identification of an etiologic agent. In some patients, chronic hepatitis caused by CMV, hepatitis B or C, or nontuberculous mycobacteria may lead to portal hypertension and liver failure. Antiretroviral drugs such as zidovudine and didanosine may also cause reversible elevation of transaminases. Pancreatitis with increased pancreatic enzymes may be the result of drug therapy, e.g., pentamidine or didanosine, or rarely, opportunistic infections.

Renal Disease AIDS nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children.78 A direct effect of HIV on renal epithelial cells has been suggested as the cause, but immune complexes, hyperviscosity of the blood (secondary to hyperglobulinemia), and nephrotoxic drugs are other possible factors.42 A wide range of histologic abnormalities has been reported: focal glomerulosclerosis, mesangial hyperplasia, segmental necrotizing glomerulonephritis, and minimal-change disease. 42 ,78 Nephrotic syndrome is the most common manifestation of renal disease, with edema, hypoalbuminemia, proteinuria, and azotemia with normal blood pressureY Polyuria, oliguria, and hematuria also have been observed in some patients. In children, focal glomerulosclerosis generally progresses to renal failure within 6 months to a year, but other histologic abnormalities may remain stable for prolonged periods. 78

Skin Many cutaneous manifestations seen in HIV-infected children are inflammatory or infectious disorders that are not unique to this population. These disorders tend to be more widespread and respond less consistently to conventional therapy than in the uninfected child. Seborrheic dermatitis or eczema that is severe and unresponsive to treatment may be an early nonspecific sign of HIV infection. Recurrent or chronic episodes of herpes simplex virus (HSV), herpes zoster, molluscum contagiosum, anogenital warts, and candidal infection are common and may be difficult to control. Allergic drug eruptions are also common, in particular related to sulfonamides, and generally respond to withdrawal of the drug. Epidermal hyperkeratosis with dry, scaling skin is frequently observed, and sparse hair or hair loss may be seen in the later stages of the disease. Unusual complications such as pyomyositis and pyoderma gangrenosum have been reported. 35,62

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Malignant Diseases In contrast to adults, malignant diseases have been reported infrequently in HIV-infected children, representing only 2% of AIDS-defining illnesses. 18 It is likely, however, that the incidence of malignant disease will increase as more children are infected and their life expectancy is prolonged. Non-Hodgkin's lymphoma and primary eNS lymphoma are the most commonly reported malignant diseases in children.3 Recently there have been several reports of multiple soft tissue tumors such as leiomyoma, leiomyosarcoma, and rhabdosarcoma in HIV-infected children. 22 Kaposi's sarcoma is exceedingly uncommon in the pediatric population.

DIAGNOSIS

Demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay and confirmatory test (e.g., Western blot or immunofluorescence assay) establishes the diagnosis of HIV infection in any child more than 18 months of age. 17 Diagnosis in the younger infant is not as straightforward because maternal HIV antibody passively crosses the placenta during gestation, and serum tests for IgG antibody to HIV do not differentiate between infant and maternal antibody. Virtually 100% of infants born to HIV-infected mothers test antibody positive at birth, but most infants who are not infected will lose maternal antibody between 6 and 12 months of age. Because a small proportion of uninfected infants continues to test HIV-antibody positive for up to 18 months, positive IgG antibody tests cannot be used to make a definitive diagnosis of HIV infection in infants under this age. The presence of IgA or IgM anti-HIV in the infant's circulation can indicate HIV infection, as these immunoglobulin classes do not cross the placenta; however, detectable quantities of IgA anti-HIV are not generally produced until 3 to 6 months of age, so that this test is less useful in young infants (sensitivity 50% to 60% at 3 months and 60% to 100% at 6 months).48, 65 IgM anti-HIV assays have been both insensitive and nonspecific and need further refinement before being valuable for clinical use. 66 Tests identifying viral presence, such as HIV culture and HIV DNA or RNA polymerase chain reaction (peR), are considerably more valuable in young infants. These tests, which are highly specific (>98%), have sensitivity of 40% to 50% in the first month of life, 80% to 100% by 2 to 3 months, and 90% to 100% by 6 months. 69 Demonstration of p24 antigen in the infant's blood is also very specific but is limited by the test's low sensitivity; p24 antigen can be bound by excess maternal antibodies to produce an immune complex that is undetectable by the standard p24 antigen assays. A modification of the test that dissociates the immune complexes (leD) has improved the test considerably such that the sensitivity of the leD p24 antigen test has a sensitivity of 85% by 3 months and >90% by 6 months of age. 69

