Pediatric Annals

Clinical Aspects of HIV Infection in Children

Joseph A Church, MD

Abstract

Children at risk for human immunodeficiency virus (HIV) infection include those bom to HIV-infected mothers, those transfused with contaminated blood products, adolescents engaging in high-risk sexual behavior, and rarely, sexual abuse victims.

Because of the difficulty in interpreting standard HlV antibody tests in young children, the Centers for Disease Control and Prevention (CDC) has defined HIV infection in children according to the age at which maternal antibody is likely to represent a significant influence on standard antibody assays (Table I).1

The CDC also has developed a classification system for HIV infection in children (Table 2).1 A perinatally exposed infant and child whose infectious status is not determined is classified as P-O; HIV-infected asymptomatic children are considered to be P-I; and HIV-infected children with symptoms are classified as P-2. Classes P-I and P-2 are further subdivided; P-I class is divided by immune function and P-2 is divided by specific signs or symptoms. Acquired immunodeficiency syndrome (AIDS) defining conditions are divided into six categories:

* specific secondary infectious diseases (P-2, D-I),

* recurrent, serious bacterial infections (P-2, D- 2),

* progressive neurologic disease (P-2, B),

* lymphoid interstitial pneumonitis (P-2, C),

* specified secondary cancers such as lymphomas and Kaposi's sarcoma (P-2, E-I), and

* HIV wasting syndrome (contained in P-2, A).

PATHOGENESIS OF HIV

Acquired immune deficiency syndrome may be defined conceptually as the most serious clinical consequences of retrovirus-induced immune dysregulation. This definition implies a spectrum of clinical disorders, incorporates a specific etiology, and identifies the pathophysiologic process. Human immunodeficiency virus is the etiologic agent of AIDS in humans.2,3 Previously termed human T lymphotropic virus type III (HTLV/III), lymphadenopathyassociated virus, and AIDS-related virus, HIV belongs to the human retrovirus subfamily Lentivirinea and contains RNA as its genomic nucleic acid. Lentiviruses generally display species specificity and are known to infect monkeys, cats, goats, sheep, and horses. Characteristics of lentivirus infections include long clinical latency from infection to the development of recognizable signs and symptoms, progressive immunologic dysfunction, and neurologic disease. Although two subtypes of HIV have been isolated, HIV-I and HIV-2, HIV-I is the only subtype to infect significant numbers of individuals in the United States.

Human immunodeficiency virus p24 antigen detection is a useful and highly specific test for the presence of HIV. Unfortunately, the sensitivity of the assay is limited due to the complexing of HIV antigen with passively transferred maternal antibodies. Recently, it was shown that by dissociating these HIV p24 antigencontaining complexes, the sensitivity of this procedure can be markedly enhanced.58

Currently, direct culture for HIV and polymerase chain reaction for identification of HIV-specific nucleic acid sequences are the methods of choice for detecting virus in peripheral blood.59'61 In experienced laboratories, both of these assays appear to be highly sensitive and specific and have predictive values of over 90% in infants greater than one month of age. Although false negative tests may be seen and false positive results have been reported, the increasing availability and reliability of these assays for routine diagnosis has reduced dependence upon nonspecific and insensitive measures such as serial assessment of HIV antibody levels.

BREAST-FEEDING

A number of well-described cases indicate that HlV may be transmitted through breast-feeding.62 Despite these individual reports, the impact of breastfeeding on the overall rate of HIV transmission from mother to infant has not been settled. At least two studies have suggested that the rate of HIV transmission was not affected by breast-feeding.63,64 Other data siipcesr rbaf a 14% increase in the rate may be attributable to breast-feeding,65 and this rate may be strikingly increased in situations where breast-feeding mothers are acutely infected with HIV during the postnatal…

Children at risk for human immunodeficiency virus (HIV) infection include those bom to HIV-infected mothers, those transfused with contaminated blood products, adolescents engaging in high-risk sexual behavior, and rarely, sexual abuse victims.

