Menu
Menu
Menu
Menu
BACKGROUND: Despite recent declines in new pediatric HIV infections and childhood HIV-related deaths, pneumonia remains the leading cause of death in HIV-infected children under 5. We describe the patient population, etiology and outcomes of childhood pneumonia in Zambian HIV-infected children. METHODS: As one of the 9 sites for the Pneumonia Etiology Research for Child Health study, we enrolled children 1-59 months of age presenting to University Teaching Hospital in Lusaka, Zambia, with World Health Organization-defined severe and very severe pneumonia. Controls frequency-matched on age group and HIV infection status were enrolled from the Lusaka Pediatric HIV Clinics as well as from the surrounding communities. Clinical assessments, chest radiographs (CXR; cases) and microbiologic samples (nasopharyngeal/oropharyngeal swabs, blood, urine, induced sputum) were obtained under highly standardized procedures. Etiology was estimated using Bayesian methods and accounted for imperfect sensitivity and specificity of measurements. RESULTS: Of the 617 cases and 686 controls enrolled in Zambia over a 24-month period, 103 cases (16.7%) and 85 controls (12.4%) were HIV infected and included in this analysis. Among the HIV-infected cases, 75% were <1 year of age, 35% received prophylactic trimethoprim-sulfamethoxazole, 13.6% received antiretroviral therapy and 36.9% of caregivers reported knowing their children's HIV status at time of enrollment. A total of 35% of cases had very severe pneumonia and 56.3% had infiltrates on CXR. Bacterial pathogens [50.6%, credible interval (CrI): 32.8-67.2], Pneumocystis jirovecii (24.9%, CrI: 15.5-36.2) and Mycobacterium tuberculosis (4.5%, CrI: 1.7-12.1) accounted for over 75% of the etiologic fraction among CXR-positive cases. Streptococcus pneumoniae (19.8%, CrI: 8.6-36.2) was the most common bacterial pathogen, followed by Staphylococcus aureus (12.7%, CrI: 0.0-25.9). Outcomes were poor, with 41 cases (39.8%) dying in hospital. CONCLUSIONS: HIV-infected children in Zambia with severe and very severe pneumonia have poor outcomes, with continued limited access to care, and the predominant etiologies are bacterial pathogens, P. jirovecii and M. tuberculosis.
The Zambia PERCH study site was located at the University Teaching Hospital (UTH) in the densely populated capital, Lusaka (population 1.7 million17). While Zambia is considered a lower-middle-income country (per capita income $4300), at the time of the study (November 2011 to October 2013), approximately 74% of the country’s population was living in extreme poverty (<$2/d).18 UTH provides free health services to the most impoverished in Lusaka. As the primary academic and tertiary healthcare facility and the main country-wide referral center, UTH has a 425-bed in-patient pediatric ward with dedicated Malnutrition and Intensive Care Units. Access to mechanical ventilation was limited and rarely used. Obtaining radiographs required taking children to the Radiology Department at some distance from the pediatric wards and at the caregivers’ expense, therefore, were not routinely performed (for nonstudy patients). Oxygen, however, was routinely available. The majority of children presenting for pneumonia care at UTH are referred from outlying Lusaka clinics after receiving 1 dose of antibiotics. Hib conjugate vaccine was introduced in 2004 with 81% estimated 3-dose coverage before the study.19 PCV10 was only universally introduced in July 2013 during the final 3 months of study enrollment. In 2013, HIV prevalence in Lusaka among women of childbearing age was 19.4%.20 Antenatal PMTCT care was nearly universal (91%) in Zambia, leading to a decline in vertical HIV transmission from 24% in 2009 to 12% by 2012.21 By 2013, an estimated 54% of the 150,000 Zambian HIV-infected children were accessing antiretroviral therapy (ART).22 While pediatric HIV seroprevalence rates at UTH were unavailable at the time of PERCH, a 2007 study found 29.2% HIV antibody positive rate among over 11,500 children tested in the pediatric ward.23 At the time of PERCH, the standard of care for HIV-infected children <2 years was to initiate ART regardless of CD4 count or clinical staging.24 For 2- to 5-year-old children, ART was initiated if the CD4 count was ≤750 cells/mm3, CD4 percentage <25% or clinical concern for advanced disease based on WHO staging.24 The most common first-line ART regimen consisted of lopinavir/ritonavir plus 2 nucleoside reverse transcriptase inhibitors. CTM prophylaxis beginning at 4–6 weeks of age was universally recommended and available for all HIV-infected and exposed children. PERCH methods have been published elsewhere.15,25 Unless otherwise noted, cases for this analysis were HIV-infected hospitalized children between the ages of 1 and 59 months living in the Lusaka catchment area presenting with signs and symptoms of WHO-defined severe or very severe pneumonia (2005 definition), including cough and/or difficulty in breathing, plus danger signs (central cyanosis, difficulty breast-feeding/drinking, vomiting everything, multiple or prolonged convulsions, lethargy/unconsciousness or head nodding) defined as “very severe pneumonia,” or lower chest wall indrawing in the absence of danger signs defined as “severe pneumonia.”26 Cases were enrolled on weekdays from 0730 to 1800 hours due to weekend constraints for sample processing and limited weekend and nighttime staffing. Nighttime admissions were eligible for study enrollment the following morning. HIV-infected controls, recruited from Pediatric HIV clinics in the Lusaka area without evidence of pneumonia, were age-frequency matched to HIV-infected cases using 4 strata: 1–5, 6–11, 12–23 and 24–59 months. A few HIV-infected controls were (incidentally) enrolled during routine community control recruitment.16 Cases were examined at admission and 24 and 48 hours postadmission. Cases