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Choosing the appropriate diagnostic assay depends on the age of the child, the predictive value of the test at that age, laboratory availability, and cost. Virus culture and PCR are expensive ($150 to $250 and $150 to $175, respectively) and have limited availability because of their technical complexity.69 The p24 antigen and IgA assays are less expensive ($10 to $50), but also are less likely to be diagnostic in the very young infant; in addition, these methods are generally available only through reference laboratories. A diagnostic algorithm for infants without ongoing postnatal exposure (i.e., not being breast-fed) is shown in Figure 1. OTHER LABORATORY FINDINGS

Hypergammaglobulinemia is common among HIV -infected children. It is often used as a nonspecific indicator of HIV infection in infants between 6 and 18 months of age when serologic findings are difficult to interpret and other more definitive tests are not available. B cell dysfunction is responsible for the markedly elevated levels of IgG, most of which are the IgGl and IgG3 subclasses. Elevated serum levels of IgA and IgM can also be found. Paradoxically, the overproduced

At birth: HIV culture/PCR

+ Repeat within one month until 2 concordant results

Repeat within one month

Repeat at 3 months

Repeat 6 months of age

Follow HIV antibody at 12 + 18 months until seronegative

*: p24 antigen must be used as confirmatory test Figure 1. Diagnostic testing of infants born to HIV + mothers. (Adapted from Working Group on Antiretroviral Therapy: National Pediatric HIV Resource Center: Antiretroviral therapy and medical management of the HIV-infected child. Pediatr Infec Dis J 12:513522,1993.)

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immune globulins are generally dysfunctional, and patients are unable to produce consistently antigen-specific antibodies. Thus there is predilection of HIV-infected patients to recurrent bacterial infections with encapsulated organisms (e.g., S. pneumoniae, H. injluenzae, and Salmonella) that require opsonization for efficient clearance. Hypogammaglobulinemia is rare but is associated with rapidly progressive disease and poor prognosis. Hematologic abnormalities are common and are caused by multiple factors, including bone marrow suppression by HIV and by other infections, malnutrition, and adverse reactions to drugs. Thrombocytopenia, anemia, leukopenia, and/or granulocytopenia are frequently encountered and may occur in otherwise asymptomatic HIV -infected children. Autoimmune thrombocytopenia may be the presenting manifestation of disease and is usually responsive to antiretroviral drugs, or intravenous immunoglobulin (lVIG) with or without corticosteroids. 4,29 When it occurs in the terminal phase of the illness, it is often refractory to therapy.29 Anemia may be drug induced (zidovudine, dapsone, or antibiotics), or the result of iron or vitamin B12 deficiency or chronic infection; a positive direct Coombs' test is common and may be associated with low-grade hemolysis. Neutropenia may also be drug induced or due to chronic infection and may require the use of granulocyte colony-stimulating factor (GCSF) if the absolute neutrophil count remains consistently depressed «500 mm3 ).57 In contrast to the classic progressive deterioration in the number of CD4 lymphocytes, absolute lymphopenia occurs less frequently in the pediatric population than in HIV-infected adults.

PREVENTION

Until more effective therapy for HIV infection is available, prevention is the only means to control this disease. Education regarding the routes of transmission, the hazards of recreational drug use, and the value of sexual abstinence and safe sex practices should begin at an early age. Use of condoms and the adjunctive use of a spermicide containing nonoxynol 9 are an important means of reducing sexual transmission but are not completely effective. A more specific prevention mode in pediatrics is interruption of perinatal transmission. Results of a multicenter placebo-controlled trial (AIDS Clinical Trials Group Protocol #076) using zidovudine (ZDV, AZT) therapy in pregnant women as early as 14 weeks of gestation through delivery and in their newborns for the first 6 weeks of life showed that vertical transmission was reduced from 25.5% in the placebo recipients to 8.3% in ZDV recipients. 2o Toxicity from ZDV therapy in both the mothers and infants was minimal. Studies utilizing HIVantibody concentrate (HIVIG) are in progress to further reduce perinatal transmission. In addition, several studies evaluating the role of route of delivery demonstrated a slightly decreased transmission rate among

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women delivered by cesarean section, although the statistical significance was marginaF9 An HIV vaccine that can prevent infection, or at least the development of disease, is the ultimate goal of prevention. Although several different types of vaccines are being investigated (e.g., whole virus, viral subunits [gp120, gp160j, viral proteins alone or in combination with other vectors [i.e., vaccinia, bacteria]), an effective vaccine appears to be in the distant future. Studies exploring the immunogenicity, safety, and tolerability of several candidate vaccines for the pediatric population are now being conducted.

