Marc Foca

Endemic Pseudomonas aeruginosa Infection in a Neonatal Intensive Care Unit

BACKGROUND Nosocomial infections due to Pseudomonas aeruginosa have been well described, but the environmental reservoir of the organism varies. We conducted an epidemiologic and molecular investigation of endemic P. aeruginosa infection among infants in a neonatal intensive care unit that was associated with carriage of the organisms on the hands of health care workers. METHODS In August 1998, colonization or infection with P. aeruginosa was identified in six infants. Surveillance cultures for P. aeruginosa were obtained from the other 27 infants in the unit, and possible environmental reservoirs were also assessed. The hands of health care workers were inspected and cultured, and risk factors for P. aeruginosa colonization were evaluated. Isolates were analyzed for clonality by pulsed-field gel electrophoresis. RESULTS Surveillance cultures showed that three additional infants were colonized with P. aeruginosa. Cultures of environmental specimens were negative, but cultures of the hands of 10 of 165 health care workers (6 percent) were positive for P. aeruginosa. Increasing age (P=0.05) and a history of the use of artificial fingernails or nail wraps (P=0.03) were both risk factors for colonization of the hands. From January 1997 to August 1998, 49 infants were infected or colonized with P. aeruginosa. Pulsed-field gel electrophoresis demonstrated that 17 of these infants and 1 health care worker who had onychomycosis had the same clone. Infants who were exposed to this health care worker in August 1998 were at greater risk of having this clone than infants who were not exposed to this health care worker (odds ratio, 41.2; 95 percent confidence interval, 1.8 to 940.0; P=0.006). CONCLUSIONS An increased rate of infection and colonization with P. aeruginosa among infants in neonatal intensive care units should be investigated by assessing potential reservoirs, including environmental sources as well as patients and health care workers.

Effect of Perinatal Antiretroviral Drug Exposure on Hematologic Values in HIV-Uninfected Children: An Analysis of the Women and Infants Transmission Study

BACKGROUND With the increasing use of antiretroviral (ARV) drugs to prevent mother-to-child transmission of human immunodeficiency virus (HIV), large numbers of infants are exposed, with possible consequent toxicity. METHODS Hematologic values in 1820 uninfected HIV- and ARV-exposed children were compared with those in 351 ARV-unexposed children from the Women and Infants Transmission Study. Hemoglobin concentrations and platelet, neutrophil, lymphocyte, and CD4+ and CD8+ cell counts were analyzed at birth and ages 2, 6, 12, 18, and 24 months. Multivariate analysis was conducted age 0-2 and 6-24 months, with adjustment for multiple cofactors. RESULTS Hemoglobin concentrations and neutrophil, lymphocyte, and CD4+ cell counts were significantly lower at age 0-2 months in infants exposed to ARV drugs than in those who were not. At 6-24 months, differences in hemoglobin concentrations and neutrophil counts were no longer significant, whereas differences in platelet, lymphocyte, and CD4+ cell counts persisted and CD8+ cell counts became significantly lower. In comparison with ARV monotherapy, combination therapy was associated with larger decreases in neutrophil, lymphocyte, and CD8+ cell counts at age 0-2 months but with only differences in CD8+ cell counts at age 6-24 months. Clinically significant abnormalities were rare and did not differ by exposure to ARV drugs. CONCLUSION Infants exposed to ARV drugs have small but significant differences in several hematologic parameters for the first 24 months of life. These results indicate the need for long-term follow-up of uninfected infants with ARV exposure.

Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents

BACKGROUND There is limited evidence about longer-term effects of combination antiretroviral therapy that includes protease inhibitors (PIs) on the immunological status of HIV-1-infected children. Better understanding might help to resolve questions on when to initiate treatment. METHODS The change in percentage of CD4-positive T lymphocytes (CD4%) was investigated in 1012 previously treated HIV-1-infected children (aged 0-17 years) who were enrolled in research clinics in the USA before 1996 and followed up to 2000. 702 started PI-based combination therapy. Data analyses ignored subsequent treatment changes. FINDINGS Among the 1012 children, the median CD4% increased from 22% to 28% between 1996, when PIs were first prescribed, and 2000. For the 702 who started PI-based therapy, the mean CD4% increase after 3 years was largest among participants with the greatest immunosuppression (15.7%, 10.6%, 5.1%, and 2.0% for participants with CD4% before therapy of <5%, 5-14%, 15-24%, and >25%; p<0.0001). After adjustment for pre-PI CD4%, the mean increase was largest among the youngest participants (9.2%, 8.0%, and 4.3% for ages <5 years, 5-9 years, and >10 years; p=0.001). However, only a minority of significantly immunocompromised participants (33%, 26%, and 49% of those with pre-PI CD4% of <5%, 5-14%, or 15-24%) achieved CD4% values above 25%, whereas 84% of those with pre-PI values above 25% maintained such values. INTERPRETATION Although PI-based therapy was associated with substantial improvements in CD4%, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4%. Randomised investigation of when to start combination therapy in children, particularly infants, is needed.

Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study.

Background:To evaluate rate and types of birth defects according to timing of antiretroviral exposure among babies born to HIV-infected women. Methods:Anomalies identified during the prenatal, neonatal, or follow-up period were classified using criteria of the Antiretroviral Pregnancy Registry. Antiretroviral use was classified as none, second or third trimester only, or first trimester. Results:From January 1, 1990 through June 30, 2004, 2527 live births (LBs) occurred to 2353 women. Defects were identified in 90 babies for a rate of 3.56 defects per 100 LBs. The rate of defects was 3.19 per 100 LBs (24 of 752 LBs) with first-trimester antiretroviral exposure, 3.54 per 100 LBs (41 of 1158 LBs) with exposure later in pregnancy, and 4.05 of 100 LBs (25 of 617 LBs) with no antiretroviral use. Only genital abnormalities, specifically hypospadias, were significantly increased among babies born to women with first-trimester exposure to antiretrovirals (7 of 382 male LBs) compared with the 2 other groups (2 of 892 male LBs; P = 0.007). On logistic regression, use of zidovudine in the first trimester was associated with hypospadias (adjusted odds ratio = 10.68, 95% confidence interval: 2.11 to 54.13; P = 0.004). Conclusions:In general, data were reassuring, although the frequency of exposure to newer agents was limited. The increased risk of hypospadias after first-trimester exposure must be explored, because this association has not been detected previously.

Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life.

Introduction:HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood. Methods:We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African–American or Hispanic Tanner stage 5 men aged 20–25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls. Results:HIV-infected men were similar in age and BMI, but were more likely to be African–American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4–1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14–17% lower bone stiffness by finite element analysis. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence. Conclusion:At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.

Antiretroviral exposure and lymphocyte mtDNA content among uninfected infants of HIV-1-infected women.

OBJECTIVE: Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase γ, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction. METHODS: We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay. RESULTS: Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure. CONCLUSIONS: Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children.

Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics.

To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV‐infected women and appropriate NVP dosing in this population.

Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection.

