Advances in research and major improvements in the treatment and management of HIV infection have brought about a substantial decrease in the incidence of new HIV infections and AIDS in children born in the United States and Western Europe. Most HIV-infected children are born in developing countries. It is estimated that in 2004, 640,000 children <15>
ETIOLOGY.
HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. The HIV-1 genome contains 2 copies of single-stranded RNA that is 9.2 kb in size. At both ends of the genome there are identical regions, called long terminal repeats, which contain the regulation and expression genes of HIV. The remainder of the genome includes 3 major sections: the GAG region, which encodes the viral core proteins (p24, p17, p9, p6, which are derived from the precursor p55); the POL region, which encodes the viral enzymes (i.e., reverse transcriptase [p51], protease [pl0], and integrase [p32]); and the ENV region, which encodes the viral envelope proteins (gp120 and gp41, which are derived from the precursor gp160). Other regulatory proteins, such as tat (pl4), rev (p19), nef (p27), vpr (pl5), and vif (p23), are involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest, promotion of nuclear import of viral reverse transcription complexes, downregulation of cell surface receptors CD4 and class I major histocompatibility complex, proviral DNA synthesis, and virus release ( Fig. 1 ).
Figure 1 The human immunodeficiency virus and associated proteins and their functions
The major external viral protein of HIV-1 is a heavily glycosylated gp120 protein that is associated with the transmembrane glycoprotein gp41; gp41 is very immunogenic and is used to detect HIV-1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface receptor of T lymphocytes. This tropism for CD4+ T cells is beneficial to the virus because it reduces the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. Several chemokines serve as co-receptors for the envelope glycoproteins, permitting membrane fusion and entry into the cell. Most HIV strains have a specific tropism for 1 of the chemokines, including the fusion-inducing molecule CXCR-4, which has been shown to act as a co-receptor for HIV attachment to lymphocytes, and CCR-5, a β chemokine receptor that facilitates HIV entry into macrophages. Several other chemokine receptors (CCR-3) have also been shown in vitro to serve as virus co-receptors.
Other mechanisms of attachment of HIV to cells use non-neutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell surface receptors, such as mannose-binding protein on macrophages and DC-specific C-type lectin (DC-SIGN) on dendritic cells, also bind to the HIV-1 envelope glycoprotein and increase the efficiency of viral infectivity. Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, and gp41 interacts with the fusion receptor on the cell surface. Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves accessory viral proteins (nef, vif) and binding of cyclophilin A (a host cellular protein) to p24. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, and duplication of the DNA copies produces double-stranded circular DNA. The HIV-1 reverse transcriptase is error prone and lacks error-correcting mechanisms. Thus, many mutations arise, creating wide genetic variation in HIV-1 isolates even within an individual patient. The circular DNA is transported into the cell nucleus, where it is integrated into chromosomal DNA and referred to as the provirus. The provirus has the advantage of latency as it can remain dormant for extended periods. Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other pathogens) and cellular activation. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which in turn leads to production of viral proteins necessary for viral assembly.
HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce, among others, the virus-specific protease (p10). This enzyme is critical for HIV-1 assembly. Several HIV-1 antiprotease drugs have been developed, targeting the increased sensitivity of the viral protease, which differs from the cellular proteases. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (p17). As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released.
The diversity of HIV (groups M [main], O [outlier], N [non-M, non-O]) probably occurred from multiple zoonotic infections from primates in different geographic regions. Group M diversified to several subtypes (or clades A to H). In each region of the world, certain clades predominate. For example, clade B is found in the United States and South America, clade E in Thailand, and clade C in South Africa. Clades are mixed in some patients due to HIV recombination, and some crossing between groups (i.e., M and O) has been reported.
HIV-2 is known to cause infection in several monkey species. It is a rare cause of infection in children. It is most prevalent in Western Africa, but recently cases from Europe and Southern Asia have been reported. The diagnosis of HIV-2 infection is more difficult because the standard confirmatory assays (immunoblot) are HIV-1 specific and may give indeterminate results with HIV-2 infection. If HIV-2 infection is suspected, a specific immunoblot test that detects antibody to HIV-2 peptides should be used. In addition, the recently approved rapid tests should not be used in patients suspected to be HIV-2 infected because they test only for HIV-1. Third generation standard enzyme-linked immunosorbent assays (ELISA) should be used because they capture both HIV-1 and HIV-2.
EPIDEMIOLOGY. The World Health Organization (WHO) estimated that >39 million persons worldwide were living with HIV infection at the end of 2004, including 2.2 million children <15>500,000 and 9% in metropolitan areas with populations of 50,000–500,000.
