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Background: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children.Methods: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART.Results: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died).Conclusions: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Rubella is a disease of public health significance owing to its adverse effects during pregnancy and on pregnancy outcomes. Women who contract rubella virus during pregnancy may experience complications such as foetal death or give birth to babies born with congenital rubella syndrome. Vaccination against rubella is the most effective and economical approach to control the disease, and to avoid the long term effects and high costs of care for children with congenital rubella syndrome as well as to prevent death from complications. Zimbabwe commenced rubella surveillance in 1999, despite lacking a rubella vaccine in the national Expanded Programme on Immunization, as per the World Health Organization recommendation to establish a surveillance system to estimate the disease burden before introduction of a rubella vaccine. The purpose of this analysis is to describe the disease trends and population demographics of rubella cases that were identified through the Zimbabwe national measles and rubella case-based surveillance system during a 5-year period between 2007 and 2011. Methods: Data from the Zimbabwe National Measles Laboratory for the 5-year study period were analysed for age, sex, district of origin, seasonality, and rubella IgM serostatus. Results: A total of 3428 serum samples from cases of suspected measles in all administrative districts of the country were received by the laboratory during this period. Cases included 51% males and 49% females. Of these, 2999 were tested for measles IgM of which 697 (23.2%) were positive. Of the 2302 measles IgM-negative samples, 865 (37.6%) were rubella IgM-positive. Ninety-eight percent of confirmed rubella cases were children younger than 15 years of age. Most infections occurred during the dry season. Conclusions: The national case-based surveillance revealed the disease burden and trends of rubella in Zimbabwe. These data add to the evidence for introducing rubella-containing vaccine into the national immunization programme. [ABSTRACT FROM AUTHOR]

Cotrimoxazole reduces systemic and intestinal inflammation in HIV infection by suppressing gut-resident Streptococci and immune cell activation. Cotrimoxazole curbs inflammation: Prophylactic antibiotics are used in HIV-endemic areas and have been shown to reduce mortality and morbidity. Using samples from a clinical trial where HIV-positive children were randomized to continue or stop cotrimoxazole, Bourke et al. examined potential mechanisms behind these protective effects. They observed decreases of certain types of Streptococcus in the gut and decreased systemic inflammatory markers in children who continued treatment. Treatment of primary samples from HIV-infected adults or a gut epithelial cell line revealed that cotrimoxazole dampened inflammatory cytokine production. Their results showcase how this antibiotic interacts with the gut microbiome and the immune system to alter the inflammatory response with beneficial outcomes. Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Background: Rubella is a disease of public health significance owing to its adverse effects during pregnancy and on pregnancy outcomes. Women who contract rubella virus during pregnancy may experience complications such as foetal death or give birth to babies born with congenital rubella syndrome. Vaccination against rubella is the most effective and economical approach to control the disease, and to avoid the long term effects and high costs of care for children with congenital rubella syndrome as well as to prevent death from complications. Zimbabwe commenced rubella surveillance in 1999, despite lacking a rubella vaccine in the national Expanded Programme on Immunization, as per the World Health Organization recommendation to establish a surveillance system to estimate the disease burden before introduction of a rubella vaccine. The purpose of this analysis is to describe the disease trends and population demographics of rubella cases that were identified through the Zimbabwe national measles and rubella case-based surveillance system during a 5-year period between 2007 and 2011.Methods: Data from the Zimbabwe National Measles Laboratory for the 5-year study period were analysed for age, sex, district of origin, seasonality, and rubella IgM serostatus.Results: A total of 3428 serum samples from cases of suspected measles in all administrative districts of the country were received by the laboratory during this period. Cases included 51% males and 49% females. Of these, 2999 were tested for measles IgM of which 697 (23.2%) were positive. Of the 2302 measles IgM-negative samples, 865 (37.6%) were rubella IgM-positive. Ninety-eight percent of confirmed rubella cases were children younger than 15 years of age. Most infections occurred during the dry season.Conclusions: The national case-based surveillance revealed the disease burden and trends of rubella in Zimbabwe. These data add to the evidence for introducing rubella-containing vaccine into the national immunization programme. [ABSTRACT FROM AUTHOR]