Because of the difficulty in interpreting standard HlV antibody tests in young children, the Centers for Disease Control and Prevention (CDC) has defined HIV infection in children according to the age at which maternal antibody is likely to represent a significant influence on standard antibody assays (Table I).1

The CDC also has developed a classification system for HIV infection in children (Table 2).1 A perinatally exposed infant and child whose infectious status is not determined is classified as P-O; HIV-infected asymptomatic children are considered to be P-I; and HIV-infected children with symptoms are classified as P-2. Classes P-I and P-2 are further subdivided; P-I class is divided by immune function and P-2 is divided by specific signs or symptoms. Acquired immunodeficiency syndrome (AIDS) defining conditions are divided into six categories:

* specific secondary infectious diseases (P-2, D-I),

* recurrent, serious bacterial infections (P-2, D- 2),

* progressive neurologic disease (P-2, B),

* lymphoid interstitial pneumonitis (P-2, C),

* specified secondary cancers such as lymphomas and Kaposi's sarcoma (P-2, E-I), and

* HIV wasting syndrome (contained in P-2, A).

PATHOGENESIS OF HIV

Acquired immune deficiency syndrome may be defined conceptually as the most serious clinical consequences of retrovirus-induced immune dysregulation. This definition implies a spectrum of clinical disorders, incorporates a specific etiology, and identifies the pathophysiologic process. Human immunodeficiency virus is the etiologic agent of AIDS in humans.2,3 Previously termed human T lymphotropic virus type III (HTLV/III), lymphadenopathyassociated virus, and AIDS-related virus, HIV belongs to the human retrovirus subfamily Lentivirinea and contains RNA as its genomic nucleic acid. Lentiviruses generally display species specificity and are known to infect monkeys, cats, goats, sheep, and horses. Characteristics of lentivirus infections include long clinical latency from infection to the development of recognizable signs and symptoms, progressive immunologic dysfunction, and neurologic disease. Although two subtypes of HIV have been isolated, HIV-I and HIV-2, HIV-I is the only subtype to infect significant numbers of individuals in the United States.

Figure 1. Schematic diagram of HIV virion.

Figure 1. Schematic diagram of HIV virion.

Figure 2. Life cycle of HIV.

Figure 2. Life cycle of HIV.

An appreciation of virus structure and replicative cycle is essential for an understanding of the pathogenesis of HIV-associated disease.4 The virus envelope consists of a unit membrane- lipid bilayer studded with virus-specific glycoproteins and variable hostcell proteins (Figure 1). A glycoprotein of 120 kd molecular weight (gpl20) represents a critical feature of the HIV surface and plays an important role in determining HIV target cell tropism. A unique feature of HIV is the selective infection of cells bearing the CD4 surface glycoprotein (Figure 2). This selectivity is mediated by the specific interaction of gpl 20 on individual HIV virions with CD4 on the surfaces of "helper" T-cells, monocytes, macrophages, and macrophage-related cells, including microglial cells of the central nervous system.

Following adhesion of virus to target cells, the respective membranes fuse and viral RNA, in conjunction with virus-specific reverse transcriptase, enters the target cell cytoplasm. Viral genomic RNA is "reversely transcribed" to DNA, which then is transported to the target cell nucleus. Virus-specific DNA randomly integrates into the host-cell DNA and in this form constitutes a "provirus." Upon activation of the infected host cell, proviral DNA transcription is upregulated with resultant production of HI V-specific genomic RNA and messenger RNA. Subsequent translation of viral messenger RNA to virus-specific proteins produces the final components required for cytoplasmic assembly and budding of mature, free virions.

The pathologic consequences of HIV infection reflect three processes which, although likely interrelated, induce recognizable patterns of clinical disease: immunologic attrition resulting from CD4 + "helper" T-cell loss and dysfunction, central nervous system infection, and inappropriate and uncontrolled immune activation.

Potential mechanisms by which HIV induces T-cell deficiency are listed in Table 3. Although not the focus of this article, one or more of these processes are likely responsible for the progressive loss of T-cell functions.5 As functional CD4+ T-ceIIs are required for the generation of protective, antigen-specific Tand B-cell responses, progressive T-cell loss results in an acquired, combined immune deficiency.