Although adolescents (13–24 yr of age) with AIDS represent a minority of U.S. cases (approximately 5%), they constitute 1 of the fastest growing groups of newly infected persons in the country. Considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data severely under-represents the impact of the disease in adolescents. Based on a median incubation period of 8–12 yr, it has been estimated that 15–20% of all AIDS cases were acquired between 13 and 19 yr of age. Risk factors for HIV infection vary by gender in adolescents. The majority of teenaged males with AIDS who acquired HIV through sexual contact had male-to-male transmission. In contrast, more than half of adolescent females with AIDS were infected through heterosexual contact and ⅙ through IDU, compared with 8% and 6%, respectively, in teenaged males.
As in the pediatric population, adolescent racial and ethnic minority populations are over-represented, especially among females. In addition, a greater proportion of female adolescents have AIDS (male : female ratio 1.2 : 1) than do female adults >25 yr of age (male : female ratio 4.5 : 1).
Transmission. Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission, accounting for almost all new cases. Rates of transmission of HIV from mother to child have varied in different parts of the United States and among countries. The United States and Europe have documented transmission rates in untreated women between 12–30%. Transmission rates in Africa and Haiti are higher (25–52%). Perinatal treatment of HIV-infected mothers with anti-retroviral drugs has dramatically decreased these rates to <2%>4 hr duration of ruptured membranes and birthweight <2,500>50,000 copies/mL), some transmitting mothers in each group were asymptomatic or had a low, but detectable, viral load. Thus, in the USA it is recommended to consider cesarean section if the viral load is >1,000 copies/mL.
Transfusions of infected blood or blood products have accounted for 3–6% of all pediatric AIDS cases. The period of highest risk was between 1978 and 1985, before the availability of HIV antibody-screened blood products. Whereas the prevalence of HIV infection in individuals with hemophilia treated before 1985 was as high as 70%, heat treatment of factor VIII concentrate and HIV antibody screening of donors has virtually eliminated HIV transmission in this population. Blood donor screening has dramatically reduced, but not eliminated, the risk for transfusion-associated HIV infection. The rate of HIV transmission through antibody-screened blood in the USA is estimated to be approximately 1/60,000 transfused units. In many developing countries, screening of blood donors is not uniform, and the risk for transmitting HIV infection via transfusion is substantial.
Although HIV can be isolated rarely from saliva, it is in very low titers
PATHOGENESIS. When the mucosa serves as the portal of entry for the HIV, the 1st cells to be infected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transports them to the lymphoid tissue. HIV does not infect the dendritic cell but it binds to its DC-SIGN surface molecule, which allows the virus to survive until it reaches the lymphatic tissue. In the lymph node, the virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T 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. Additional factors (co-receptors) are necessary for HIV fusion and entry into cells. These factors include the chemokines CXCR4 (fusion) and CCR5. Other chemokines (CCR1, CCR3) may be necessary for the fusion of certain HIV strains. Individuals with homozygous CCR5 deletion mutation are highly protected from HIV infection. Usually, CD4 lymphocytes, recruited to respond to viral antigen, migrate to the lymph nodes where they become activated and proliferate, making them highly susceptible to HIV infection. This antigen-driven migration and accumulation of CD4 cells within the lymphoid tissue may contribute to the generalized lymphadenopathy characteristic of the acute retroviral syndrome in adults and adolescents. HIV preferentially infects the very cells that respond to it (HIV-specific memory CD4 cells), which accounts for the progressive loss of these cells' response and the subsequent loss of control of HIV replication. When HIV replication reaches a threshold (usually within 3–6 wk from the time of infection), a burst of plasma viremia occurs. This intense viremia causes flulike symptoms (fever, rash, lymphadenopathy, arthralgia) in 50–70% of infected adults. With establishment of a cellular and humoral immune response within 2–4 mo, the viral load in the blood declines substantially, and patients enter a phase characterized by a lack of symptoms and a return of CD4 cells to only moderately decreased levels.
Early HIV-1 replication in children has no apparent clinical manifestations. Whether tested by virus isolation or by PCR for viral nucleic acid sequences, fewer than 50% of HIV-1-infected infants demonstrate evidence of the virus at birth. The virus load increases by 1–4 mo, and almost all HIV-infected infants have detectable HIV-1 in peripheral blood by 4 mo of age.