GENERAL MANAGEMENT A multidisciplinary team approach is essential for successful management of pediatric HIV infection. Close attention should be paid to nutritional status, which is often delicately balanced and may require aggressive preemptive intervention (e.g., nasogastric or gastric feedings or parenteral nutrition) to achieve adequate caloric and protein intake. Megestrol acetate, a progesterone derivative that stimulates appetite, has been effective in HIV-infected adults and anecdotally beneficial in children. 10 Painful oropharyngeal lesions and dental caries are frequent and may interfere with eating; routine dental evaluations and careful attention to oral hygiene should be encouraged. Development should be evaluated regularly with provision of necessary physical, occupational, and/ or speech therapy. Recognition of pain in the young child may be difficult, and effective pharmacologic and nonpharmacologic protocols for pain management should be instituted, especially during the terminal phase of the disease. Prevention of PCP is one of the most important goals of HIV management. Because the peak age at which PCP has occurred in the pediatric population (3 to 6 months) is often before a definitive diagnosis of HIV infection has been established, guidelines for initiation of PCP prophylaxis were issued in 1991.1 4 These recommendations were based on age-related changes in normal CD4 lymphocyte values in the first years of life and studies that correlated CD4 counts in infants with development of PCP.26 Unfortunately, PCP cases have continued to occur sporadically in infants younger than 1 year of age with CD4 counts above the threshold for prophylaxis. Therefore, revised guidelines have been published such that all infants between 6 weeks and 1 year of age either (1) born to HIV-infected mothers or (2) proved to be HIV-infected should receive prophylaxis regardless of the CD4 count or percentage. (Table 3).When the infant is older than 1 year of age the previously established guidelines should be used. The best prophylactic regimen is 150/750 mg/m2/day of TMP /SMZ given as two daily doses 3 days a week. 14 If the patient experiences a mild allergic reaction (i.e., rash), desensitization is usually successful to allow daily TMP /SMZ prophylaxis. For severe adverse reactions to TMP /SMZ, alternative therapy

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Table 3. RECOMMENDATIONS FOR PCP PROPHYLAXIS AND CD4+ MONITORING FOR HIV-EXPOSED INFANTS AND HIV-INFECTED CHILDREN Age

PCP Prophylaxis

Birth to 4-6 weeks

No prophylaxis

4-6 weeks to 4 months

Prophylaxis for all

4-12 months HIV-infected or indeterminate Prophylaxis for all HIV infection reasonably excluded* 1-5 years, HIV-infected 6-12 years, HIV-infected

No prophylaxis Prophylaxis or CD4+ Prophylaxis or CD4 +

CD4 + Monitoring 1,3,6,9,12 months of age 1,3,6,9,12 months of age 1,3,6,9,12 months of age None

if CD4 + count <500 Every 3--4 months§ percent <15%H if CD4 + count <200 Every 3-4 months§ percent < 15%+

*:0-2 negative HIV diagnostic tests (culture or PCR), both of which are performed at :0-1 month of age and one of which is performed at :0-4 months of age, or :0-2 negative HIV IgG antibody tests performed at >6 months of age in a child who has no clinical evidence for HIV disease. tChiidren 1 to 2 years of age who were on PCP prophylaxis and had a CD4 + count <750 or percent <15% in the first year of life should continue on prophylaxis. :j:Prophylaxis should be considered on a case·by·case basis for children who may otherwise be at risk for PCP, such as children with rapidly declining CD4+ counts or percents or with Category C conditions (16). §More frequent monitoring (e.g., monthly) is recommended for children whose CD4+ counts or percents are approaching the threshold for prophylaxis. Adapted from Simonds RJ, Lindegren ML, Thomas P, et al: Prophylaxis against Pneumocystis carinii pneumonia among children with perinatally acquired HIV infection in the United States. N Engl J Med 332:786-790, 1995.