Although the importance of direct HIV infection of neurons in the central nervous system is still debated, it is clear that HIV infects microglial cells of the central nervous system.6 It is likely that this infection results in exaggerated activation of these macrophage-like cells with resultant local tissue damage and consequently the signs and symptoms of neuroencephalopathy. 7

Inappropriate or uncontrolled immune activation is likely associated with additional features of HIV infection,8 including proliferative disorders such as lymphoid interstitial pneumonitis, hepatosplenomegaly, and Kaposi's sarcoma, and the systemic features of fatigue, fever, and wasting. The exaggerated activation of macrophages in several organ systems appear to mediate local tissue damage through the production of pro- inflammatory cytokines such as IL·!, IL-6, and tumor necrosis factor. These mediators may be responsible for much of the local tissue damage, as well as the systemic manifestations of HIV infection.

Table

TABLE 1Definition of HIV Infection in Children

TABLE 1

Definition of HIV Infection in Children

CLINICAL MANIFESTATIONS

Important features of the clinical manifestations of HIV disease in children include variable time of onset and an extraordinarily wide spectrum. Young infants may present with signs and symptoms of HIV infection that strongly suggest intrauterine infection; other children may show no outward signs of HIV for over 10 years.

Systemic Manifestations

Failure to thrive is a universal feature of HIV infection in pediatrics. Regardless of route of infection or length of time asymptomatic, every child who survives with HlV will eventually fail to grow or develop weight loss as a major problem. HIV-associated wasting is due to reduced caloric intake secondary to anorexia and elevated resting energy expenditure associated with chronic infection.9,10 Chronic fatigue and low-grade fever often accompany the wasting process.

Of increasing importance as a cause of progressive wasting associated with HIV infection in children, Mycobacterium avium complex is the most common life-threatening bacterial infection in adults with HIV. It affects patients with very low CD4 counts, usually under 50/mm3, and manifests as fever, weight loss, and abdominal pain.11·12 As children with HIVassociated severe immunocompromise live longer, Mycobacterium avium complex likely will become the major threat to their survival.

Table

TABLE 2Classification of HIV Infection in Children Under 1 3 Years of Age

TABLE 2

Classification of HIV Infection in Children Under 1 3 Years of Age

Table

TABLE 3Potential Mechanisms of CD4+ T-CeII Depletion and Dysfunction

TABLE 3

Potential Mechanisms of CD4+ T-CeII Depletion and Dysfunction

Neurologic Manifestations

A variety of clinical patterns of neurodevelopmental involvement may be seen in HIV-infected children.6·13·14 Progressive encephalopathy is characterized by impaired brain growth, progressive motor dysfunction, and loss of developmental milestones. These children display a unique motor dysfunction with weakness, flaccidity, hyperreflexia and spasticity, and toe-walking with a wide-based, shuffling gait. Cortical atrophy and basal ganglion calcification is often apparent on brain imaging in these children.

Other children may progress normally physically and cognitively for a limited period of time and then plateau developmentally and fail to reach new milestones.

Static encephalopathy is a fixed process in which subjects may manifest developmental delay but milestones are not lost. Further, motor and cognitive skills may be acquired albeit at a rate below normal, or cognitive development may proceed despite persistent motor dysfunction.

Human immunodeficiency virus encephalopathy also may result in learning disorders, although the primary role of HIV in this manifestation is clouded by the high frequency of this type of problem in children born to mothers at high-risk for HIV because of substance abuse. Additional neurologic problems that have been reported in pediatric HIV infection have included seizure disorders, cerebral-vascular accident (stroke), central nervous system lymphoma, and aseptic meningitis. A specific dysmorphic syndrome, HTLV-III embryopathy, was reported to be associated with intrauterine HIV infection.15 However, carefully controlled studies did not confirm the presence of characteristic craniofacial dysmorphism in children exposed to perinatal HIV infection.16 Peripheral neuropathy also may be seen as both a primary manifestation of HIV or as a complication of antiviral treatment with drugs such as didanosine (DDI).

