Thrombopoietin levels in HIV-associated thrombocytopenia in children.

OBJECTIVES: To determine the mechanism of human immunodeficiency virus (HIV)-associated thrombocytopenia by using thrombopoietin (TPO) levels. STUDY DESIGN: TPO levels were measured in 14 HIV+ children with thrombocytopenia (TCP+), 28 HIV+ children without thrombocytopenia (TCP-), and 15 matched control subjects. RESULTS: For the patients with moderate symptoms, TPO levels were similar for the TCP+ and TCP- groups (251 pg/mL vs 263 pg/mL; P =.98) and similar to those of control subjects. For the patients with severe symptoms, TPO levels were significantly higher for the TCP+ group versus the TCP- group (1172 pg/mL vs 222 pg/mL; P =.03). Patients with severe symptoms and thrombocytopenia had significantly higher TPO levels than those with moderate symptoms and thrombocytopenia (P <.005), were more likely to require growth factors, and did not respond to treatment with intravenous immunoglobulin. CONCLUSIONS: TPO levels can distinguish 2 groups of patients with HIV-associated thrombocytopenia. Patients with severe disease had elevated TPO levels, did not respond to treatment with intravenous immunoglobulin, and were more likely to be growth factor-dependent, suggesting marrow failure.

Streptococcus pneumoniae bacteremia in children infected with HIV: presentation, course, and outcome.

OBJECTIVE: To examine the presentation, course, and outcome of pneumococcal bacteremia in children infected with human immunodeficiency virus (HIV). METHODS: A retrospective series of HIV-infected children less than 18 years of age with Streptococcus pneumoniae bacteremia from four urban, tertiary care hospitals was evaluated. The main outcome measures included persistent bacteremia, the development of a focal infection, and death. RESULTS: Seventy-two episodes of pneumococcal bacteremia were identified in 59 patients. Fifty-four first episodes were included; 26/54 were occult. Mean temperature was 39.8 degrees C. In patients with bacteremia, white blood cells (WBCs) > or = 15,000 and > or = 10,000 had sensitivities of 40% and 75%, respectively. At the time of bacteremia, age >3 years old was associated with a lower mean WBC count compared with episodes occurring in patients <3 years old (11.2 vs 16.1, P < 0.05). Patients with occult bacteremia who were discharged with antibiotics (12 i.m., 7 p.o.) were less likely than patients without antibiotic treatment to have persistent bacteremia at a return visit within 72 hours (0/19 vs 2/5, P < 0.05). No patient with occult bacteremia died, progressed to clinical meningitis, or had other sequelae. Two of fifty-four patients died as a result of their first episode of invasive pneumococcal disease. Both patients who died had meningitis and appeared ill on initial presentation. CONCLUSIONS: Neither a WBC count > or = 15,000 nor > or = 10,000 is a sensitive indicator of pneumococcal bacteremia in HIV-infected children. Empiric antibiotics are useful to decrease the risk of persistent bacteremia. Children infected with HIV who have occult pneumococcal bacteremia appear to do well with appropriate antibiotics. Patients who are afebrile and well appearing on reevaluation may be safely treated as outpatients.

Amebic osteomyelitis in a child with acquired immunodeficiency syndrome: a case report.

Disseminated Acanthamoeba infection has been described in immunocompromised or debilitated patients. The usual sites of involvement are skin, sinus, and brain. Sporadic reports of Acanthamoeba infection in patients infected with the human immunodeficiency virus are present in recent literature, predominantly in adults, and one case involving an 8-year-old child. We describe a case of amebic osteomyelitis, seen in a 6-year-old child with vertically acquired human immunodeficiency virus and a 6-month history of cutaneous Acanthamoeba infection.

Epstein-Barr virus DNA in the blood of infants, young children, and adults by age and HIV status.