In adults, the long period of clinical latency (up to 8–12 yr) is not indicative of viral latency. In fact, there is a very high turnover of virus and CD4 lymphocytes (more than a billion cells per day), which gradually causes deterioration of the immune system, evidenced particularly by depletion of CD4 cells. Several mechanisms for the depletion of CD4 cells in adults and children have been suggested, including HIV-mediated single cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus-specific immune responses (natural killer cells, antibody-dependent cellular cytotoxicity), superantigen-mediated activation of T cells (rendering them more susceptible to infection with HIV), autoimmunity, and programmed cell death (apoptosis). The viral burden in the lymphoid organs is greater than that in the peripheral blood during the asymptomatic period. As HIV virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. 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 infected productively yet resist killing, explains their role as reservoirs of HIV and as effectors of tissue damage in organs such as the brain.
Cell-mediated and humoral responses occur early in the infection. CD8 T cells play an important role in containing the infection. These cells produce various ligands (MIP-1α, MIP-1β, RANTES), which suppress HIV replication by blocking the binding of the virus to the co-receptors (CCR5). HIV-specific cytotoxic T lymphocytes (CTLs) develop against both the structural (ENV, POL, GAG) and regulatory (tat) viral proteins. The CTLs appear at the end of the acute retroviral infection as the viral replication is controlled by killing HIV-infected cells before new viruses are produced and by secreting potent antiviral factors that compete with the virus for its receptors (CCR5). Neutralizing antibodies appear later during the infection and seem to help in the continued suppression of viral replication during clinical latency. There are at least 2 possible mechanisms that control the steady-state viral load level during the chronic clinical latency. One mechanism may be the limited availability of activated CD4 cells, which prevent further increase in viral load due to a set point (controlled) replication. The other mechanism, the immune control, suggests that the development of an active immune response (whose magnitude is controlled by the amount of viral antigen) limits viral replication at a steady state. There is no general consensus about which of these 2 mechanisms is more important. The CD4 cell limitation mechanism accounts for the effect of anti-retroviral therapy, whereas the immune control mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of the immune response, which, in turn, slows disease progression.
A group of cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, interleukin 1 (IL-1), IL-2, IL-3, IL-6, IL-8, IL-12, IL-15, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor, play an integral role in upregulating HIV expression from a state of quiescent infection to active viral replication. Other cytokines, such as interferon-γ (IFN-γ), IFN-β, and IL-13, exert a suppressive effect on HIV replication. Certain cytokines (IL-4, IL-10, IFN-γ, TGF-β) reduce or enhance viral replication depending on the infected cell type. The interactions among these cytokines influence the concentration of viral particles in the tissues. Plasma concentrations of cytokines need not be elevated for them to exert their effect, because 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.
Commonly HIV isolated during the clinical latency period grows slowly in culture and produces low titers of reverse transcriptase. These isolates are called non-syncytium-inducing (NSI) viruses, which use CCR5 as their co-receptor. By the late stages of clinical latency, the isolated virus is phenotypically different. It grows rapidly and to high titers in culture and it uses CXCR4 as its co-receptor. These isolates are called syncytium-inducing (SI) viruses. The switch from NSI to SI increases the capacity of the virus to replicate, to infect a broader range of target cells (CXCR4 is more widely expressed on resting and activated immune cells), and to kill T cells more rapidly and efficiently. As a result, the clinical latency phase is over and progression toward AIDS is noted. 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 high levels of viremia and an increased disappearance of CD4 T cells during the later stages of disease.
Before HAART was available, 3 distinct patterns of disease were described in children. Approximately 15–25% of HIV-infected newborns in developed countries present with a rapid disease course, with onset of AIDS and symptoms during the 1st few months of life and, if untreated, a median survival time of 6–9 mo. In resource-poor countries, the majority of HIV-infected newborns will have this rapidly progressing disease. 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. Most children in this group have a positive HIV-1 culture and/or detectable virus in the plasma (median level 11,000 copies/mL) in the 1st 48 hr of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases and peaks by 2–3 mo of age (median 750,000 copies/mL) and subsequently declines slowly. In contrast to the viral load in adults, the viral load in infants stays high for at least the 1st 2 yrs of life.
The majority of perinatally infected newborns (60–80%) in developed countries present with a 2nd pattern, that of a much slower progression of disease, with a median survival time of 6 yr. Many patients in this group have a negative viral culture or PCR in the 1st wk of life and are therefore considered to be infected intrapartum. In a typical patient, the viral load rapidly increases by 2–3 mo of age (median 100,000 copies/mL) and slowly declines over a period of 24 mo. The slow decline in viral load is in sharp contrast to the rapid decline after primary infection seen in adults. This observation can be explained only partially by the immaturity of the immune system in newborns and infants.
