PEDIATRIC AIDS AND HIV INFECTION
Most children with AIDS in the United States are infected perinatally. Intravenous (IV) drug abuse and sexual contact with HIV-infected partners are the maternal risk factors in nearly all perinatal cases. Mother-to-child HIV transmission rates have dropped below 2% with the use of highly active antiretroviral drugs treatment (HAART) during pregnancy from a rate of 25% without prophylaxis. In the United States, 166 children younger than the age of 13 years were diagnosed with HIV in 2009, 13 of whom were diagnosed with AIDS. In contrast, among older children (older than age 13 years), the incidence of HIV infection continues to rise mostly in boys as a result of male-to-male sexual transmission. Racial and ethnic minority children are disproportionately affected by perinatal HIV infection accounting in 2009 for 90% of HIV infections. Most infections occur in the last trimester of pregnancy and at the time of delivery. Risk factors for vertical transmission are recent maternal HIV seroconversion, high viral burden, and maternal AIDS. Premature infants are also at increased risk of infection. Infection may result from exposure to blood and other body fluids at delivery. Breastfeeding is, thus, not recommended in the United States; cesarean section is not routinely recommended unless maternal viral burden is high.
Determining transmission of HIV infection to offspring based on detection of HIV antibody has been replaced by infant HIV polymerase chain reaction (PCR). Further, maternal HIV infection status is no longer required to determine infant HIV infection status. The Centers for Disease Control and Prevention (CDC) surveillance definition states a child is considered definitively infected if he or she has positive virologic results on two separate specimens or is aged older than 18 months and has either a positive virologic test or a positive confirmed HIV antibody test. HIV-seropositive children who do not meet these criteria are considered perinatally exposed and later seroreverters when antibodies turn negative. The 1994 clinical classification system for confirmed cases of HIV infection in children has been replaced by a five staging system that applies to both adults and children: 0, 1, 2, 3, or unknown. Stage 0 corresponds to early infection as noted by a negative HIV test within 6 months of HIV diagnosis. Stages 1 to 3 are classified immunologically (absolute CD4 count or percent CD4 count) depending on the child’s age (younger than 12 months, 1 to 5 years, and older than 6 years): stage 1, no evidence of immune suppression; stage 2, moderate immune suppression; and stage 3, severe immune suppression (either a low CD4 count or whether an opportunistic illness was diagnosed) (Table 147.1
). T-cell counts in infants and toddlers are higher for a specific immune category and reach adult levels after age 6 years.
TABLE 147.1 Infection Stage Based on Age-Specific CD4+ T-lymphocytes Count or Age-Specific CD4+ T-lymphocyte Percentage of Total Lymphocytes
No evidence of suppression
Adapted from Selik RM, Mokotoff, ED, Branson B, et al. Revised surveillance case definition for HIV infection—United States, 2014. MMWR Morb Mortal Wkly Rep. 2014;63:1-10.
Because of early testing, most HIV-positive children are identified soon after birth, especially in States with universal perinatal screening. HIV DNA PCR is the preferred diagnostic method, whereas quantitative HIV RNA PCR is more sensitive in determining plasma concentration (copies/mL) of HIV RNA, commonly referred to as plasma viral load. By age 6 months, 100% of HIV-infected children are identified by a positive PCR. In newborns, a negative PCR test for HIV does not exclude infection but decreases the risk of HIV infection to 3%. Viral load runs higher in asymptomatic children than in asymptomatic adults. Sustained high viral load and low CD4 count predict progression to AIDS. High viral loads in early infancy predict early onset of symptomatic HIV disease. In the post-HAART era, most progression to AIDS is related to nonadherence to HAART of any cause (i.e., medical or social), which in turn facilitates development of drug resistance. HIV-1 syncytial-inducing phenotypes are linked to aggressive early symptomatic disease.
Mild HIV infection includes diarrhea, unexplained persistent fever, lymphadenopathy, and parotitis. Lymphoid interstitial pneumonitis and recurrent bacterial infections are seen in HIV-infected children but not in infected adults. Prior to the advent of antiretroviral therapy, severe manifestations in early infancy, such as progressive encephalopathy or opportunistic infections (e.g., Pneumocystis carinii), carried a poor prognosis for survival but with effective antiretroviral therapy, these disorders are compatible with survival to adulthood.
MECHANISM OF ACTION
HIV infection is maintained by viral persistence in helper T lymphocytes and macrophages. HIV strains with tropism for monocytederived macrophages have a predilection to infect cerebral vascular endothelium and the central nervous system (CNS). Infected macrophages traverse the blood-brain barrier and infect microglial cells; astrocytes are infected nonproductively, whereas neurons are spared from direct infestation. Neuronal dropout is seen as the disease advances, but it is not known how HIV induces neural damage. Postulated mechanisms include release of soluble neurotoxins by HIV-infected macrophages and lymphocytes (e.g., cytokines, quinolinic acid, viral antigens, or undefined viral products), neurotoxin amplification by astrocyte-macrophage interaction, and impaired blood-brain barrier function secondary to HIV-related endothelial damage. Nonproductive infection of a portion of astrocytes is reported to amplify bystander neurotoxicity. These neurotoxins are thought to produce a reversible metabolic encephalopathy that may disappear with effective antiretroviral treatment.