Despite the potential for neurologic complications, many HIV-infected children do remarkably well for many years. However, the extraordinary emotional stress of dealing with their own chronic illness, that of their parents, or even parental loss may result in behavior problems at home or school or overt signs of depression.

Dermatologie Manifestations

Common childhood skin infections such as skin and nail candidiasis, varicella, and molluscum contagiosum are seen frequently in HIV-infected children.17 However, depending on the degree of immune compromise, these disorders may be difficult to manage. Varicella (chicken pox) may be a life-threatening infection, and varicella -zoster (shingles) and recurrent or chronic varicella infection may be particularly problematic in a child with profound T-cell deficiency. Condylomata acuminata, or venereal warts, although uncommon, may be difficult to treat and often require multiple surgical interventions. Less serious, though bothersome, severe seborrheic dermatitis is often seen. As HIV disease progresses, atrophy of skin, nails, and hair may be observed and may reflect chronic malnutrition or the effects of persistent infectious complications. A recently described papulopustular dermatitis, eosinophilic folliculitis, has been seen in some children. The etiology and best management of this process is yet to be determined. As reported in HIV-infected adults, African-American children treated with zidovudine (ZDV, formerly AZT) may show a diffuse darkening of their skin color. This produces no adverse effects but may raise parental concern. Ecchymosis or petechiae may reflect primary or drug-associated thrombocytopenia; Kaposi's sarcoma may mimic an ecchymotic lesion in the rare instances in which it has affected children.

Drug hypersensitivity reactions occur more frequently in HIV-infected patients than in non-HIV infected patients and usually manifest as cutaneous reactions.18 Trimethoprim-sulfamethoxazole is the most common offender, although adverse effects may be seen with virtually any drug commonly used in the treatment of HIV or its complications. Most drug rashes are generalized, pruritic, maculopapular eruptions, although urticarial and serum sickness-like responses and more severe reactions including StevensJohnson syndrome can occur.

Eye Manifestations

The severe infectious retinopathies seen in adults with AIDS are not as common in children.19 Although cytomegalovirus and toxoplasmosis retinitis have been seen, their incidence in children is remarkably low despite a very high prevalence of cytomegalovirus infection. Simple infectious problems such as blepharitis and conjunctivitis, in contrast, are seen regularly. Unusually long eyelashes are an unusual and unexplained feature of HIV infection in children and often require periodic trimming.

Ear, Nose, and Throat Manifestations

Chronic bacterial otitis media and chronic sinusitis are among the most common infectious complications seen in children with HIV infection and may be the primary presenting manifestation of a parent's underlying immune deficiency or dysfunction.20 Hemo' philus influenzae (both non-a and non-b), Streptococcus pneumoniae, and Moraxella catarrhalis are usually identified as the causative agents. Complete eradication of these infections often is difficult or impossible, and chronic antibiotic administration often is necessary to control symptoms. Progression to chronic mastoiditis has been seen in several patients. Conductive hearing loss may result from the persistent infections.

Tonsillar and adenoidal hypertrophy may occur and reflect the generalized lymphoid hypertrophy that also manifests as lymphadenopathy and splenomegaly. Obstructive sleep apnea or chronic infection of these hypertrophied lymphoid tissues occasionally may occur. Some children develop a persistent hoarseness which, although at times related to laryngeal candidiasis, often has no identifiable etiology.20

Oral manifestations of HIV infection are common. Unusually severe or recalcitrant oral candidiasis (thrush) is one of the most frequent complications seen in HIV infection. Although less common in children than in adults with HIV infection, severe or recurrent aphthous ulcers are particularly unpleasant because of their painful nature and suppression of oral intake with subsequent nutritional compromise. Severe dental caries and periodontitis are significant dental complications, and children may require major restorative work performed under general anesthesia to control rampant decay and gum disease.20

Cervical adenopathy and parotid gland swelling are often noted. Tender parotitis may be the primary physical manifestation of HIV infection and at times is the primary indication for antiviral intervention. Parotitis also may be responsible for an elevation in serum amylase levels, and this must be differentiated from amylase elevation secondary to pancreatitis.20

Pulmonary Manifestations

Pulmonary complications of pediatric HIV infection may be categorized into infectious and noninfectious etiologies.21 Recurrent, lobar bacterial pneumonias may be seen in any child whose ability to generate protective antibodies is compromised. Causative organisms include S pneumoniae, hemolytic streptococci, and H influenzae type b. Mycoplasma pneumoniae may cause atypical pneumonia or a lobar pneumonia in older children, but also has been seen in HIVinfected children under 3 years of age with interstitial pneumonitis.