The 3rd pattern of disease (long-term survivors) occurs in a small percentage (<5%) style="font-weight: bold; color: rgb(204, 0, 0);">CLINICAL MANIFESTATIONS.
The clinical manifestations of HIV infection vary widely among infants, children, and adolescents. In most infants, physical examination at birth is normal. Initial symptoms may be subtle, such as lymphadenopathy and hepatosplenomegaly, or nonspecific, such as failure to thrive, chronic or recurrent diarrhea, interstitial pneumonia, or oral thrush, and may be distinguishable only by their persistence. Whereas systemic and pulmonary findings are common in the USA and Europe, chronic diarrhea, wasting, and severe malnutrition predominate in Africa. Symptoms found more commonly in children than adults with HIV infection include recurrent bacterial infections, chronic parotid swelling, lymphocytic interstitial pneumonitis (LIP), and early onset of progressive neurologic deterioration.
The HIV classification system is used to categorize the stage of pediatric disease by using 2 parameters: clinical status and degree of immunologic impairment ( Table 1 ). Among the clinical categories, category A (mild symptoms) includes children with at least 2 mild symptoms such as lymphadenopathy, parotitis, hepatomegaly, splenomegaly, dermatitis, and recurrent or persistent sinusitis or otitis media ( Table 2 ). Category B (moderate symptoms) includes, for example, children with LIP, oropharyngeal thrush persisting for >2 mo, recurrent or chronic diarrhea, persistent fever for >1 mo, hepatitis, recurrent herpes simplex virus (HSV) stomatitis or HSV esophagitis or pneumonitis, disseminated varicella (i.e., with visceral involvement), cardiomegaly, or nephropathy (see Table 2 ). Category C (severe symptoms) includes, for example, children with 2 serious bacterial infections (sepsis, meningitis, pneumonia) in a 2 yr period, esophageal or lower respiratory tract candidiasis, cryptococcosis, cryptosporidiosis (>1 mo), encephalopathy, malignancies, disseminated mycobacterial infection, Pneumocystis pneumonia, cerebral toxoplasmosis (onset >1 mo of age), and severe weight loss.
The immune classification is based on the absolute CD4 lymphocyte count or the percentage of CD4 cells (see Table 1 ). Age adjustment of the absolute CD4 count is necessary because counts that are relatively high in normal infants decline steadily until 6 yr of age, when they reach adult norms. If there is a discrepancy between the CD4 count and percentage, the disease is classified into the more severe category.
TABLE 1 -- Pediatric HIV Classification for Children Younger Than 13 Years
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| IMMUNOLOGIC CATEGORIES |
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| AGE-SPECIFIC CD4+ T-LYMPHOCYTE COUNT PERCENTAGE OF TOTAL LYMPHOCYTES[*] | CLINICAL CLASSIFICATIONS[†] |
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| <12> | 1–5 yr | 6–12 yr |
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| IMMUNOLOGIC DEFINITIONS | μ | % | μ | % | μ | % | N* | A* | B*[‡] | C*[‡] |
| 1: No evidence of suppression | ≥1500 | ≥25 | ≥1000 | ≥25 | ≥500 | ≥25 | N1 | A1 | B1 | C1 |
| 2: Evidence of moderate suppression | 750–1499 | 15–24 | 500–999 | 15–24 | 200–499 | 15–24 | N2 | A2 | B1 | C2 |
| 3: Severe suppression | <750 | <15 | <500 | <15 | <200 | <15 | N3 | A3 | B3 | C3 |
*N : No sign or symptom, A : Mild signs or symptoms, B : Moderate Signs or symptoms, C : Severe signs or symptoms
Modified from the Centers for Disease Control and Prevention: 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: Human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM.MMWR Recomm Rep 1994;43(RR-12):1–19. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 382.
