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Background. Human immunodeficiency virus–exposed but uninfected (HIV-EU) children have a higher mortality rate than the children of HIV-negative mothers (HIV-unexposed). Causal mediators of the poor health outcomes of HIV-EU children remain poorly defined. Methods. We conducted a hospital-based prospective cohort study of children aged 1 to 23 months with clinically defined pneumonia. The children were recruited at a referral hospital in Gaborone, Botswana, between April 2012 and June 2016. The primary outcome, treatment failure at 48 hours, was assessed by an investigator blinded to the children’s HIV-exposure status. We examined associations between HIV exposure and pneumonia outcomes in HIV-uninfected children. We next determined whether the effect of HIV exposure on outcomes was mediated by low-birth-weight status, nonbreastfeeding, malnutrition, in utero exposure to combination antiretroviral therapy, or pneumonia severity. Results. A total of 352 HIV-uninfected children were included in these analyses, including 245 (70%) HIV-unexposed and 107 (30%) HIV-EU children. Their median age was 7.4 months, and 57% were male. Treatment failure occurred in 111 (32%) children, and 19 (5.4%) children died. HIV-EU children were more likely to fail treatment (risk ratio [RR], 1.57 [95% confidence interval (CI), 1.19–2.07]; P = .002) and had a higher in-hospital mortality rate (RR, 4.50 [95% CI, 1.86–10.85]; P = .001) than HIV-unexposed children. Nonbreastfeeding mediated 47% of the effect of HIV exposure on the risk of in-hospital death. Conclusions. HIV-EU children have worse pneumonia outcomes than HIV-unexposed children. Nonbreastfeeding mediates nearly half of the effect of HIV exposure on pneumonia mortality. Our findings provide additional evidence for a mortality benefit of breastfeeding by HIV-EU children.
This study was conducted between April 2012 and June 2016 at Princess Marina Hospital, a referral medical center in Gaborone, Botswana. The country’s HIV prevalence among adults aged 15 to 49 years was 22.2% in 2015 [13]. HIV-infected women in Botswana are counseled to exclusively breastfeed their children until they are at least 6 months of age unless replacement feeding is deemed to be acceptable, feasible, affordable, sustainable, and safe (AFASS); free infant formula is provided to HIV-infected women who meet these criteria, including mothers who are on combination antiretroviral therapy. Haemophilus influenzae type B (Hib) and 13-valent pneumococcal conjugate (PCV-13) vaccinations were introduced in Botswana in November 2010 and July 2012, respectively. These vaccines are administered routinely to infants in Botswana at 2, 3, and 4 months of age. Coverage estimates in 2014 for 3 doses of Hib vaccine and 3 doses of PCV-13 vaccine were 95% and 81%, respectively [14]. Children aged 1 to 23 months with pneumonia, defined by the World Health Organization (WHO) as “cough or difficulty in breathing with lower chest wall indrawing” [15], were eligible for inclusion. The presence of 1 or more danger signs (central cyanosis, convulsions, inability to drink, and abnormal sleepiness) at enrollment classified children as having WHO-defined severe pneumonia [15]. We excluded children with a chronic medical condition (other than HIV infection) that predisposed them to pneumonia, hospitalization in the previous 14 days, asthma, wheezing with resolution of lower chest wall indrawing after 2 or fewer bronchodilator treatments, or previous enrollment in this study. All children were recruited within 6 hours of triage in the emergency department. Recruitment occurred between Monday and Friday from 7:30 am to 4:30 pm and, when staffing was available, during evenings and weekends. Clinical care was provided on a pediatric ward staffed by medical officers and pediatric residents and supervised by pediatricians. Supplemental oxygen and continuous positive airway pressure (CPAP) were routinely available on the ward, but access to mechanical ventilation in the hospital’s 6-bed intensive care unit was limited. Antibiotic treatment decisions were made by the supervising pediatrician. Sociodemographic and clinical data were collected at enrollment from the initial physical examination, review of infant and maternal medical records, and a face-to-face questionnaire completed with the child’s caregivers. Severe acute malnutrition was defined as weight for length of less than −3 standard deviations from the median on standard WHO growth curves, a mid-upper arm circumference of less than 115 mm (for children aged 6 months or older), or bilateral edema of nutritional origin [16]. Hypoxia was defined as an oxygen saturation of <90% while breathing room air. Proximity to health care services was categorized as travel of <1 or ≥1 hour before first contact with the health system (at a clinic or hospital) on the enrollment date. To assess for current breastfeeding, caregivers were asked, “When this illness started, was the child breastfeeding?” Research staff assessed the children, reviewed their hospital charts daily until hospital discharge (or death), and recorded additional clinical information, including level of respiratory support and the dates and times of antibiotic doses. Study data were managed using REDCap electronic data-capture tools hosted at the Children’s Hospital of Philadelphia in