includes dapsone, aerosolized or intravenous pentamidine, or atovaquone (which is currently being tested in children).14 IVIG was used empirically for prophylaxis against recurrent bacterial infections during the early 1980s, and a subsequent placebo-controlled trial found that it was beneficial in children whose CD4 count was >200/mm3 •S9 However, a recent study found that in HIV-infected children taking zidovudine who also received TMP /SMZ for PCP prophylaxis, monthly IVIG provided no additional benefit in preventing serious bacterial infections. Thus, it is recommended that monthly IVIG should be given only to HIV-infected children who are not receiving TMP /SMZ and who (1) have suffered from at least two documented serious bacterial infections within 1 year, (2) have laboratory-documented inability to make antigen-specific antibodies, or (3) are hypogammaglobulinemic. 85 Other indications for IVIG include thrombocytopenia and bronchiectasis. 8s SPECIFIC THERAPY

Although there has been great progress in our understanding of the pathogenesis of HIV and its disease manifestations, the currently avail-

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able treatment against HIV is quite limited. The drug of choice is zidovudine (ZDV), which inhibits reverse transcriptase activity and thus the formation of the provirus by preventing its DNA elongation. All experts agree that ZDV should be offered to HIV-infected children with evidence of significant immunodeficiency or HIV-associated symptoms. 25 The major parameter reflecting significant immunodeficiency is a depressed CD4 lymphocyte count. Because normal CD4 counts in young children are higher than in adults, the following thresholds for initiation of ZDV therapy are recommended 85 : 1. For infants less than 1 year of age: <1750 CD4 cells/mm3 2. For infants 1 to 2 years of age: <1000 CD4 cells/mm3 3. For children 2 to 6 years of age: <750 CD4 cells/mm3 4. For children >6 years of age: <500 CD4 cells/mm3

In all children before initiation of therapy two CD4 counts should be obtained to verify the number. Regardless of the CD4 count, any symptom that fulfills the CDC criteria for AIDS (i.e., encephalopathy, opportunistic infections, severe failure to thrive or wasting syndrome, recurrent severe bacterial infections, and HIV-associa ted malignant disease) is considered an indication for ZDV therapy. Thrombocytopenia «75,000/ fLL) and hypogammaglobulinemia (IgG<250 mg/ dL) are also indications to begin antiretroviral therapy. There is some controversy whether to initiate ZDV therapy in HIV-infected children with LIP, parotitis, persistent thrush, recurrent or persistent diarrhea, cardiomegaly, nephrotic syndrome, neutropenia «750/fLL), or severe anemia (Hgb<7 g/ dL).85 In these cases, most experts agree that if the potential benefit from ZDV therapy seems to be greater than its potential side eff~cts, therapy should be offered. Recent studies in adults raised doubts about the advisability of giving ZDV very early in the course of the infection in asymptomatic patients. 24 Although a modest benefit from ZDV therapy was documented in these studies, it was transienU4 Thus, most experts do not recommend routine antiretroviral therapy for asymptomatic children with normal immunity or for children who are mildly symptomatic (i.e., those with lymphadenopathy, hepatomegaly, or hypergammaglobulinemia as their only finding). This consensus seems to contradict the recent data showing that the virus actively replicates in the lymphoid tissues even in asymptomatic patients. 33 In addition, because disease progression is more rapid in many children compared with adults, extrapolation from adult data may be unjustified for the pediatric patient. Thus, antiretroviral therapy should be considered for the asymptomatic patient, especially if the CD4 count is falling rapidly, or in infants and children with mild signs or symptoms of disease. The recommended dose of ZDV varies by age: for newborns it is 12 mg/kg/ d divided every 6 hours; for infants and children less than or equal to 13 years of age it is 720 mg/m2/d divided every 6 hours. A recent study (AIDS Clinical Trials Group Protocol 128) suggests that a reduction of ZDV to 360 mg/m2/d divided every 6 hours in children