TABLE 2 -- Clinical Categories for Children Younger Than 13 Years of Age with HIV infection
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| CATEGORY N: NOT SYMPTOMATIC | |
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| Children who have no signs or symptoms considered to be the result of HIV infection or have only 1 of the conditions listed in category A. | |
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| CATEGORY A: MILDLY SYMPTOMATIC | |
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| Children with 2 or more of the conditions listed but none of the conditions listed in categories B and C. | |
| • | Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral at 1 site) | |
| • | Hepatomegaly | |
| • | Splenomegaly | |
| • | Dermatitis | |
| • | Parotitis | |
| • | Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media | |
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| CATEGORY B: MODERATELY SYMPTOMATIC | |
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| Children who have symptomatic conditions other than those listed for category A or C that are attributed to HIV infection. | |
| • | Anemia (hemoglobin <8> | |
| • | Bacterial meningitis, pneumonia, or sepsis (single episode) | |
| • | Candidiasis, oropharyngeal (thrush), persisting (>2 mo) in children older than 6 mo of age | |
| • | Cardiomyopathy | |
| • | Cytomegalovirus infection, with onset before 1 mo of age | |
| • | Diarrhea, recurrent or chronic | |
| • | Hepatitis | |
| • | Herpes simplex virus (HSV) stomatitis, recurrent (>2 episodes within 1 year) | |
| • | HSV bronchitis, pneumonitis, or esophagitis with onset before 1 mo of age | |
| • | Herpes zoster (shingles) involving at least 2 distinct episodes or more than 1 dermatome | |
| • | Leiomyosarcoma | |
| • | Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex | |
| • | Nephropathy | |
| • | Nocardiosis | |
| • | Persistent fever (lasting >1 mo) | |
| • | Toxoplasmosis, onset before 1 mo of age | |
| • | Varicella, disseminated (complicated chickenpox) | |
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| CATEGORY C: SEVERELY SYMPTOMATIC | |
| • | Serious bacterial infections, multiple or recurrent (i.e. any combination of at least 2 culture-confirmed infections within a 2 yr period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections) | |
| • | Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs) | |
| • | Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes) | |
| • | Cryptococcosis, extrapulmonary | |
| • | Cryptosporidiosis or isosporiasis with diarrhea persisting >1 mo | |
| • | Cytomegalovirus disease with onset of symptoms after 1 mo of age (at a site other than liver, spleen, or lymph nodes) | |
| • | Encephalopathy (at least 1 of the following progressive findings present for at least 2 mo in the absence of a concurrent illness other than HIV infection that could explain the .ndings): (1) failure to attain or loss of developmental milestones or loss of intellectual ability, veri.ed by standard developmental scale or neuropsychologic tests; (2) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by CT or MRI (serial imaging required for children younger than 2 yr of age); or (3) acquired symmetric motor deficit manifested by 2 or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance | |
| • | HSV infection causing a mucocutaneous ulcer that persists for greater than 1 mo or bronchitis, pneumonitis or esophagitis for any duration affecting a child older than 1 mo of age | |
| • | Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes) | |
| • | Kaposi sarcoma | |
| • | Lymphoma, primary, in brain | |
| • | Lymphoma, small, noncleaved cell (Burkitt), or immunoblastic; or large-cell lymphoma of B-lymphocyte or unknown immunologic phenotype | |
| • | Mycobacterium tuberculosis infection, disseminated or extrapulmonary | |
| • | Mycobacterium, other species or unidenti.ed species infection, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes) | |
| • | Pneumocystis jiroveci pneumonia | |
| • | Progressive multifocal leukoencephalopathy | |
| • | Salmonella (nontyphoid) septicemia, recurrent | |
| • | Toxoplasmosis of the brain with onset at after 1 mo of age | |
| • | Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following .ndings: (1) persistent weight loss >10% of baseline; (2) downward crossing of at least 2 of the following percentile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child 1 yr of age or older; OR (3) <5th>30 days); OR (2) documented fever (for >30 days, intermittent or constant) |
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Modified from the Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: Human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM.MMWR Recomm Rep 1994;43(RR- 12):1ndash;19.
Infections.
Approximately 20% of AIDS-defining illnesses in children are recurrent bacterial infections caused primarily by encapsulated organisms such as Streptococcus pneumoniae and Salmonella ( Table 3 ). Other pathogens, including Staphylococcus, Enterococcus, Pseudomonas aeruginosa, and Haemophilus influenzae, and other gram-positive and gram-negative organisms may also be seen. Most of these infections are the result of HIV-related disturbances in humoral immunity. The most common serious infections are bacteremia, sepsis, and bacterial pneumonia, accounting for >50% of infections in HIV-infected children. Meningitis, urinary tract infections, deep-seated abscesses, and bone/joint infection occur less frequently. Milder recurrent infections, such as otitis media, sinusitis, and skin and soft tissue infections, are very common and may be chronic with atypical presentations.
