Antibiotic resistance among pathogens causing disease in Jamaican children with HIV/AIDS.

OBJECTIVE: There are limited data regarding the antimicrobial resistance patterns of pathogens in children with HIV/AIDS from developing countries. We aimed to determine the prevalence and antibiotic susceptibility patterns of bacterial pathogens causing urinary tract infections (UTIs) and sepsis in a cohort of 219 HIV-infected Jamaican children. METHODS: This cross-sectional study examined clinical and microbiological data for children enrolled in the Kingston Paediatric/Perinatal HIV/AIDS programme from September 1, 2002 to May 31, 2007. Cases were defined as physician-diagnosed, laboratory confirmed UTIs and sepsis based on Centers for Disease Control and Prevention (CDC) criteria. Only isolates from urine, blood and sterile sites were considered. RESULTS: Forty-four patients (20.1%) accounted for 74 episodes of UTIs and sepsis. Mean number of infections was 1.7 +/- 1.3 per patient. There were 31 males (70.5%) and mean age at time of infection was 5.6 +/- 4.7 years. Bacterial infections comprised cystitis (n = 52, 70.3%), bacterial pneumonia (n = 15, 20.3%), meningitis (n = 4, 5.4%), septicaemia (n = .2, 2.7%) and bone infection (n = 1, 1.4%). Among 52 UTIs, 39 were caused by a single organism. The most common UTI isolates included Escherichia coli (n = 21, 53.8%) and Enterobacter spp (n = 5, 12.8%). Among 22 cases of sepsis, isolates included Streptococcus pneumoniae (n = 8, 36.4%) and coagulase negative Staphylococcus (n = 6, 27.3%). All E coli isolates at two of three clinical sites were resistant to cotrimoxazole. There were 79.7% (n = 51) of infectious episodes with a cotrimoxazole-resistant organism occurring among those on cotrimoxazole prophylaxis. CONCLUSIONS: Escherichia coli was the most frequent bacterial isolate. Cotrimoxazole is a poor choice for empiric treatment of sepsis and UTIs in this clinical setting.

Prospective cohort study of children born to human immunodeficiency virus-infected mothers, 1985 through 1997: trends in the risk of vertical transmission, mortality and acquired immunodeficiency syndrome indicator diseases in the era before highly active antiretroviral therapy.

OBJECTIVES: To assess changes in the risk of vertical transmission of HIV and changes in both mortality and morbidity among children in southern Connecticut with HIV infection after the introduction of treatment of HIV-infected pregnant women with antiretroviral drugs and of regimens to prevent or to treat AIDS indicator diseases in infected children. METHODS: The risk of vertical transmission of HIV, the rates of death and of AIDS indicator diseases and temporal trends in each were determined for children born in the first 5 years of a prospective, longitudinal cohort study (Period 1: December 1, 1985, through November 30, 1990) compared with those for children born during the latter 7 years of the study (Period 2: December 1, 1990, through November 30, 1997). RESULTS: Of 347 infants enrolled, HIV infection status could be determined for 341; 44 (12.9%) were infected. The risk of vertical transmission declined from 20.7% among children born in Period 1 to 6.5% among children born in period 2 (rate ratio, 3.2; 95% confidence interval, 1.7 to 6.0; P = 0.0001). Of the 21 infected children who died, 11(52%) were < or =18 months of age and 18 (86%) were < or =36 months of age at the times of death. Approximately one-fourth of infected children born during each period died at < or =18 months of age. Among those < or =36 months of age, 15 deaths occurred during 878 person months of observation for those born in Period 1 compared with 3 deaths that occurred during 334 person months for those born in Period 2 (rate ratio, 1.9; 95% confidence interval, 0.5 to 10.3; P = 0.45). Of the 44 children infected with HIV, 32 had one or more AIDS indicator diseases (a total of 67 episodes), 73% of which occurred when the children were < or =36 months of age. Among children born in Period 2, none developed Pneumocystis carinii pneumonia and the rates of Mycobacterium avium complex disease and of wasting syndrome declined, but the differences in rates of disease were not statistically significant. CONCLUSION: A substantial and statistically significant decline in the risk of vertical transmission of HIV-1 occurred during the 12-year study period. In contrast although there was a trend toward a decrease in mortality among HIV-infected children < or =36 months of age and changes in the overall rates of AIDS indicator diseases among children born in Period 1 compared with Period 2, the differences were not statistically significant.