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with mild to moderate symptoms would result in a substantial cost savings without sacrificing clinical effectiveness. Children older than 13 years of age should receive the adult dose (500 mg/ d divided in three to five doses).85 If oral therapy cannot be given, two thirds of the oral dose can be given intravenously. In children there should be close monitoring for ZDV-related side effects, which primarily include anemia, neutropenia, and elevated serum transaminase levels. Alternative antiretroviral drugs should be considered if intolerance to AZT develops, or when it fails to slow the progression of the disease, particularly if the patient develops encephalopathy or failure to thrive while receiving ZDV. In addition, development of cardiomyopathy, AIDS-defining opportunistic infections, or rapid deterioration in CD4 counts should also be considered an indication to change antiretroviral agents. Didanosine (ddI) is currently the second drug of choice. 12 The recommended dose is 180 to 240 mg/m2/d given orally every 12 hours. The side effects of this drug include pancreatitis and rarely anemia and neutropenia. When the efficacy and tolerance of ZDV alone (720 mg/ m 2/ d) given to symptomatic children was compared with ddI alone (240 mg/m2/d) or the combination of ZDV (360 mg/m2/d) and ddI (180 mg/m2/d), ZDV was the least effective of the three regimens (ACTG protocol 152). In addition, patients receiving ZDV alone had a significantly increased risk of developing hematologic and chemical toxicities. Thus, in symptomatic children, monotherapy with ddI or the combination of ZDV and ddI is recommended at the time of this writing. Zalcitabine (ddC) is inferior to AZT as a single agent, but, in rare situations in which AZT and/or ddI cannot be used, it might be an acceptable substitution. 82 The recommended dose is 0.03 mg/kg/d divided every 8 hours. Although this dose might be too low for an antiretroviral effect, the potential for development of peripheral neuropathy (the most common side effect of this drug) has limited studies using higher doses; however, recent pharmacokinetic data in the pediatric popUlation suggest that a higher dose (0.06 mg/kg/ d) may be considered in the few children who do not respond to any other treatmenU2 Combination therapy of ZDV with either ddI Or ddC is currently being investigated. Because the efficacy of combination therapy is as yet unproven in children, one should consider the potential for additive toxicity with these combinations prior to their use. New agents being investigated in HIV-infected children include non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The physician caring for HIV-infected children should closely follow the outcome of these studies so that improved treatment regimens can be instituted promptly. PROGNOSTIC INDICATORS

In general, children with symptomatic (AIDS-defining) HIV infection during the first year of life are more likely to have rapidly progres-

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sive disease and shorter life expectancy?5 Similarly, the occurrence of opportunistic infections, progressive encephalopathy, or hypogammaglobulinemia at any age often carries a poor prognosis. 8 In contrast, generalized lymphadenopathy, hepatosplenomegaly, LIP, parotitis, and recurrent bacterial infections are associated with a more favorable prognosis. 6 Laboratory markers associated with progression to AIDS include significantly depressed CD4 lymphocyte counts for age, rapid deterioration of CD4 counts, and persistently positive p24 antigenemia. 8

References 1. Andiman W A, Martin K, Rubinstein A, et al: Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet 28:1390-1393, 1985 2. Andiman WA, Simpson BJ, Olsen B, et al: Rate of transmission of human immunodeficiency virus type 1 infection from mother to child and short-term outcome of neonatal infection. Am J Dis Child 144:758-766, 1990 3. Arico M, Caselli D, D' Argenio P, et al: Malignancies in children with human immunodeficiency virus type 1 infection. Cancer 68:2473-2477, 1991 4. Ballem PJ, Belzberg A, Devine DV, et al: Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 327:1779-1784, 1992 5. Benson CA, Ellner JJ: Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis 17:7-20, 1993 6. Berkelman RL, Heyward WL, Stehr-Green JK, et al: Epidemiology of human immunodeficiency virus infection and acquired immunodeficiency syndrome. Am J Med 86:761-770, 1989 7. Bernstein LJ, Krieger BZ, Novick B, et al: Bacterial infection in the acquired immunodeficiency syndrome of children. Pediatr Infect Dis J 4:472-475, 1989 8. Blanche S, Tardieu M, Duliege AM, et al: Longitudinal study of 94 symptomatic infants with perina tally acquired human immunodeficiency virus infection. Am J Dis Child 144:1210-1214, 1990 9. Bozzette SA: The use of corticosteroids in Pneumocystis carinii pneumonia. J Infect Dis 162:1365-1369,1990 10. Brady MT, Koranyi KI, Hunkler JA: Megestrol acetate for treatment of anorexia associated with human immunodeficiency virus infection in children. Ped Infect Dis J 13:754-755, 1994 11. Busch MP, Eble BE, Khayam-Bashi H, et al: Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells. N Engl J Med 325:1-5, 1991 12. Butler K, Husson RT, Balis FM, et al: Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med 324:137-144, 1991 13. Centers for Disease Control and Prevention: AIDS in Adolescents Slide Series L-265 (5). Atlanta, United States Dept. of Health and Human Ser~ices, 1993 14. Centers for Disease Control and Prevention: Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with the human immunodeficiency virus. MMWR 40:1-13,1991 15. Centers for Disease Control and Prevention: HIV / AIDS Surveillance Report, 5(no. 4), 1994 16. Centers for Disease Control and Prevention: Human immunodeficiency virus transmission in household settings in United States. MMWR 43:347-356, 1994 17. Centers for Disease Control and Prevention: 1994 Revised Classification System for Human Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. MMWR RR-12:1-1O, 1994