The classic opportunistic infection of HIV infection is Pneumocystis carinii pneumonia (PCP). This disorder is a diffuse, desquamative alveolopathy that results in compromised oxygenation. The clinical manifestations are age and immune status-dependent. Fever may be intermittent. Productive cough, exercise/ activity intolerance, dyspnea, and tachypnea are seen, but these symptoms may not be apparent early on in the infection. Cyanosis may be minimal or absent at rest. On physical examination, tachypnea, retractions, and expiratory grunt are typically seen in symptomatic children, although there is a notable absence of adventitious sounds on auscultation of the chest. Nonspecific laboratory investigations will reveal hypoxemia in all children with symptomatic PCP. Oxygen desaturation with exercise or a selectively elevated blood lactate dehydrogenase level are suggestive of PCP. A definitive diagnosis can only be made by proof of organisms in the lung by bronchoalveolar lavage 22 or open-lung biopsy. The treatment of acute PCP is generally initiated with trimethoprim-sulfamethoxazole and corticosteroids. Primary or secondary prophylaxis with trimethoprimsulfamethoxazole is highly effective in preventing PCP.

Many other organisms have been involved in the pulmonary disease associated with HIV infection in children. These have included a variety of viral agents, such as adenovirus, influenza A, parainfluenza, and respiratory syncytial vims. Measles vims can cause a devastating pneumonia in immunocompromised children, and prior immunization with measles vaccine does not guarantee protection in a child whose immune response to routine vaccines may not be adequate. Mycobacterium avium complex and increasingly Mycobacterium tuberculosis2*'2* also have been reported as causes of infectious pneumonias in pediatric HIV. Mycobacterium tuberculosis is of particular concern because of its communicability to health care workers, the emergence of multidrug-resistant organisms, and the failure of routine tuberculin skin tests to identify infected patients due to their underlying immune deficiency.

Reactive airway disease is common among children with immunodeficiency disorders. It is likely that their chronic airway inflammation associated with frequent or persistent infection results in inflammationinduced airway hyperreactivity. It is important to recognize this process because treatment is often simple and effective.

Lymphoid interstitial pneumonitis (LIP) is the most common noninfectious opportunistic pulmonary disease seen in pediatric HIV infection. Lymphoid interstitial pneumonitis is characterized by a diffuse infiltration of the alveolar and small airway walls with lymphocytes and plasma cells, and it is often associated with hypertrophy of the bronchialassociated lymphoid tissue. The primary infiltrating cells are CD8+ T-cells in HIV-associated LIP. The etiology of LIP is unclear, although possibly it represents an exaggerated immunologic response to HIVinfected cells in the lungs. Clinical symptoms of tachypnea, cough, dyspnea, and exercise intolerance are often subtle or unappreciated. Not infrequently, a miliary interstitial infiltrate is noted throughout the lung fields on radiograph, and the extensive pulmonary process appears out of proportion to the clinical symptoms. Clinical criteria have been used to make a diagnosis of lymphoid interstitial pneumonitis, although a definitive diagnosis can only be made with open- lung biopsy.

Other noninfectious pulmonary diseases seen in HIV include nonspecific pulmonary fibrosis and pulmonary hypertension and recurrent or severe aspiration pneumonitis as a complication of encephalopathy.

Cardiac Manifestations

Although rarely responsible for presenting signs or symptoms of HlV infection, cardiac abnormalities have been reported in a significant proportion of HIV-infected children.25 Although conductive abnormalities may be seen, dilated cardiomyopathy is the major heart manifestation seen in children. Human immunodeficiency virus alone appears to be able to initiate this process, although complicating infections and the use of anti-viral agents may exacerbate the disorder. Cardiomegaly seen on chest radiograph and reduced shortening fraction noted on echocardiogram may result from the cardiomyopathy, and overt congestive heart failure is the most serious clinical consequence.