Opportunistic infections are generally seen in children with severe depression of the CD4 count. In adults, these infections usually represent reactivation of a latent infection acquired early in life. In contrast, young children generally have primary infection and, lacking prior immunity, often have a more fulminant course of disease. This principle is best illustrated by Pneumocystis carinii (jiroveci) pneumonia (PCP), the most common opportunistic infection in the pediatric population . The peak incidence of PCP occurs at age 3–6 mo, with the highest mortality rate in children <1>
TABLE 3 -- 1993 Revised Case Definition of AIDS-Defining Conditions for Adults and Adolescents 13 Years of Age and Older
| Candidiasis of bronchi, trachea, or lungs |
| Candidiasis, esophageal |
| Cervical cancer, invasive |
| Coccidioidomycosis, disseminated or extrapulmonary |
| Cryptococcosis, extrapulmonary |
| Cryptosporidiosis, chronic intestinal (>1 mo duration) |
| Cytomegalovirus disease (other than liver, spleen, or nodes) |
| Cytomegalovirus retinitis (with loss of vision) |
| Encephalopathy, HIV related |
| Herpes simplex:chronic ulcer(s) (>1 mo duration) or bronchitis, pneumonitis, or esophagitis |
| Histoplasmosis, disseminated or extrapulmonary |
| Isosporiasis, chronic intestinal (>1 mo duration) |
| Kaposi sarcoma |
| Lymphoma, Burkitt (or equivalent term) |
| Lymphoma, immunoblastic (or equivalent term) |
| Lymphoma, primary or brain |
| Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary |
| Mycobacterium tuberculosis infection, any site, pulmonary or extrapulmonary |
| Mycobacterium, other species or unidentified species infection, disseminated or extrapulmonary |
| Pneumocystic jiroveci pneumonia |
| Pneumonia, recurrent |
| Progressive multifocal leukoencephalopathy |
| Salmonella septicemia, recurrent |
| Toxoplasmosis of brain |
| Wasting syndrome attributable to HIV |
| CD4+ T-lymphocyte count <200/μ> |
Modified from the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41(RR-17):1–19.
| Red Book: 2006 Report of the Committee on Infectious Disease, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 379. |
The classic clinical presentation of PCP includes acute onset of fever, tachypnea, dyspnea, and marked hypoxemia; in some children, more indolent development of hypoxemia may precede other clinical or x-ray manifestations. Chest x-ray findings most commonly consist of interstitial infiltrates or diffuse alveolar disease, which rapidly progresses. Nodular lesions, streaky or lobar infiltrates, or pleural effusions may occasionally be seen. Diagnosis is established by demonstration of P. carinii (jiroveci) with appropriate staining of bronchoalveolar fluid lavage; rarely, an open lung biopsy is necessary.
The 1st line therapy for PCP is intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) (15–20 mg/kg/day of TMP and 75–100 mg/kg/day of SMZ every 6 hr IV) with adjunctive corticosteroids if the Pao2 is <70>
Central Nervous System.
The incidence of CNS involvement in perinatally infected children is 50–90% in developing countries but lower in developed countries, with a median onset at 19 mo of age. This may range from subtle developmental delay to progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, impaired brain growth resulting in acquired microcephaly, and symmetric motor dysfunction. Encephalopathy may be the initial manifestation of the disease or may present much later when severe immune suppression occurs. With progression, marked apathy, spasticity, hyperreflexia, and gait disturbance may occur, as well as loss of language, oral, fine, and/or gross motor skills. The encephalopathy may progress intermittently, with periods of deterioration followed by transiently stable plateaus. Older children may exhibit behavioral problems and learning disabilities. Associated abnormalities identified by neuroimaging techniques include cerebral atrophy in up to 85% of children with neurologic symptoms, increased ventricular size, basal ganglia calcifications, and, less frequently, leukomalacia.
Focal neurologic signs and seizures are unusual and may imply a comorbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with a new onset of focal neurologic findings, headache, seizures, and mental status changes. Characteristic findings on neuroimaging studies include a hyperdense or isodense mass with variable contrast enhancement or a diffusely infiltrating contrast-enhancing mass. CNS toxoplasmosis is exceedingly rare in young infants, but may occur in HIV-infected adolescents; the overwhelming majority of these cases have the presence of serum IgG antitoxoplasma as a marker of infection. Other opportunistic infections of the CNS are rare and include CMV, JC virus (progressive multifocal leukoencephalopathy), HSV, and Cryptococcus or Coccidioides meningitis. Although the true incidence of cerebrovascular disorders (both hemorrhagic and nonhemorrhagic strokes) is unclear, 6–10% of children from large clinical series have been affected.
Respiratory Tract.