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18. Centers for Disease Control and Prevention: Pediatric AIDS Slide Series L-262 (5). Atlanta, United States Dept. of Health and Human Services, 1993 19. Centers for Disease Control and Prevention: Women with AIDS Slide Series L-264 (5). Atlanta, United States Dept. of Health and Human Services, 1993 20. Centers for Disease Control and Prevention: Zidovudine for the prevention of HIV transmission from mother to infant. MMWR 43:285-288, 1994 21. Chadwick EG, Connor EJ, Hanson CG, et al: Tumors of smooth muscle origin in HIV-infected children. JAMA 263:3182-3184, 1990 22. Chadwick EG, Nieuwenhuis T, Yogev R, et al: Phase I evaluation of zalcitibine (ddC) administered to HIV-infected children. The First National Conference on Human Retroviruses and Related Infections, Washington, DC, December, 1993 23. Coffin JM: Structure and classification of retroviruses. In Levy A (ed): The Retroviridae, vol. I. New York, Plenum Press, 1992, pp 19-49 24. Concorde Coordinating Committee: Concord: MRC/ ANRS randomized double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 343:871-881,1994 25. Connor E, McSherry G: Antiretroviral treatment of human immunodeficiency virus infection in children. Sem Pediatr Infect Dis 2:285-300, 1991 26. Denny T, Yogev R, Gelman R, et al: Lymphocyte subsets in healthy children during the first 5 years of life. JAMA 267:1484-1488, 1992 27. Duliege AM, Messiah A, Blanche S, et al: Natural history of HIV type 1 infection in children: Prognostic value of laboratory tests on the bimodal progression of the disease. Pediatr Infect Dis J 11:630-635, 1992 28. Dunn DT, Newel ML, Ades AE, et al: Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 340:585-588, 1992 29. Ellaurie M, Burns ER, Bernstein LJ, et al: Thrombocytopenia and human immunodeficiency virus in children. Pediatrics 82:905-908, 1988 30. Epstein LG, Sharer LR, Oleske JM, et al: Neurological manifestations of human immunodeficiency virus infection in children. Pediatrics 78:678-687, 1986 31. European Collaborative Study: Children born to women with HIV-1 infection: natural history and risk of transmission. Lancet 337:253-260, 1991 32. European Collaborative Study: Risk factors for mother-to-child transmission of HIV1. Lancet 339:1007-1012, 1992 33. Fauci AS: Multifactorial nature of human immunodeficiency virus disease: Implications for therapy. Science 262:1011-1018,1993 34. Gabiano C, Tovo PA, deMartino M, et al: Mother-to-child transmission of human immunodeficiency virus type 1: Risk of infection and correlates of transmission. Pediatrics 90:369-374, 1992 35. Gardiner JS, Zauk AM, Minnefor AB, et al: Pyomyositis in an HIV-positive premature infant: Case report and review of the literature. J Pediatr Orthop 10:791-793, 1990 36. Gaynor R: Cellular transcription factors involved in the regulation of HIV-1 gene expression. AIDS 6:347-363, 1992 37. Goedert JJ, Duliege AM, Amos CI, et al: High risk of HIV-1 infection for first-born twins. Lancet 338:1471-1475, 1991 38. Green we The molecular biology of human immunodeficiency virus type 1 infection. N Engl J Med 324:308-317, 1991 39. Ho DD, Bredesen DE, Vinters HV, et al: The acquired immunodeficiency syndrome (AIDS) dementia complex. Ann Intern Med 111:400-410, 1989 40. Homsy J, Meyer M, Tateno M, et al: The Fc and not the CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science 244:1357-1360, 1989 41. Hughes WT, Leoung G, Kramer F, et al: Comparison of Atovaquone 566C80 and trimethoprim-su!famethoxazole to treat P. carinii pneumonitis in patients with AIDS. N Engl J Med 328:1521-1527, 1993 42. Inguilli E, Tejani A, Fikrig S, et al: Nephrotic syndrome associated with acquired immunodeficiency syndrome in children. J Pediatr 119:711-716, 1991 43. Joshi VV, Gadol C, Connor E, et al: Dilated cardiomyopathy in children with acquired immunodeficiency syndrome: A pathologic study of five cases. Hum Pathol 19:6973, 1988