Gastrointestinal and Hepatobiliary Manifestations

Candida esophagitis is an AIDS-defining condition. Manifested as dysphagia or painful swallowing, this process may not be associated with significant oral candidiasis, and a high degree of suspicion is necessary for proper diagnostic intervention. Reflux esophagitis, cytomegalovirus esophagitis, and aphthouslike esophageal ulcers may produce similar symptoms.

A host of infectious agents may be associated with enteritis or enterocolitis manifested as acute, chronic, or recurrent diarrhea.26 Salmonella, shigella, giardiasis, campylobacteriosis, and rotavirus may infect HIVinfected children as well as their normal counterparts. However, the severity and duration of symptoms may be worse in immunocompromised children, and response to therapy is less predictable and often incomplete. Mycobacterium avium complex, Cryptosporidium, cytomegalovirus, and adenovirus may all induce opportunistic enteropathy. Clostridium difficile colitis is a common problem in HIV-infected children because of the frequent use of systemic antibiotics in this population. Nonspecific HIV enteropathy may be due to overgrowth of normal gut flora secondary to local immunodeficiency and antibiotic use. Heavy growth of Candida albicans or Pseudomonas aeruginosa in stool cultures is often seen in these patients.

Human immunodeficiency virus may be associated with hepatic pathology and nonspecific elevation of liver function tests.27 Cytomegalovirus and hepatitis B virus may be associated with acute or chronic hepatitis in HIV-infected children who are at high risk for exposure to these viruses. Cholangitis and cholecystitis have been reported in adults with HIV disease and are likely to be seen in children as survival is prolonged. Cytomegalovirus and microsporidiosis have been identified as causes of biliary tract infection.

Pancreatitis manifested as acute or persistent midepigastric pain and elevation of serum amylase, lipase, and triglyceride levels may be caused by cytomegalovirus or may be induced by anti-viral therapy with DDI or zalcitabine or by anti-pneumocystic therapy with pentamidine.28

Endocrine and Skeletal Muscle Manifestations

Short stature and delayed puberty are known complications of HIV infection in children. Although a number of hormonal abnormalities including low growth hormone secretion29 have been described in HIV infection, these are inconsistent. Growth failure usually does not result from a recognized endocrine cause,30 and even in adults oven endocrine dysfunction is rare.31

Nonspecific myopathy and myositis have been reported in patients with HIV infection. As with cardiomyopathies, skeletal muscle disease may be related directly to HIV infection or to the use of antiviral agents such as ZDV.32

Rheumatic disorders have been reported in up to 1 1% of adults with HIV,33 and circulating immune complexes have been noted in up to 93% of children with HIV.34 However, classic rheumato logic disorders appear to be unusual in pediatric HIV infection.

Table

TABLE 4Diagnoses in 167 Children with AIDS-Defining Conditions*

TABLE 4

Diagnoses in 167 Children with AIDS-Defining Conditions*

Renal and Urogenital Manifestations

Human immunodeficiency vims-associated nephropathy has been described in a significant proportion of adults and perinatally- infected children.35,36 Primarily manifesting as nephrotic syndrome with edema and proteinuria, HIV-associated nephropathy is most often associated with focal and segmental glomerulosclerosis on histologic examination. Perhaps reflecting a mild form of this process, chronic low-grade proteinuria with or without hematuria is seen in some children.

Human immunodeficiency vims- infected adolescents who have engaged in high-risk sexual behaviors are likely to have been treated for multiple episodes of sexually transmitted diseases (STDs) prior to the diagnosis of HIV infection. Monitoring these youth for acquisition of new STDs is an essential component of their ongoing care.

Recurrent urinary tract infections may be seen in HIV-infected children37; however, the relationship of this problem to immune deficiency is unclear.

Hematologic Manifestations and Malignancies

Anemia, granulocytopenia, lymphopenia, and thrombocytopenia all occur frequently in HIV infection.38·39 Lymphopenia is usually a manifestation of progressive immune deficiency and generally is seen late in the course of a patient's disease. Thrombocytopenia may occur as a primary manifestation of HIV infection or secondary to drug treatment.