Genetically and epidemiologically related "non-syncytium-inducing" isolates of HIV-1 display heterogeneous growth patterns in macrophages.

The objective of this study was to identify phenotypic parameters that could distinguish among seemingly homogeneous non-syncytium-inducing (NSI) viruses and that might provide a surrogate marker for clinical progression in pediatric human immunodeficiency virus type 1 (HIV-1) infection. We undertook a pilot analysis of 15 independent HIV-1 isolates collected prospectively from two mothers and their four children who displayed a spectrum of disease stages ranging from CDC categories A1 to C3. Viruses were evaluated for their ability to replicate in primary cells (including monocyte-derived macrophages [MDM]) and cell lines, for their co-receptor preference and for genetic features of the V3 hypervariable domain of env. Virtually all isolates displayed NSI phenotypes that were restricted in their capacity to replicate in cell lines and displayed V3 loops with uniformly low net positive charges. NSI viruses from two symptomatic children and one mother were macrophage-tropic, whereas NSI isolates from two asymptomatic children were unable to replicate in MDM and were designated primary lymphotropic viruses. Only one isolate was syncytium-inducing (SI), replicated in a variety of cell lines and in MDM, used multiple co-receptors, and was dual tropic, rather than a mixture of T-cell tropic and M-tropic viruses, as assessed by genetic analysis. Phenotypic heterogeneity among NSI viruses is revealed in the ability of isolates to replicate in MDM. This characteristic is related to disease stage and provides a potentially new in vitro criterion to distinguish among NSI isolates that is unlinked to other surrogate markers.

The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies.

BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Association between the biological characteristics of HIV-1, vertical transmission of infection and clinical progression of pediatric disease.

The design of effective prophylactic measures to prevent the vertical transmission of HIV-1 and of therapies to alter the natural progression of pediatric HIV disease requires a thorough understanding of basic pathogenetic principles. Maternal viral load, the biological behavior of HIV, such as replicative capacity in different types of cells, monocyte/macrophage tropism, and the capacity of the infant's cells to support infection have all been assessed for their contribution to the risk of mother-to-child transmission. Similarly, the effects of viral load and phenotype (e.g. replicative capacity, cell tropism, syncytium-inducing capacity and the use of chemokine co-receptors) have all been investigated as parameters associated with variations in the expression of clinical disease in children. Some of the extant data are conflicting, but general principles regarding pathogenesis are beginning to emerge.

Medical management of the pregnant woman infected with human immunodeficiency virus type 1 and her child.

Heterosexual contact and intravenous drug use continue to result in new cases of human immunodeficiency virus type 1 (HIV-1) infection among adolescents and women of childbearing age. In North American and European surveys, 0.1% to 0.3% of childbearing women are infected with HIV; rates are 10 to 20 times higher in some inner-city areas. Timely, comprehensive, and well-coordinated care of the pregnant HIV-infected mother offers a unique opportunity to significantly influence two lives simultaneously. The mother can be offered therapeutic and prophylactic agents to treat her own infection, including antiretroviral therapy, which has been shown to markedly reduce the risk of vertical HIV-1 transmission. Recent advances in diagnostic virology now make it possible to definitively identify by 3 to 4 months of age those infants who are infected with HIV. Infants infected with HIV can be offered effective prophylaxis against Pneumocystis carinii pneumonia, which has dramatically reduced the incidence of this once common infection. Infected infants also should be monitored closely to institute antiretroviral therapy, and to diagnose and treat opportunistic and intercurrent infections and other acquired immunodeficiency syndrome-defining illnesses in a timely way.