Polymerase chain reaction (PCR) methodology was used to detect Epstein-Barr virus (EBV) DNA in peripheral blood mononuclear cells (PBMCs) from children and adults whose HIV status (i.e., infected or uninfected) is known. Initial EBV infections especially occurred in children between the ages of 7 and 24 months. EBV-positive children with vertically acquired HIV infection tended to have a detectable blood level of EBV DNA for a period of years, and their EBV DNA blood levels often exceeded 10,000 copies/0.1 ml of blood--hundreds of times higher than levels typically found in EBV-positive, HIV-uninfected children of the same age. EBV DNA was found in PBMCs in 26% of 49 HIV-infected mothers who were sampled during their pregnancy, but the median EBV DNA level in their EBV-positive samples was low--only 50 copies/0.1 ml blood. In limited tests with specimens from children infected with both HIV and EBV, high blood levels of EBV DNA unexpectedly appeared to be associated with decreased blood levels of HIV DNA (p = .063).

HIV DNA blood levels in vertically infected pediatric patients: variations with age, association with disease progression, and comparison with blood levels in infected mothers.

Blood levels of HIV DNA in our vertically infected pediatric patients typically followed a characteristic age-related pattern: continuously increasing with increasing age to a peak between ages 4 and 8 months, and thereafter rather steadily declining. Median HIV DNA levels peaked about 3 months earlier in children who by age 24 months developed more severe rather than less severe HIV disease. Children at particular risk of developing severe HIV disease by age 24 months commonly had > 800 HIV DNA copies per 0.1 ml of blood at age 3 weeks to 2 months, > 1,000 copies at 2 to 4 months, and > 2,500 copies at ages 4 to 6 months. Near the time of delivery mothers who transmitted HIV had significantly higher median blood levels of HIV DNA than mothers who did not transmit, but median HIV DNA levels in infected mothers as a group were low compared with those in pediatric patients > or = 1 month of age.

Viral studies of mothers with human immunodeficiency virus infection at delivery and their infants in the first 3 days of life.

OBJECTIVE: We studied 49 mother-infant pairs for human immunodeficiency virus (HIV) (a) to assess the virological and immunological status of HIV-infected mothers at delivery and their infants within the first 3 days of the infant's life, and (b) to correlate these findings with eventual infection outcome in the infant. METHOD: Maternal blood from women in labor and infant's blood within 3 days of life were tested for the titer of HIV immunoglobulin G (IgG) antibody, for presence of HIV by culture, for p24 antigen, for HIV DNA by polymerase chain reaction (PCR), and for absolute T-helper cell count (CD4). RESULTS: Eight infants were in the confirmed infected (CI) group, with a transmission rate of 21%. Thirty infants were in the confirmed uninfected (CU) group. In the mother, mean anti-HIV IgG titer was 1:2600 (CI group) and 1:3350 (CU group); in the infant, the mean titer was 1:3250 (CI group) and 1:2710 (CU group). Eighty-seven percent of the mothers were culture-positive in the CI group compared to 33% in the CU group (p = 0.005). Eighty-seven percent of CI infants were PCR-positive at birth; none was PCR-positive in the CU group (sensitivity = 87%; specificity = 100%). Sixty-two percent of CI infants were culture-positive at birth, whereas none was positive in the CU group (sensitivity = 62%; specificity = 100%). Of the uninfected infants, 23% were positive for p24 antigen at birth. CONCLUSIONS: HIV IgG antibody titers in mothers and their infants at birth were markedly elevated in both CI and CU groups but were not protective against infection. However, the high titers explain the long duration of this antibody in the blood of infants born to infected mothers. Culture positivity in the mother at delivery correlated highly with eventual infection in the infant (p = 0.005). HIV antigen, specifically p24 antigen, was detectable in uninfected infants when tested at birth.

HIV antibody responses in children of HIV-infected mothers.