Patients may present with "idiopathic thrombocytopenic purpura" as the initial manifestation of HIV infection. Granulocytopenia usually occurs as a complication of antiviral or antibiotic drug treatment. Many of the drugs used in the treatment of HIV and its complications are additive in their bone marrow toxicity. For example, patients admitted to the hospital for the treatment of bacterial pneumonia may be treated with ZDV, trimethoprim-sulfamethoxazole (as PCP prophylaxis), and a third-generation cephalosporin. It is predictable that patients will become granulocytopenic within 1 to 2 weeks of this myelotoxic regimen. In contrast, monocytosis often is seen even when other blood elements are depressed. Macrocytic anemia is a universal complication of ZDV therapy, although iron deficiency and vitamin deficiencies may complicate this picture.

Acquired circulating anticoagulants as the cause for prolonged activated partial thromboplastin time have been reported in children with AIDS.40 These lupustype anticoagulants do not cause clinical manifestations of a bleeding disorder, although the coagulation abnormalities may be noted in patients being studied in preparation for surgical procedures.

Recognized as frequent complications of HIV in adults, malignancies are seen in a significant number of children infected with HIV through transfusions or perinatal exposure.41 Lymphoid malignancies, including non-Hodgkin's, central nervous system, and gastrointestinal tract lymphomas are seen in children and affect an estimated 3% of patients. Children appear less susceptible to Kaposi's sarcoma, although a small number of pediatric cases have been reported. In contrast, children seem uniquely prone to tumors of smooth muscle origin, leiomyoma and leiomyosarcoma.42 Both Kaposi's sarcoma and these smooth muscle tumors may not represent tme malignancies; rather they may reflect local tissue responses to inappropriate levels of HIV-induced growth factors.

Table 4 places in perspective the most common diagnoses in children with AIDS-defining conditions as identified through the County of Los Angeles Department of Health Services Pediatric AIDS Surveillance Study. Similar information is provided in Table 5, which lists the signs and symptoms seen in symptomatic HIV children who have not developed an AIDS-defining condition.

Immunologic Features of HIV Infection

An overwhelming number of studies have examined various aspects of immunologic function in HIV infection in children43 and adults.44 Immunological tests of direct clinical utility include examination of CD4 + helper T-cell numbers,45,46 p24 antigenemia,7 specific antibody responses to routine immunizing agents,47 and evaluation of immunologic activation with sedimentation rate,48 ß2 microglobulin levels,49 or neopterin levels.50 Each of these measurements have been used as a surrogate marker of HIV disease activity in adults and children, and these measures have proven helpful in identifying individuals in whom antiviral intervention is indicated or prophylactic antibiotics initiated.51 Elevation of serum immunoglobulin levels with IgG or IgA often three to four times the upper limit of normal for age is a common feature of HIV infection. Despite these increased levels, patients often tail to generate protective levels of antigen-specific antibody following routine infections or immunizations. This "dysgammaglobulinemia" is a reasonable indication for intravenous immunoglobulin therapy.

Table

TABLESSelected Clinical Findings in 1 48 Symptomatic (Non-AIDS) HIV-infected Children

TABLES

Selected Clinical Findings in 1 48 Symptomatic (Non-AIDS) HIV-infected Children

THE DIAGNOSTIC CHALLENGE OF A CHILD BORN TO AN HIV-INFECTED MOTHER

The indications for HIV testing in symptomatic and asymptomatic children are listed in Table 6. Once a decision to test is made, an understanding of the sensitivity and specificity of the available assays is essential.52 Clinically available HIV antibody assays, including enzyme-linked immunosorbent assay (ELISA) and Western blot assay, detect primarily IgG antibodies with a very high degree of sensitivity. In adult patients, these assays are also highly specific. Although sensitive and specific in detecting the presence of IgG antibodies in children born to HIVinfected mothers, these assays produce a high rate of false positivity for actual HIV infection because of the transplacental passage of IgG antibodies from mother to infant. Approximately 80% of babies born to HIV-infected mothers in the United States will not be infected with the virus, although they will test positive with antibody assays. To circumvent the presence of confounding maternal IgG antibodies, two alternative methods for detecting infant-specific HIV antibodies have been evaluated: in vitro production of virus-specific antibodies by patients' lymphocytes53·54 and detection of patient-specific IgA antibodies to HIV in serum55,56 or saliva.57 Although potentially useful, these methods are not routinely available or standardized.