Pennsylvania [17]. Women in Botswana are tested routinely for HIV during pregnancy using dual parallel rapid testing. Children of a mother with documented negative HIV testing results during pregnancy, at delivery, or at enrollment were classified as HIV-unexposed. Children whose mother tested positive for HIV before or at delivery were considered HIV-exposed. HIV-exposed children were classified as HIV-EU if they tested negative for HIV after the age of 6 weeks if they were exclusively formula fed, at least 6 weeks after breastfeeding cessation, or at enrollment. HIV testing of infants less than 18 months of age was performed using the Amplicor 1.5 HIV-1 DNA polymerase chain reaction (PCR) assay (Roche, Alameda, California). Testing of infants aged 18 months or older was performed using dual parallel rapid testing and, for children with positive or discordant results, a confirmatory HIV DNA PCR assay. Before April 2014, infant HIV testing was performed at the discretion of the clinical team. Thereafter, we collected a dried blood spot from all HIV-exposed infants and performed HIV testing using the Amplicor 1.5 HIV-1 DNA PCR assay. The primary outcome, treatment failure, was assessed at 48 (±2) hours by a study physician or nurse blinded to enrollment data, including the child’s HIV-exposure status. Treatment failure was defined as persistent lower chest wall indrawing, the development of new WHO danger signs, an oxygen saturation of <80% while breathing room air, need for CPAP or mechanical ventilation, and/or death. This definition was adapted for our setting from criteria used in previous studies of childhood pneumonia [18–20]. Training sessions were held every 3 months for study physicians and nurses throughout the study to standardize the assessment process. Children who were discharged from the hospital before 48 hours were considered treatment responders, but we attempted to contact their caregivers by telephone to confirm treatment response. Secondary outcomes included days of respiratory support (supplemental oxygen, CPAP, or mechanical ventilation), length of stay, and in-hospital death. For each day, only the highest level of respiratory support required by a child was recorded. The length of stay was calculated from time of triage in the emergency department to the time of hospital discharge or death. The analyses presented herein included only children who were classified as HIV-unexposed or HIV-EU. We documented baseline characteristics of the study population according to HIV-exposure status by using frequencies and percentages for categorical variables and medians and 25th and 75th percentiles for continuous variables. To assess for differences in these characteristics according to HIV-exposure status, we used the χ2 or Fisher exact test for categorical variables and 2-sample t tests for continuous variables. We used Cox proportional hazards to estimate risk ratios (RRs) for treatment failure and in-hospital mortality according to HIV-exposure status [21]. Given the right-skewed distribution of days of respiratory support and lengths of stay, we used negative binomial regression models to estimate incidence rate ratios (IRRs) for these outcomes according to HIV-exposure status. The analyses were adjusted for age and proximity to health care services (travel of <1 or ≥1 hour to a clinic or hospital for the current illness), which were potential confounding variables identified on the basis of subject matter knowledge and construction of a causal diagram (Figure 1) [12]. Causal diagram depicting the relationship between child HIV-exposure status and pneumonia outcome. We next sought to determine whether the following clinical variables were mediators of the effect of HIV exposure on pneumonia outcomes: (1) low-birth-weight status, (2) current nonbreastfeeding, (3) severe malnutrition, (4) in utero exposure to combination antiretroviral therapy (compared with zidovudine monotherapy or no antiretroviral therapy), and (5) WHO-defined severe pneumonia. We first included HIV exposure, the candidate mediator, and the potential confounders of age and proximity to healthcare services in log binomial regression models for the outcomes of interest (treatment failure at 48 hours and in-hospital death). We next used logistic regression to evaluate whether HIV exposure was associated with each candidate mediator by adjusting for the same potential confounders. We considered a variable to be a significant mediator of the effect of in utero HIV exposure if we found evidence of associations with both the outcome and the exposure (P < .20). For candidate mediators that met these criteria, we calculated the ratio of the natural indirect effect to the total effect on the risk-difference scale, which can be interpreted as the proportion of the total effect of HIV exposure on the outcome that is mediated by that variable [22]. All statistical analyses were conducted using SAS 9.4 software (SAS Institute, Cary, North Carolina). This study was approved by the Health Research and Development Committee (Botswana Ministry of Health), the Princess Marina Hospital Ethics Committee, and the University of Pennsylvania, Children’s Hospital of Philadelphia, and Duke University institutional review boards. A legal guardian provided written informed consent for each child included in this study.
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