Glial nodules and endothelial hyperplasia with calcification, dystrophic calcification, and perivascular mononuclear inflammation are common pathologic findings of subacute encephalitis in HIV-infected brains. The glial nodule comprises a cluster of chronic inflammatory cells in the neuropil and is often associated with multinucleated giant cells that are presumed to arise from coalescent microglia.
Two types of encephalopathy are seen in children: progressive and static. The evolution of the progressive encephalopathy may be fulminant, inexorably progressive, or stepwise. Progressive encephalopathy is characterized by loss of developmental milestones, progressive pyramidal tract dysfunction, and acquired microcephaly or impaired brain growth. The static encephalopathy is less well defined and may not be related to direct HIV CNS disease.
The neurologic abnormalities commonly include abnormalities of muscle tone, hyperreflexia, clonus, and impaired head growth. Hypotonia with corticospinal tract dysfunction may be seen in infants early in the course of the encephalopathy and evolves into a spastic diparesis; with newer antiretroviral treatments, progression to a spastic tetraparesis, with or without pseudobulbar palsy, is seldom seen. Ataxia and rigidity are uncommon. Prior to HAART, progressive neurologic dysfunction was the first evidence of progression to AIDS in 10% of infected children. In young children, early presentation may mimic a leukodystrophy. At the time of onset of neurologic symptoms, there is always evidence of underlying HIV infection, such as immunologic compromise (low CD4 counts) or high viral load. Many infected children exhibit global developmental delay, regardless of neurologic findings.
The rate of neurologic abnormalities reported in HIV-infected cohorts before the advent of antiretroviral treatments was 15% to 30%. The incidence of progressive HIV encephalopathy in 2000 was less than 2% in the cohort followed. Children most at risk are those who have recovered from HIV encephalopathy. Older HIV-infected children may show problems in visual-spatial processing functions and expressive language and may develop AIDS dementia complex indistinguishable from that described in adults. Children with HIV encephalopathy who respond to antiretroviral therapy may show reversal of microcephaly and cognitive impairments. The most frequent sequelae of “arrested” HIV encephalopathy are learning difficulty and nonprogressive mild spastic diparesis.
HIV-associated myelopathy, polyneuropathy, and myopathy are rare in children. Spinal cord pathology may show demyelinating changes of the corticospinal tracts, vacuolar changes, or myelitis attributable to HIV or other virus. Acute inflammatory demyelinating polyneuropathy is a rare complication in pediatric HIV.
HIV brain infection is nonfocal and subcortical. Seizures are not common. Focal signs or seizures raise the possibility of neoplasm, strokes, or, less likely, opportunistic infections.
Primary Central Nervous System Lymphoma
Rates of CNS lymphoma have decreased since the advent of HAART from an incidence ratio (IR; HIV-infected children/uninfected children) of 1,994 down to an IR of 1,088. CNS lymphoma is still the most common cause of focal cerebral signs in HIV-infected children (see also Chapter 99
). It is often multifocal, and seizures are reported in about 33% of patients. It may be difficult to differentiate this tumor from a toxoplasmic brain abscess by neuroimaging, but a positive PCR for Epstein-Barr virus (EBV) in cerebrospinal fluid (CSF) is highly suggestive of CNS lymphoma. Thallium single-photon emission computed tomography (SPECT) and magnetic resonance (MR) spectroscopy may prove helpful in distinguishing CNS toxoplasmosis from lymphoma (Table 147.2
). Diagnostic confirmation may require brain biopsy.
Untreated HIV infection produces inflammation of cerebral vessels, increasing the risk of stroke, which occurred at a rate of 1.3% a year in symptomatic HIV-infected children. More than 50% of strokes were hemorrhagic and occurred with thrombocytopenia (especially immune thrombocytopenic purpura) or CNS neoplasia. Nonhemorrhagic stroke and subarachnoid hemorrhage are attributed to an arteriopathy of large vessels in the circle of Willis (fusiform aneurysms) or meninges (Fig. 147.1
). HIV-related strokes may be clinically silent, so the true incidence is probably higher. In cases of stroke, varicella-zoster virus (VZV) should be excluded as the etiologic agent by CSF PCR, especially when small intracranial vessels are involved. Ocular involvement should be excluded by pupillary dilatation for ophthalmologic assessment. Any vasculopathy in an HIV-infected patient is presumed to be infectious (from either HIV
or VZV) and should be treated with appropriate antiretroviral and antiviral medication.
TABLE 147.2 Distinguishing Features between Central Nervous System Lymphoma and Toxoplasmosis Abscess
Distribution of lesion
Often solitary, subependymal spread
Typically multifocal, basal ganglia or corticomedullary junction
Often ring or nodular
Increased choline peak
Decreased choline peak
MR, magnetic resonance; rCBV, relative cerebral blood volume; SPECT, single-photon emission computed tomography (thallium); MRS, magnetic resonance spectroscopy.
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