Table

TABLE 6lndications for HIV Testing in Children

TABLE 6

lndications for HIV Testing in Children

Human immunodeficiency virus p24 antigen detection is a useful and highly specific test for the presence of HIV. Unfortunately, the sensitivity of the assay is limited due to the complexing of HIV antigen with passively transferred maternal antibodies. Recently, it was shown that by dissociating these HIV p24 antigencontaining complexes, the sensitivity of this procedure can be markedly enhanced.58

Currently, direct culture for HIV and polymerase chain reaction for identification of HIV-specific nucleic acid sequences are the methods of choice for detecting virus in peripheral blood.59'61 In experienced laboratories, both of these assays appear to be highly sensitive and specific and have predictive values of over 90% in infants greater than one month of age. Although false negative tests may be seen and false positive results have been reported, the increasing availability and reliability of these assays for routine diagnosis has reduced dependence upon nonspecific and insensitive measures such as serial assessment of HIV antibody levels.

BREAST-FEEDING

A number of well-described cases indicate that HlV may be transmitted through breast-feeding.62 Despite these individual reports, the impact of breastfeeding on the overall rate of HIV transmission from mother to infant has not been settled. At least two studies have suggested that the rate of HIV transmission was not affected by breast-feeding.63,64 Other data siipcesr rbaf a 14% increase in the rate may be attributable to breast-feeding,65 and this rate may be strikingly increased in situations where breast-feeding mothers are acutely infected with HIV during the postnatal period.66 At the present time, in developed countries where safe alternatives are available, it is recommended that HIV-infected mothers should not breast-feed their infants.62

HIV INFECTION CONTROL

Effective prevention of nosocomial and occupational HIV infection is readily achievable.67 The strategy of universal precautions focuses attention on specific types of potentially infected body fluids rather than on the individual patients labeled as "HIV positive" or "blood and body fluid precautions." The guiding principle of universal precautions is the protection from sharps injury or mucous membrane contamination with selected body fluids, including blood, genital secretions, cerebrospinal fluid, or body fluids likely to be contaminated with blood, such as pericardial and pleural fluid. Except in instances where visible blood contamination is apparent, specific barrier protection is not indicated for other body fluids such as feces, urine, vomitus, nasal secretions, saliva, and sweat. Particular attention must be focused upon prevention of needlestick and other sharps injuries with instruments contaminated with blood or bloody body fluids. Prospective studies of seroconversion following percutaneous injuries with HIVcontaminated instruments indicate that HIV transmission occurs approximately once in 250 to 500 injuries with HIV-contaminated sharps.

Selective use should be made of face masks, gowns, gloves, and protective eyewear depending on the nature of the potential exposures to prevent blood or bloody body fluid contact with mucous membranes. There is no significant risk of HIV transmission in the standard setting of a routine medical examination. Careful handwashing is indicated for all patients to avoid the spread of other infectious agents, and hepatitis B vaccination is recommended for all healthcare workers.

Extending these concepts, the American Academy of Pediatrics has published specific guidelines addressing the issues of the HIV-infected child in day care and foster care.68

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TABLE 1

Definition of HIV Infection in Children

TABLE 2

Classification of HIV Infection in Children Under 1 3 Years of Age

TABLE 3

Potential Mechanisms of CD4+ T-CeII Depletion and Dysfunction

TABLE 4

Diagnoses in 167 Children with AIDS-Defining Conditions*

TABLES

Selected Clinical Findings in 1 48 Symptomatic (Non-AIDS) HIV-infected Children

TABLE 6

lndications for HIV Testing in Children

10.3928/0090-4481-19930701-08

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