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44. Jura E, Chadwick EG, Joseph S, et al: Varicella-zoster virus (VZ) infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 8:586-590, 1989 45. Kavanaugh-McHugh AL, Ruff AI, Rowe S, et al: Cardiac abnormalities in a multicenter interventional study of children with symptomatic HIV infection (Abstract). Pediatr Res 28:1040, 1991 46. Krasinski K, Borkowsky W, Bonk S, et al: Bacterial infections in HIV-infected children and adolescents. Pediatr Infect Dis J 8:216-220, 1989 47. Krivine A, Firtion G, Cao L, et al: HIV replication during the first weeks of life. Lancet 339:1187-1189,1992 48. Landesman S, Weiblen B, Mendez H, et al: Clinical utility of HIV-IgA immunoblot assay in the early diagnosis of perinatal HIV infection. JAMA 266:3443-3446, 1991 49. Levy JA: Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 57:185-212, 1993 50. Lewis LL, Butler KM, Husson RN, et al: Defining the population of human immunodeficiency virus-infected children at risk for Mycobacterium avium-intracellulare infection. J Pediatr 121:677-683, 1992 51. Lindegren ML, Hanson C, Miller K, et al: Epidemiology of human immunodeficiency virus infection in adolescents, United States. Pediatr Infect Dis J 13:525-535, 1994 52. Lipshultz SE, Orav EI, Sanders SP, et al: Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. New Engl J Med 327:1260-1265, 1992 53. Markowitz LE, Chandler FW, Roldan EO: Fatal measles pneumonia without a rash in a child with AIDS. J Infect Dis 158:481-483, 1988 54. McClain KL, Leach CT, Jenson HB, et al: Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. New Engl J Med 332:12-18, 1995 55. McDougal JS, Klatzmann DR, Maddon PJ: CD4-gp 120 interactions. Curr Opin Immunol 3:552-558, 1991 56. Mofenson LM, Blattner WA: Human Retroviruses. In Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases, ed 3. Philadelphia, 1992, p 1777 57. Mueller BU, Jacobsen F, Butler KM, et al: Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection. J Pediatr 121:797-802, 1992 58. National Hemophilia Foundation Information Exchange Medical Bulletin 137, July 1991 59. National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group: Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. New Engl J Med 325:73-80, 1991 60. Oxtoby MJ: Perina tally acquired human immunodeficiency virus infection. Pediatr Infect Dis J 9:609-619, 1990 61. Oxtoby MJ: Vertically Acquired HIV Infection in the United States. In Pizzo PA, Wilfert CM (eds): Pediatric AIDS, The Challenge of HIV Infection In Infants, Children, and Adolescents, ed 2. Baltimore, Williams & Wilkins, 1994, pp 3-20 62. Paller A, Sahn EE, Garen PD, et al: Pyoderma gangrenosum in pediatric acquired immune deficiency syndrome. J Pediatr 117:63-66, 1990 63. Pantaleo G, Graziosi C, Fauci AS: The immunopathogenesis of human immunodeficiency virus infection. New Engl J Med 328:327-335, 1993 64. Persaud D, Chandwani S, Rigaud M, et al: Delayed recognition of human immunodeficiency virus infection in preadolescent children. Pediatrics 90:688-691, 1992 65. Quinn TC, Kline RL, Halsey N, et al: Early diagnosis of perinatal HIV infection by detection of viral-specific IgA antibodies. JAMA 266:3439-3442, 1991 66. Rakusan TA, Parrott RH, Sever JL: Limitations in the laboratory diagnosis of vertically acquired HIV infection. J Acquir Immune Defic Syndr 4:116-121, 1991 67. Reisinger EC, Vogetseder W, Berzow D, et al: Complement-mediated enhancement of HIV-1 infection of the monoblastoid cell line U937. AIDS 4:961-965,1990 68. Rodgers MF, Ou C-Y, Rayfield M, et al: Use of polymerase chain reaction for early detection of the proviral sequences of human immunodeficiency virus in infants born to seropositive mothers. New Engl J Med 320:1649-1654, 1989 69. Rodgers MF, Schochetman G, Hoff R: Advances in diagnosis of HIV infection in