About 25% of the children of untreated HIV-infected mothers are later determined to be HIV-infected. At birth, all of the children of HIV-infected mothers have HIV-IgG antibody, which is transferred transplacentally from the mothers to their children, and infected children produce HIV-IgG antibody in response to their infection. Most infected children have detectable HIV-IgA by 3 months of age. We have studied HIV antibody responses in three groups of children of HIV-infected mothers at 9 to 12 months and 15 to 24 months of age. The groups were classified by Centers for Disease Control and Prevention (CDC) criteria and included: (I) HIV seroreverters (SR); (II) HIV-infected; Non- to mildly symptomatic (N+A); and (III) HIV-infected; Moderately to Severely Symptomatic (B+C). HIV-IgG antibody was detected in some SR children at low titer levels (10 to 20) through 11 months of age but not at 12 or later. For both the N+A and B+C groups, there were no significant changes in the mean HIV-IgG titers from 9-12 to 15-24 months of age. Also, no significant difference in titers were found between the two infected groups for both age groups. HIV-IgA antibody responses were more frequently positive at 15 to 24 months for all seven antigens studied for the N+A than the B+C patients; however, statistical significance was attained only for gp41 (p < or = 0.01). N+A children showed more responses to the viral antigens at 15-24 months than at 9-12 months. This increase in HIV-specific IgA among the N+A children may be important in restricting their HIV infections. Total IgG levels were significantly higher in the HIV-infected groups than in the SR (p < or = 0.0001), but no differences were detected between the N+A and B+C groups. Total IgA increased over time in the N+A patients from 9-12 to 15-24 months. A similar trend was apparent in the B+C group, but did not reach statistical significance. Both N+A and B+C patients at 15-24 months had significantly higher total IgA levels than did the SR at 9-12 months of age. The B+C group had significantly lower CD4 counts for both age groups than did the N+A or SR groups (p < or = 0.0001).

Coinfection with herpesviruses in young children of HIV-infected women.

Coinfection with herpesviruses in young children born to human immunodeficiency virus (HIV)-infected women was studied with blood samples from children who were 9-12 months and 15-24 months of age. Three groups of children were included: (I) HIV-uninfected, asymptomatic (HIV-); (II) polymerase chain reaction (PCR) and/or culture-positive and asymptomatic or mildly symptomatic (HIV+ asymptomatic); and (III) PCR and/or culture-positive and symptomatic (HIV+ symptomatic). Significantly more of the HIV+ symptomatic patients had cytomegalovirus (CMV) antibody than the HIV patients. In addition, CMV antibody levels were significantly higher in the HIV+ symptomatic patients than in either of the other two groups. Human herpesvirus 7 (HHV-7) antibody titers were significantly different among the three groups of patients; however, no pairwise comparisons were significant. No differences were found for HHV-6 or Epstein-Barr virus (EBV) antibody frequencies or titers. These findings suggest that infection with CMV is a cofactor or an opportunistic infection causing symptomatic HIV infections in young children.

Spectrum of chest radiographic abnormalities in children with AIDS and Pneumocystis carinii pneumonia.

This report aims to provide a description of the spectrum of radiographic findings in children with AIDS and Pneumocystis carinii pneumonia (PCP). The chest radiographs of all children with perinatally transmitted HIV infection who had PCP were reviewed. Thirty-eight episodes of PCP were noted in 32 children. The age range was 2-17 months. The radiographic findings were characterized as to pattern, severity, presence of pulmonary air cyst, thoracic air leak, thoracic lymphadenopathy, and pleural effusion. The initial distribution of disease was as follows: diffuse (n = 20), patchy (n = 12), focal (n = 4), normal (n = 2). In nearly one-third of children parenchymal abnormalities were mild enough that most normal lung markings were visible. During the course of the illness pneumothorax was noted in eight cases, pulmonary air cyst in five, and pneumomediastinum in one. Pleural effusions were noted in three (5%) cases. Thoracic lymphadenopathy was not observed in any case. The authors concluded that the initial chest radiographic appearance of PCP in children with AIDS is variable. The initial chest radiograph may be normal. The distribution was patchy or focal in nearly one-half of all cases with parenchymal abnormalities. Pulmonary air cysts or thoracic air leaks were noted during the course of the illness in approximately one-third of all cases.

Abdominal lymphadenopathy in children with AIDS.

PURPOSE: To identify conditions associated with abdominal lymphadenopathy in children with vertically-transmitted human immunodeficiency virus (HIV) infection. METHODS: Abdominal computed tomography (CT) scans were performed on 29 children over an eight-year period. The presence or absence of abdominal lymphadenopathy (> 10 mm in diameter) was prospectively evaluated at the time of CT. Clinical and histopathologic data in these children was reviewed. RESULTS: Abdominal lymphadenopathy was noted in eight (28%) children. The lymphadenopathy was isoattenuating relative to adjacent muscle in all cases. The most common specific associated diagnosis was systemic infection with Mycobacterium avium intracellulare (three children). One child had disseminated Kaposi sarcoma while four children had no known associated systemic infection or neoplasm. CONCLUSIONS: Abdominal lymphadenopathy was noted at CT in 28% of all HIV-infected children studied with CT and represented a nonspecific finding. The presence of lymphadenopathy should raise the suspicion of disseminated mycobacterial infection; however, it may also be observed in the absence of known systemic infection or neoplasm.