Reduction in the risk of vertical transmission of HIV-1 associated with treatment of pregnant women with orally administered zidovudine alone.

In a prospective cohort study of 267 children born to mothers infected with HIV-1 in New Haven, Connecticut, an abrupt decline in the risk of mother-to-child transmission occurred in 1990 and persisted at least through December, 1993. A retrospective, observational study was undertaken to identify factors that might be responsible for this decline. Three variables were assessed: the use of orally administered zidovudine during pregnancy, the CD4+ T-lymphocyte count of the mother, and the mode of delivery. The risk of transmission was 18.6% (36/194; 95% CI: 14.1-24.8%) in infants of all women not treated with zidovudine compared with 5.5% (3/55; 95% CI: 1.1-15.1%) in infants of all women who were treated (odds ratio: 0.25; p = 0.02). In a subgroup of women with known CD4+ cell counts, the risk of transmission was 21.1% (20/95; 95% CI: 13.4-30.6%) in untreated women compared with 5.5% (3/55) in those who received zidovudine (odds ratio: 0.22; p = 0.01). In women with CD4+ T-cell counts < 200/microl, the differences remained significant (39.1% in those not treated vs. 4.2% in those treated; p < 0.004). There was an inverse relationship between CD4+ cell count and risk of transmission: among untreated mothers whose T-lymphocyte counts were > or = 500, 200-499, or < 200/microl, HIV-1 was transmitted to the offspring of 8.2, 30.4, and 39.1% of offspring, respectively (p < 0.002 by the exact trend test). There was no significant association between mode of delivery and vertical transmission of HIV. We conclude that treatment with orally administered zidovudine alone (500 mg/day) in the course of routine prenatal care is associated with a significant reduction in the risk of vertical transmission.

Invasive pneumococcal infections in children infected with HIV are not associated with splenic dysfunction.

OBJECTIVES: Children infected with HIV-1 are more likely to acquire infections associated with the encapsulated bacterial pathogens of childhood than their non-HIV-infected peers. The goal of the current study was to determine what proportion of community-acquired, invasive pneumococcal disease in HIV-infected children could be attributed to splenic dysfunction, as measured by enumerating the number of pocked red blood cells (RBCs) in peripheral blood. METHODS: Splenic reticuloendothelial function was assessed semiquantitatively by examining the morphology of the RBCs of 84 children born to HIV-infected mothers using phase interference microscopy. Surveillance of medical records, and a review of the Yale-New Haven Hospital Clinical Microbiology computerized database, revealed that all of the bacterial cultures of blood and cerebrospinal fluid from these patients were positive. RESULTS: Of the 84 children assessed, 70 were infected with HIV (median age 66 months) and 14 were uninfected seroreverters (controls). Sixty-one of the 70 HIV-infected children met the CDC criteria for moderate or severe immunodeficiency and/or moderate or severe symptomatic conditions. Seventeen of the 70 HIV-infected children experienced 23 invasive bacterial infections. Streptococcus pneumoniae was responsible for all 23 infections. The median age at the time of first infection among these 17 subjects was 20 months (range, 10-58 months). There were no episodes of invasive bacterial infections in the remaining 53 HIV-infected children nor among the 14 controls. All 84 children studied, including those with invasive pneumococcal disease, had normal proportions (i.e., < 2%) of pocked erythrocytes in peripheral blood. CONCLUSION: Splenic dysfunction, as measured by the pocked RBC count, does not account for the increased occurrence of invasive pneumococcal disease found in children infected with HIV.

Development of a prognosis-based clinical staging system for infants infected with human immunodeficiency virus.