that survived to discharge were seen 30 days after discharge to ascertain vital status. Chest radiographs (CXRs) were performed at admission and classified as normal, consolidation, other infiltrate, consolidation and other infiltrate or uninterpretable based on WHO methods.27,28 Clinical assessments of controls were completed at the time of enrollment. Specimen collection and laboratory methods were highly standardized across study sites.29–33 From all participants, we collected nasopharyngeal/oropharyngeal (NP/OP) swabs for polymerase chain reaction (PCR) for respiratory pathogens using a 33-pathogen multiplex quantitative PCR (FTD Resp-33; Fast-track Diagnostics, Sliema, Malta) and culture (plus serotyping) for pneumococcus, blood for pneumococcal PCR and serum for antibiotic activity testing.31 From cases, we also collected blood for bacterial culture and induced sputum for MTB culture. For four pathogens with similar prevalence in cases and controls, positivity was defined using quantitative PCR density thresholds; including S. pneumoniae (≥2.2 log10 copies/mL) from whole blood34 and S. pneumoniae (≥6.9 log10 copies/mL),35 H. influenzae (≥5.9 log10 copies/mL),36 CMV (≥4.9 log10 copies/mL) and Pj (≥4 log10 copies/mL),36 NP/OP (CMV threshold analysis available from authors). Maternal HIV status was obtained from the infant perinatal card or if the mother indicated she was HIV-infected. The child’s blood was tested by PCR if <18 months or HIV antibody if ≥18 months as per Zambian guidelines. Odds ratios (OR) and 95% confidence intervals (CI) of pathogens detected on NP/OP PCR in cases compared with controls were calculated using logistic regression adjusted for age in months and presence of all other pathogens detected on NP/OP PCR to account for associations between pathogens. Logistic regression adjusted for age in months was used to compare clinical characteristics by case–control status and, among cases, by vital status. Results were stratified by HIV infection and exposure status. The percent of pneumonia due to each pathogen was estimated using the PERCH Integrated Analysis (PIA) method, which is described in detail elsewhere (see reference 39, Appendix Section III B).37–39 In brief, the PIA is a Bayesian nested partially latent class analysis that integrates the results for each case from blood culture, NP/OP PCR, whole-blood PCR for pneumococcus and induced sputum culture for MTB. The PIA also integrates test results from controls to account for imperfect test specificity of NP/OP PCR and whole-blood PCR. Blood culture results (excluding contaminants) and MTB results were assumed to be 100% specific (ie, the etiology for a case was attributed 100% to the pathogen that was detected in their blood by culture). The model assumes that each child's pneumonia was caused by a single pathogen. The PIA accounts for imperfect sensitivity of each test/pathogen measurement by using a priori estimates of their sensitivity (ie, estimates regarding the plausibility range of sensitivity which varied by laboratory test method and pathogen) (Supplemental Digital Content 1, http://links.lww.com/INF/D818). Sensitivity of blood culture was reduced if blood volume was low (<1.5 mL) or if antibiotics were administered before specimen collection. Sensitivity of NP/OP PCR for S. pneumoniae and H. influenzae was reduced if antibiotics were administered before specimen collection. As a Bayesian analysis, both the list of pathogens and their starting “prior” etiologic fraction values were specified a priori, which favored no pathogen over another (ie, “uniform”). The pathogens selected for inclusion in the analysis included any noncontaminant bacteria detected by culture in blood at any of the 9 PERCH sites, regardless of whether it was observed at the Zambia site specifically, MTB, and all of the multiplex quantitative PCR pathogens except those considered invalid because of poor assay specificity (Klebsiella pneumoniae40 and Moraxella catarrhalis). A category called “Pathogens Not Otherwise Specified” was also included to estimate the fraction of pneumonia caused by pathogens not tested for or not observed. A child negative for all pathogens would still be assigned an etiology, which would be either one of the explicitly estimated pathogens (implying a “false negative,” accounting for imperfect sensitivity of certain measurements) or “Pathogens Not Otherwise Specified.” All analyses were adjusted for age (<1 vs. ≥1 year) to account for differences in pathogen prevalences by this factor; analyses stratified by pneumonia severity could not adjust for age due to small sample size. For results stratified by case clinical data (eg, to CXR+, very severe, etc), the test results from all controls were used. However, for analyses stratified by age, only data from controls representative of that age group were used. The PIA estimated both the individual and population-level etiology probability distributions, each summing to 100% across pathogens where each pathogen has a probability ranging from 0% to 100%. The population-level etiologic fraction estimate for each pathogen was approximately the average of the individual case probabilities and was provided with a 95% credible interval (95% CrI), the Bayesian analog of the confidence interval. Statistical analyses were conducted using SAS 9.3 (SAS Institute, Cary, NC), R Statistical Software 3.3.1 (The R Development Core Team, Vienna, Austria), Bayesian inference software JAGS 4.2.0 (http://mcmc-jags.sourceforge.net/) and BAKER, the R package used to perform the PIA (https://github.com/zhenkewu/baker). The study protocol was approved by the Institutional Review Boards at Boston University, the Johns Hopkins Bloomberg School of Public Health in the United States, and by the ERES Converge Ethical Review Committee in Zambia. Parents or guardians of participants provided written informed consent.