Hepatobiliary abnormalities on sonography in children with HIV infection.

Our purpose was to characterize the spectrum of hepatobiliary abnormalities on sonography in children with vertically transmitted HIV infection. Abdominal sonograms were performed on 41 children with HIV infection and correlated with clinical and histopathologic data. Hepatobiliary abnormalities were noted in 26 (63%) children. Hepatomegaly (n = 13) and abnormal hepatic echotexture (n = 13) were the most common abnormalities noted. Preexisting AIDS-related infections or neoplasms were noted significantly more frequently in children with hepatic or biliary abnormalities on sonography (18/26, 69%) than in children without abnormalities (5/15, 33%) (P = 0.0001). Most children with hepatobiliary abnormalities on sonography who underwent hepatic tissue sampling, however, did not have evidence of acute infection or neoplasia. Hepatobiliary abnormalities are frequently noted on sonography in children with HIV infection. Hepatomegaly and abnormal hepatic echotexture are the most frequent sonographic findings and are usually nonspecific.

Human immunodeficiency virus infection in infants during the first 2 months of life. Reliable detection and evidence of in utero transmission.

OBJECTIVE: To evaluate the clinical utility of a polymerase chain reaction (PCR) method for detecting human immunodeficiency virus (HIV) infection in infants 2 months of age or younger who were born to HIV-positive mothers. DESIGN: Prospective, longitudinal study lasting 3 years. The PCR tests were performed with coded peripheral blood mononuclear cell lysates, and results were compared with findings using Centers for Disease Control and Prevention (CDC) (Atlanta, Ga) criteria defining HIV infection in children. SETTING: Hospitals, particularly a pediatric hospital in Washington, DC. PATIENTS: Newborns, young infants, and HIV-infected mothers. OUTCOME MEASURE: Presence or absence of pediatric HIV infection using CDC criteria compared with a diagnosis based on the detected presence or absence of HIV proviral DNA using PCR testing. RESULTS: One or more blood samples obtained by 62 days of age from 30 (94%) of 32 HIV-infected infants were positive for HIV by routine PCR testing. Blood samples from 32 infants now confirmed to be uninfected tested negative for HIV. Human immunodeficiency virus DNA was detected in blood samples obtained within 48 hours of birth from eight of nine infected infants. In six of these newborns as well as most older infants, HIV DNA was present in such quantity that it was detectable in specimens equivalent to 0.01 mL or less of the original blood sample. CONCLUSIONS: Our PCR procedure can reliably detect the presence or absence of HIV infection during the first 2 months of life. The frequent presence and not uncommon high titer of HIV DNA within 48 hours of birth suggest that much of the transmission of HIV from mother to infant occurs well before birth.

Cellular immune factors associated with mother-to-infant transmission of HIV.

OBJECTIVE: To study a possible correlate of protection in mother-to-infant transmission of HIV infection. In particular, to determine whether lack of HIV-specific T-helper (TH) function as indicated by HIV and non-HIV antigen-stimulated interleukin (IL)-2 production of mother and/or newborn peripheral blood leukocytes (PBL) is associated with mother-to-infant transmission of HIV. METHODS: PBL from 21 HIV-seropositive pregnant women and 23 cord blood leukocytes (CBL) from their offspring were studied for in vitro TH function by IL-2 production in response to HIV and non-HIV antigens. Polymerase chain reaction (PCR) and viral culture assays were performed to determine HIV infection of the infants. RESULTS: PBL from 10 out of 21 (48%) mothers and from eight out of 23 (35%) CBL samples responded to two or more out of five synthetic gp 160 envelope (env) peptides. Three of the 23 (13%) offspring were shown to be HIV-infected by PCR and/or viral culture on follow-up. All three infected infants were from a subset whose CBL did not exhibit env-specific TH immunity. CONCLUSION: Our results demonstrate that fetal T cells can be primed to HIV env determinants in utero, suggest that HIV-specific TH immunity may be protective in newborns, and provide a possible means for identifying newborns who are at risk for HIV infection.