PURPOSE: To develop a prognosis-based clinical staging system for infants infected with human immunodeficiency virus. METHODS: Abstraction of data from medical records of 75 infected children. For each clinical finding present in infancy, the magnitude of the relative risk (RR) for early death was used to assign subjects to different clinical stages. RESULTS: Stage IV (RR > 3) included subjects with Pneumocystis carinii pneumonia, other opportunistic infections, or encephalopathy. Stage III (RR, 2 to 3) included those with anemia, thrombocytopenia, hepatitis, fever, oral candidiasis, or one or more serious bacterial infections. Stage II included those with hepatomegaly, splenomegaly, failure to thrive, or persistent diarrhea, and stage I included those who had lymphadenopathy or were free of symptoms. When clinical staging was applied to the study population at ages as early as 6 months, survival curves were significantly different (IV vs III: p < 0.0005; III vs II + I: p < 0.005). CONCLUSIONS: Clinical staging should be beneficial in advising parents about an infant's prognosis, therapeutic decision making, and stratification for clinical trials.

Syncytium-inhibiting and neutralizing activity in maternal sera fail to prevent vertical transmission of human immunodeficiency virus type 1.

OBJECTIVES: To measure the prevalence and titers of syncytium-inhibiting (SI) and neutralizing (Nt) antibodies to HIV-1 in mothers' blood close to the time of delivery and to correlate such findings with the infection status of their offspring. METHODS: We analyzed serum specimens from a convenience sample of 22 HIV-infected mothers. The HIV-1 infection status of their children was determined. Forty-five percent of the women transmitted and 55% did not transmit infection to their offspring. Cord blood samples from offspring of the mothers were also studied. We measured maternal SI antibody titers against cells infected with HIV-1/SB, a strain isolated from a transmitting mother in New Haven, as well as cells infected with the more prevalent MN strain of HIV-1. We compared SI antibody titers to the SB strain in 11 matched maternal and cord blood samples. Nt antibody titers to HIV-1/SB were also measured in 20 maternal sera. RESULTS: Using the SB and MN strains of HIV-1, we found no difference in the prevalence or titer of SI antibody in the sera of transmitting and nontransmitting mothers. Only 35% of samples were concordant for presence or absence of SI antibody to the two strains. Furthermore the presence or absence of SI antibody in cord blood did not correlate with virus transmission. Both the frequency and titer of Nt antibody to HIV-1/SB were higher in the sera of mothers who transmitted infection when compared to those who did not. Only one-half of maternal blood samples were concordant for either the presence or absence of SI and Nt antibodies. CONCLUSIONS: We could not demonstrate a correlation between the presence of two types of functional antibodies (i.e. SI and Nt) to HIV-1 in the sera of pregnant women and vertical transmission. Efforts to induce or to increase such antibodies in infected mothers by immunization with vaccines or hyperimmune globulins may not alter the risk of vertical transmission.

Invasive bacterial infections in children born to women infected with human immunodeficiency virus type 1.

To determine the rates and characteristics of invasive bacterial infections in children infected with the human immunodeficiency virus type 1 (HIV-1), we conducted a prospective, longitudinal, observational cohort study of infants born to HIV-1-infected mothers between Dec. 1, 1985, and Sept. 30, 1989. Of 104 subjects whose HIV-1 infection status could be definitively determined, 21 were infected with HIV-1 and 83 were not. In all, 11 (48%) of 23 invasive infections occurred among 10 HIV-1-infected patients and 12 (52%) of 23 occurred among 11 uninfected subjects. Infections with Streptococcus pneumoniae (n = 8), all of which were community acquired, accounted for the greatest proportion (35%) of the organisms isolated from either the blood or the cerebrospinal fluid. Five episodes of pneumococcal bacteremia occurred in the HIV-infected patients; all resolved promptly after treatment was begun, and no serious focal infections developed. Of 13 instances of bacteremia with an organism other than S. pneumoniae, seven were nosocomial. The rate of community-acquired invasive bacterial infections among the HIV-infected children was nearly three times higher than the rate in the non-HIV-infected children (overall, 1.02 infections per 100 person-months vs 0.37 infection per 100 person-months; rate ratio, 2.8; p = 0.05). Most of the increased risk occurred in children > 1 year of age. In contrast, the difference in the rates of infection between those patients in the two groups who were less than 12 months of age was not significant (1.3 infections per 100 person-months vs 0.81 infection per 100 person-months; rate ratio, 1.6; p = 0.47). We conclude that the rate of invasive bacterial infection is higher in HIV-infected children than in their peers, especially after 1 year of age.