Recurrent upper respiratory tract infections such as otitis media and sinusitis are very common. Although the typical pathogens (S. pneumoniae, H. influenzae, Moraxella catarrhalis) are most common, unusual pathogens, such as P. aeruginosa, yeast, and anaerobes may be present in chronic infections and result in complications such as invasive sinusitis and mastoiditis.
LIP is the most common chronic lower respiratory tract abnormality, historically occurring in approximately 25% of HIV-infected children. LIP is a chronic process with nodular lymphoid hyperplasia in the bronchial and bronchiolar epithelium, often leading to progressive alveolar capillary block over months to years. It has a characteristic chronic diffuse reticulonodular pattern on chest radiography rarely accompanied by hilar lymphadenopathy, which allows a presumptive diagnosis to be made radiographically before the onset of symptoms. There is an 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. Several studies suggest that LIP is associated with a primary Epstein-Barr virus infection in the setting of HIV infection.
Most symptomatic HIV-infected children experience at least 1 episode of pneumonia during the course of their disease. S. pneumoniae is the most common bacterial pathogen, but gram-negative bacteria may also be problematic; P. aeruginosa pneumonia occurs more commonly in severely symptomatic children (CDC C3 category) and is often associated with acute respiratory failure and death. Rarely, bronchiectasis can develop and cause recurrent secondary infections. PCP is the most common opportunistic infection, but other pathogens, including CMV, Aspergillus, Histoplasma, and Cryptococcus, can cause pulmonary disease. Infection with common respiratory viruses, including respiratory syncytial virus, parainfluenza, influenza, and adenovirus, may occur simultaneously and have a protracted course and period of viral shedding from the respiratory tract. 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.
Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. A prospective study of young children with symptomatic HIV infection revealed that dilated cardiomyopathy and left ventricular hypertrophy were common; the 2 yr cumulative incidence of congestive heart failure was almost 5%. Children with encephalopathy or other AIDS-defining conditions have the highest rate of adverse cardiac outcomes. Resting sinus tachycardia has been reported in up to 64% and marked sinus arrhythmia in 17% of HIV-infected children. Hemodynamic instability occurs more frequently with advanced HIV disease. Gallop rhythm with tachypnea and hepatosplenomegaly appear to be the best clinical indicators of congestive heart failure in HIV-infected children; anticongestive therapy is generally very effective, especially when initiated early. Electrocardiography and echocardiography are helpful in assessing cardiac function before the onset of clinical symptoms.
Gastrointestinal and Hepatobiliary Tract.
Oral manifestations of HIV disease include erythematous or pseudomembranous candidiasis, periodontal disease (e.g., ulcerative gingivitis or periodontitis), salivary gland disease (i.e., swelling, xerostomia), and rarely ulcerations or oral hairy leukoplakia and ulcerations. Gastrointestinal tract involvement is common in HIV-infected children. A variety of pathogens can cause gastrointestinal disease, including bacteria (Salmonella, Campylobacter, MAC), protozoa (Giardia, Cryptosporidium, Isospora, microsporidia), viruses (CMV, HSV, rotavirus), and fungi (Candida). MAC and the protozoal infections are most severe and protracted in patients with severe CD4 cell depletion. Infections may be localized or disseminated and affect any part of the gastrointestinal tract from the oropharynx to the rectum. Oral or esophageal ulcerations, either viral in origin or idiopathic, are painful and often interfere with eating. Lesions that have negative viral cultures may respond to thalidomide, which is currently investigational, or to short courses of prednisone. 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. Disaccharide intolerance is common in HIV-infected children with chronic diarrhea.
The most common symptoms of gastrointestinal disease are chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia, and failure to thrive (FTT). Prompt recognition of weight loss or poor growth velocity in the absence of diarrhea is critical. Linear growth impairment often correlates with the level of HIV viremia. Supplemental enteral feedings should be instituted, either by mouth or with nighttime nasogastric tube feedings in cases associated with more chronic growth problems; placement of a gastrostomy tube for nutritional supplementation may be necessary. The wasting syndrome, defined as a loss of >10% of body weight, is not as common as FTT in pediatric patients. The resulting malnutrition is associated with a grave prognosis and generally requires parenteral hyperalimentation.
Chronic liver inflammation evidenced by fluctuating serum levels of transaminases with or without cholestasis is relatively common, often without identification of an etiologic agent. Cryptosporidial cholecystitis is associated with abdominal pain, jaundice, and elevated gamma GT. In some patients, chronic hepatitis caused by CMV, hepatitis B or C, or MAC may lead to portal hypertension and liver failure. Several of the anti-retroviral drugs or other drugs such as didanosine, protease inhibitors, and dapsone may also cause reversible elevation of transaminases.