OBJECTIVE. An unstructured treatment interruption in children with perinatally acquired HIV infection is an issue with unresolved significance. The objective of this study was to investigate the actual prevalence and clinical outcomes of a treatment interruption in children and adolescents with perinatally acquired HIV-1 infection. METHODS. Clinical data were analyzed for 72 children and adolescents who had HIV-1 infection and stopped their medications at 4 academic centers in the United States between January 2000 and September 2004. RESULTS. Among 405 patients with perinatal HIV-1 infection, 72 (17.8%) experienced a treatment interruption during the observation period. The mean age of patients at the time of the treatment interruption was 12.8 years, and the mean length of the treatment interruption was 14 months. Medication fatigue was the most common reason for a treatment interruption. The CD4+ T-cell percentage nadir before the treatment interruption did not predict CD4+ T-cell percentage declines during the treatment interruption; however, the CD4+ T-cell percentage gain from nadir to the time of the treatment interruption predicted CD4+ T-cell percentage declines during the treatment interruption. During the median follow-up of 19 months (range: 6–48 months), 48 (67%) patients resumed antiretroviral medications. As expected, there was a continuous CD4+ T-cell percentage decrease and plasma HIV-1 RNA increase during the observation period. Overall, 7 (10%) patients were admitted to the hospital; 2 (3%) patients experienced an AIDS-defining illness. CONCLUSIONS. An unstructured treatment interruption seems to be a major issue for youth with perinatally acquired HIV-1 infection. Patients who experienced the greatest rise in CD4+ T-cell percentage on treatment had the largest CD4+ T-cell percentage decline after the treatment interruption. Close monitoring is required when a treatment interruption occurs in children and adolescents with HIV infection.

Gender differences in lymphocyte populations, plasma HIV RNA levels, and disease progression in a cohort of children born to women infected with HIV.

OBJECTIVE. We sought to document gender differences in lymphocyte subsets and plasma RNA levels in a pediatric cohort with presumed minimal hormonal differences (on the basis of age). METHODS. Blood samples from antiretroviral therapy-treated, HIV-infected children (n = 158) and HIV-uninfected children (n = 1801) who were enrolled in the Women and Infants Transmission Study were analyzed at specified study intervals with consensus protocols, and various parameters were compared. RESULTS. Antiretroviral therapy-treated, HIV-infected female children had, on average, 0.38 log10 copies per mL lower plasma RNA levels than did their male counterparts, but lymphocyte differences were not noted in this cohort. Despite their higher plasma RNA level, a greater proportion of male children survived through 8 years of age. There were no gender differences with respect to the age of diagnosis of HIV, time to antiretroviral therapy after diagnosis of HIV, or type of antiretroviral therapy. Lymphocyte differences were noted for uninfected children. CONCLUSIONS. Plasma RNA levels differed among antiretroviral therapy-treated, HIV-infected children according to gender, in a manner similar to that noted in previous pediatric and adult studies. Lymphocyte subsets varied according to gender in a cohort of HIV-exposed but uninfected children. Most importantly, overall mortality rates for this cohort differed according to gender.

Endocrine abnormalities and impaired growth in human immunodeficiency virus-infected children.

Objectives: Identify endocrine differences between human immunodeficiency virus– (HIV) infected versus uninfected children and evaluate associations of growth and body composition with endocrine measures. Study Design: Nested case-control study in 21 HIV-infected and 46 age- and sex-matched uninfected children in the Women and Infant Transmission Study. Plasma specimens from children between 2.5 to 7.0 years of age, taken during 3–4 visits, were tested for insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, dehydroepiandrosterone (DHEA), growth hormone and thyroid studies. Longitudinal mixed and generalized estimating equation models compared group means and examined effects of endocrine measures on growth and body composition, respectively. Results: HIV-infected children had lower IGFBP-3 than uninfected children (1.96 ± 0.09 mg/L versus 2.34 ± 0.06 mg/L, P < 0.001). In infected but not in uninfected children, IGFBP-3 values and DHEA:cortisol ratios were associated with weight- and body mass index–for-age z scores ([WAZ] P = 0.019, <.001 respectively, and [BMZ] P = 0.029, 0.038). DHEA concentration was associated with height-for-age z score (P = 0.049). Conclusions: In these HIV-infected children compared with their uninfected counterparts, IGFBP-3 concentration was different between groups. Infected children had multiple endocrine associations with growth and body composition not found in their uninfected peers. We hypothesize that in HIV-infected children, growth hormone resistance and shunting of precursors from adrenal androgen to cortisol production contributes to altered body composition and stunting.