Quantitative leukoviremia and immune complex-dissociated antigenemia as predictors of infection status in children born to mothers infected with human immunodeficiency virus type 1.

Four methods of culturing human immunodeficiency virus type 1 (HIV-1) from peripheral blood mononuclear cells and two serum antigen tests were assessed as predictors of infection status in children born to HIV-1-infected mothers. Of 36 infants whose cocultures were quantitative, all 15 who were deemed to be infected with HIV-1 (nine with symptoms, six without symptoms) by clinical criteria or persistence of Western blot reactive antibody had positive culture results, and all 21 uninfected seroreverters had negative culture results (sensitivity = 100%; specificity = 100%). Quantitative coculture was more sensitive than a technique in which cells were counted and stimulated with phytohemagglutin but not cocultivated with cells from seronegative donors, and more sensitive than two other qualitative techniques evaluated in samples from 80 children, in which cells were not enumerated before culture. The level of leukoviremia in children with symptoms did not differ appreciably from the level of leukoviremia in symptom-free infected children. Among those with positive results on quantitative coculture, only 40% also had free HIV-1 antigen in serum, whereas 86% had antigen in immune complexes. Among the methods evaluated, quantitative HIV-1 coculture was the best indicator of infection status in children.

Predictive value of the human immunodeficiency virus 1 antigen test in children born to infected mothers.

Our objective was to examine the utility of the human immunodeficiency virus (HIV-1) antigen test as an early predictor of HIV-1 infection among children born to infected mothers and to collect information about its performance as a diagnostic test. The Abbott HIVAG-1 Enzyme Immunoassay was used to analyze serial serum samples from patients enrolled in a longitudinal cohort study of children born to mothers infected with HIV-1. There were 85 subjects who were followed from birth whose HIV-1 infection status could be definitely determined as of March, 1990. Of these 22 (26%) were infected with HIV-1 and 63 (74%) were uninfected. Overall the sensitivity of the test was 77% (95% confidence interval (CI), 55 to 92%) and the specificity was 97% (95% CI, 89 to 99%). The positive predictive value of a single positive test was 89% (95% CI, 67 to 99%) and of two or more positive tests was 100% (95% CI, 50 to 100%). The sensitivity of the test varied greatly with age. For 36 children from whom sera were collected during the first month of life the specificity of the antigen test was 100% but the sensitivity was only 20%. Overall in the first 6 months of life the sensitivity was less than 50%. The Abbott HIV-1 antigen test is useful as an early predictor of HIV-1 infection in children whose mothers are infected.

Relation between HIV-1 syncytium inhibition antibodies and clinical outcome in children.

Syncytium formation, a feature of HIV-1-induced cytopathology, allows the virus to propagate through cell-to-cell spread. An assay has been developed to measure antibodies (syncytium inhibition, SI) that inhibit this process. Two cell lines were used: the indicator cells, which are not HIV-1 infected, bear CD4 receptors on their surface; the fusogenic HIV-1 infected cells, which do not release virus but are responsible for initiating syncytium formation, are free of CD4 receptors. Co-cultivation of about 10(5) of each of these cells induces the emergence of 70-100 multinucleated giant cells within 48 h. Sera from 34 children born to HIV-1-infected mothers were tested by western blot (WB) and SI assay. SI antibodies were detected in the blood of 15 (65%) of 23 WB-positive children and in none of 11 WB-negative children. There were striking differences in prevalence and titre of SI antibodies in children with lymphocytic interstitial pneumonitis (LIP) compared with those with opportunistic infections (OI). All 8 children with LIP had SI antibodies ranging in titre from 40 to greater than 320. By contrast, only 2 of 7 with OI had SI antibodies, in both of whom the SI titre was 20 (p less than 0.05). No sera from children who had seroreverted contained SI antibodies. The findings point to the need to identify the specific HIV-I peptides or epitopes responsible for syncytium formation since SI antibodies correlate with clinical outcome in children.