Pancreatitis with increased pancreatic enzymes with or without abdominal pain, vomiting, and fever may be the result of drug therapy (e.g., with pentamidine, didanosine, or lamivudine) or, rarely, opportunistic infections such as MAC or CMV.
Renal Disease.
Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children. 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. A wide range of histologic abnormalities has been reported, including focal glomeru losclerosis, mesangial hyperplasia, segmental necrotizing glomerulonephritis, and minimal change disease. Focal glomerulosclerosis generally progresses to renal failure within 6–12 mo, but other histologic abnormalities in children may remain stable without significant renal insufficiency for prolonged periods. Nephrotic syndrome is the most common manifestation of pediatric renal disease, with edema, hypoalbuminemia, proteinuria, and azotemia with normal blood pressure. Cases resistant to steroid therapy may benefit from cyclosporine therapy. Polyuria, oliguria, and hematuria have also been observed in some patients.
Skin Manifestations.
Many cutaneous manifestations seen in HIV-infected children are inflammatory or infectious disorders that are not unique to HIV infection. These disorders tend to be more disseminated 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 HSV, herpes zoster, molluscum contagiosum, flat warts, anogenital warts, and candidal infections 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 or to desensitization. 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.
Hematologic and Malignant Diseases.
Anemia occurs in 20–70% of HIV-infected children, more commonly in children with AIDS. The anemia may be due to chronic infection, poor nutrition, autoimmune factors, virus-associated conditions (hemophagocytic syndrome, parvovirus B19 red cell aplasia), or the adverse effect of drugs (zidovudine). In children with low erythropoietin levels, subcutaneous recombinant erythropoietin may be successful in treating the anemia.
Leukopenia occurs in almost ⅓ of untreated HIV-infected children, and neutropenia often occurs. In some cases, antineutrophil antibodies are the cause, and treatment with intravenous immunoglobulin (IVIG) has been successful. Multiple drugs used for treatment or prophylaxis for opportunistic infections such as PCP, MAC, and CMV or anti-retroviral drugs (zidovudine) may also cause leukopenia and/or neutropenia. In many cases, treatment with subcutaneous granulocyte colony-stimulating factor is successful.
Thrombocytopenia has been reported in 10–20% of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies), or due to drug toxicity, or the cause may be unknown. Treatment with IVIG or anti-D offers temporary improvement in most cases. If ineffective, a 2–3 day course of high-dose steroids (30 mg/kg/day) may be an alternative. Anti-retroviral therapy may also reverse thrombocytopenia. Deficiency of clotting factors (factors II, VII, IX) is not rare in children with advanced HIV disease and is often easy to correct (vitamin K). A novel disease of the thymus has been observed in a few HIV-infected children. These patients were found to have characteristic anterior mediastinal multilocular thymic cysts without clinical symptoms. Histologic examination shows focal cystic changes, follicular hyperplasia, and diffuse plasmocytosis and multinucleated giant cells. Spontaneous involution occurred in some cases.
In contrast to the more frequent occurrence in adults, malignant diseases have been reported infrequently in HIV-infected children, representing only 2% of AIDS-defining illnesses. Non-Hodgkin lymphoma, primary CNS lymphoma, and leiomyosarcoma are the most commonly reported neoplasms among HIV-infected children. Epstein-Barr virus is associated with most lymphomas and with all leiomyosarcomas. Kaposi sarcoma, which is caused by human herpesvirus 8, occurs frequently among HIV-infected adults but is exceedingly uncommon among HIV-infected children.
DIAGNOSIS.
All infants born to HIV-infected mothers test antibody-positive at birth because of passive transfer of maternal HIV antibody across the placenta during gestation. Most uninfected infants lose maternal antibody between 6 and 12 mo of age and are known as seroreverters. Because a small proportion of uninfected infants continues to test HIV antibody positive for up to 18 mo of age, positive IgG antibody tests, including the rapid tests, cannot be used to make a definitive diagnosis of HIV infection in infants younger than this age. The presence of IgA or IgM anti-HIV in the infant's circulation can indicate HIV infection, because these immunoglobulin classes do not cross the placenta; however, IgA and IgM anti-HIV assays have been both insensitive and nonspecific and therefore are not valuable for clinical use. In any child >18 mo of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay (EIA) and confirmatory test (immunoblot or immunofluorescence assay) establishes the diagnosis of HIV infection.