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70. 71. 72. 73. 74. 75. 76. 76a. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87.

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infants. In Pizzo PA, Wilfert CM (eds): Pediatric AIDS: The Challenge of HIV Infection in Infants, Children, and Adolescents, ed 2. Baltimore, Williams & Wilkins, 1994, pp 219-238 Rodgers MF, Thomas P A, Starcjer ET, et al: Acquired immunodeficiency syndrome in children: Report of the Centers for Disease Control national surveillance, 1982-1985. Pediatrics 79:1008-1014, 1987 Rosenberg ZF, Fauci AS: Immunopathology and pathogenesis of HIV infection. In Pizzo PA, Wilfert CM (eds): Pediatric AIDS: The Challenge of HIV Infection In Infants, Children, and Adolescents, ed 2. Baltimore, Williams & Wilkins, 1994, pp 115-128 Ryder RW, Nsa W, Hassig SE, et al: Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. New Engl J Med 320:1637-1642, 1989 Safrin S, Berger TG, Gilson I, et al: Therapy in five patients with AIDS and acyclovirresistant varicella-zoster virus infection. Ann Intern Med 115:19-21, 1991 Saint Louis ME, Kamenga M, Brown C, et al: Risk for perinatal HIV-1 transmission according to maternal immunologic, virologic, and placental factors. JAMA 269:28532859,1993 Scott GB, Hutto C, Makuch RW, et al: Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. New Engl J Med 321:1791-1796, 1989 Select Committee on Children, Youth and Families: A decade of denial: teens and AIDS in America. Washington, DC, House of Representatives, lO2nd Congress, 1-394, May, 1992 Simonds RJ, Lindegren ML, Thomas P, et al: Prophylaxis against Pneumocystis carinii pneumonia among children with perina tally acquired HIV infection in the United States. N Engl J Med 332:786-790, 1995 Smith PD, Quinn TC, Strober W, et al: Gastrointestinal infections in AIDS. Ann Intern Med 116:63-77, 1992 Strauss J, Abitbol C, Zilleruelo G, et al: Renal disease in children with the acquired immunodeficiency syndrome. New Engl J Med 321:625-630, 1989 Thomas PA, Weedon J, Krasinski K, et al: Maternal predictors of perinatal HIV transmission. Pediatr Infect Dis J 13:489-495, 1994 Toma E, Fournier S, Dumont M, et al: Clindamycin/Primaquine versus trimethoprimsulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: A randomized, double-blind pilot trial. Clin Infect Dis 17:178-184, 1993 Tovo PA, De Martino, Gabiano C, et al: Prognostic factors and survival in children with perinatal HIV-1 infection. Lancet 339:1249-1253,1992 Tze-Chiang M, Fischl MA, Boota AM, et al: Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection: A phase 1/11 study. Ann Intern Med 116:13-20, 1992 Vernon DD, Holzman BH, Lewis P, et al: Respiratory failure in children with acquired immunodeficiency syndrome and acquired immunodeficiency-related complex. Pediatrics 82:223-228, 1988 Wiley CA, Schrier RD, Nelson JA, et al: Cellular localization of human immunodeficiency syndrome virus infection within the brains of acquired immunodeficiency syndrome patients. Proc Nat! Acad Sci USA 83:7089-7093, 1986 Working Group on Antiretroviral Therapy: National Pediatric HIV Resource Center: Antiretroviral therapy and medical management of the human immunodeficiency virus-infected child. Pediatr Infect Dis J 12:513-522, 1993 World Health Organization: Consensus statement from the WHO/UNICEF consultation on HIV transmission and breastfeeding. Weekly Epidemiol Rec 67:177-179, 1992 World Health Organization Global Programme on AIDS: HIV / AIDS Summary, January, 1993

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