CT and MR evaluation of intracranial involvement in pediatric HIV infection: a clinical-imaging correlation.

PURPOSE: To review the cranial CT and MR examinations of 29 children with perinatally transmitted HIV infection and correlate the imaging findings with clinical and pathologic data. METHODS: 28 children were examined with CT, four with MR. RESULTS: CT abnormalities were seen in 25 children studied (89%), including cerebral atrophy (25 children), basal ganglia calcification (10 children), periventricular frontal white matter calcification (four children), cerebellar calcification (one child), white matter low attenuation areas (two children), intracranial hemorrhage (three children) and cerebral infarction (one child). Intracranial calcifications were only seen in association with cerebral atrophy and were never seen prior to 1 year of age. Calcifications in the periventricular white matter or cerebellum were always associated with basal ganglia calcifications. MR abnormalities were seen in all four children studied; cerebral atrophy (four children), areas of high signal intensity in white matter (four children), loss of normal posterior pituitary high signal intensity (one child). Cerebral atrophy appeared to be a nonspecific finding that was seen in some children in the absence of neurologic signs and symptoms. All children with intracranial calcifications had developmental delay. Intracranial hemorrhage was seen in children with severe thrombocytopenia. Focal intracranial infections were unusual and neoplastic lesions were not found. CONCLUSIONS: Cerebral atrophy, basal ganglia calcifications, and focal white matter lesions were the most common abnormalities seen neuroradiologically in our series of HIV-infected children; cerebral atrophy was a nonspecific finding.

Detection of human immunodeficiency virus type 1 infection in young pediatric patients by using polymerase chain reaction and biotinylated probes.

Polymerase chain reaction (PCR) testing using up to four primer pairs and biotinylated probes was 97.9% sensitive (188 of 192 specimens positive) and 100% specific (267 of 267 specimens negative) for detecting the presence or absence of human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells from pediatric patients whose HIV status has been confirmed. SK38/39 and SK145/150 were the most sensitive primer pairs, respectively detecting HIV DNA in 95.6 and 95.9% of peripheral blood mononuclear cell specimens from HIV-infected children and collectively detecting all adequately tested PCR-positive specimens. Primer pairs SK29/30 and SK68/69 respectively detected HIV DNA in only 76.4 and 76.6% of HIV-positive specimens. Among infants born to HIV-seropositive mothers, 30 who subsequently were confirmed to be infected were sampled when they were less than or equal to 6 months of age; in all but one infant, HIV DNA was found in the first specimen collected. Among the nine youngest infected infants tested, all were PCR positive by 38 days of age. PCR methods thus have reliably detected vertically transmitted HIV infection early in life.

Limitations in the laboratory diagnosis of vertically acquired HIV infection.

At present, the only well-standardized and widely available diagnostic techniques for HIV infection are detection of IgG HIV antibodies and HIV antigen. The antibody detection is sensitive, but is useful only in infants and children older than 15 months because of the presence of maternal antibodies. The utility of HIV antigen testing in neonates and young infants has not been established. A number of sensitive techniques, such as PCR, ELISPOT, and detection of HIV-specific IgM and IgA antibodies, are under development and promise to be very useful in the early diagnosis of vertical HIV infection. However, we will be able to accurately establish the sensitivity or specificity of the individual tests only when we have results of large prospective studies. These studies should compare different diagnostic methods and correlate the results of tests performed sequentially in neonates and young infants with the natural history of their disease process and eventual clinical outcome.

A novel X-linked combined immunodeficiency disease.

A novel X-linked combined immunodeficiency disease was found in five living males in an extended family in the United States. The age of the affected males ranged from 2.5 to 34 yr. The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis, otitis media, bronchitis, and pneumonia; severe varicella; and chronic papillomavirus infections. The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes, particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells, mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes. Thus, affected males in this family carry an abnormal gene on their X chromosome that results in a combined immunodeficiency that is distinct from previously reported disorders.