David P. Moore

Role of Streptococcus pneumoniae in hospitalization for acute community-acquired pneumonia associated with culture-confirmed Mycobacterium tuberculosis in children: a pneumococcal conjugate vaccine probe study.

Introduction: African children hospitalized with symptoms of severe acute pneumonia, which resolves following empiric antibiotic therapy, are sometimes identified to have underlying culture-confirmed pulmonary tuberculosis (PTB). Experimental studies suggest Mycobacterium tuberculosis infection predisposes to Streptococcus pneumoniae infection; however, diagnostic limitations make it difficult to quantify this association in children. We aimed to probe the extent of pneumococcal coinfection in children with PTB, using a vaccine-probe design study. Materials and Methods: A post hoc analysis of PTB cases occurring among 39,836 participants in a phase III randomized, double-blind placebo-controlled 9-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV9) trial in South Africa was undertaken. Hospitalization for PTB occurring during the 5.3 years of follow-up were identified and categorized as culture-confirmed PTB or probable/possible-PTB. The incidence rates of hospitalized PTB were compared between PCV9 vaccinees and placebo recipients. Results: Hospitalization for culture-confirmed PTB was 43.4% (95% CI, 9.7%–65.1%) less likely among vaccinees (n = 30) compared with placebo recipients (n = 53), incidence, 20 versus 35 per 100,000 child-years of follow-up (P = 0.0117). In HIV-infected children, culture-confirmed PTB was 47.3% (95% CI, 8.6%–69.6%) less likely among vaccinees (n = 19) compared with placebo recipients (n = 36), P = 0.0203. The incidence of possible/probable PTB did not differ by vaccination status. Conclusions: This vaccine-probe design study suggests that in a setting with high HIV and TB prevalence, culture-confirmed PTB in African children, which frequently presents with symptoms of acute pneumonia, is probably associated with superimposed pneumococcal pneumonia. Children admitted with pneumonia in these settings should be investigated for underlying PTB.

The impact of antiretroviral treatment on the burden of invasive pneumococcal disease in South African children: a time series analysis

Objective:HIV infection is a major risk factor for invasive pneumococcal disease (IPD). A national antiretroviral program was initiated in South Africa in 2004. This study evaluates the impact of the highly active antiretroviral therapy (HAART) treatment program on the burden of IPD among African children. Design:Retrospective analysis of laboratory-confirmed IPD among children under 18 years of age, from 2003 to 2008. Methods:The periods 2003–2004, 2005–2006 and 2007–2008 were defined as the early, intermediate and established HAART eras, respectively. Pneumococcal conjugate vaccine was not introduced into public immunization during this period. Results:One thousand, one hundred and seventy-one episodes of IPD were identified over the study period. Among HIV-infected children under 18 years, the burden of IPD decreased by 50.8% [95% confidence interval (CI) 41.5–58.7] and the incidence of IPD-related mortality declined by 65.2% (95% CI 47.2–77.0) from the early compared to the established HAART era. This decline in HIV-infected children was evident for pneumococcal bacteremia and pneumococcal meningitis. In addition, similar reductions were observed for serotypes included in a 7-valent pneumococcal conjugate vaccine and nonvaccine serotypes. The burden of IPD remained unchanged in HIV-uninfected children under 18 years of age over these periods. The risk of IPD, however, remained 42-fold greater in HIV-infected compared to HIV-uninfected children in the established HAART era. Conclusions:Although the HAART program has been associated with significant declines in IPD morbidity and mortality, HIV-infected African children with access to HAART remain a high-risk group for IPD. These children should therefore be prioritized in the prevention of IPD.

High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study

BackgroundThere are limited data on the prevalence of multi-drug resistant tuberculosis (MDR-TB), estimated at 0.6-6.7%, in African children with tuberculosis. We undertook a retrospective analysis of the prevalence of MDR-TB in children with Mycobacterium tuberculosis (MTB) at two hospitals in Johannesburg, South Africa.MethodsCulture-confirmed cases of MTB in children under 14 years, attending two academic hospitals in Johannesburg, South Africa during 2008 were identified and hospital records of children diagnosed with drug-resistant TB were reviewed, including clinical and radiological outcomes at 6 and 12 months post-diagnosis. Culture of Mycobacterium tuberculosis complex (MTB) was performed using the automated liquid broth MGIT™ 960 method. Drug susceptibility testing (DST) was performed using the MGIT™ 960 method for both first and second-line anti-TB drugs.Results1317 children were treated for tuberculosis in 2008 between the two hospitals where the study was conducted. Drug susceptibility testing was undertaken in 148 (72.5%) of the 204 children who had culture-confirmed tuberculosis. The prevalence of isoniazid-resistance was 14.2% (n = 21) (95%CI, 9.0-20.9%) and the prevalence of MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%). The prevalence of HIV co-infection was 52.1% in children with drug susceptible-TB and 53.9% in children with MDR-TB. Ten (76.9%) of the 13 children with MDR-TB received appropriate treatment and four (30.8%) died at a median of 2.8 months (range 0.1-4.0 months) after the date of tuberculosis investigation.ConclusionsThere is a high prevalence of drug-resistant tuberculosis in children in Johannesburg in a setting with a high prevalence of HIV co-infection, although no association between HIV infection and MDR-TB was found in this study. Routine HIV and drug-susceptibility testing is warranted to optimize the management of childhood tuberculosis in settings such as ours.

Safety of Induced Sputum Collection in Children Hospitalized With Severe or Very Severe Pneumonia

Abstract Background. Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods. IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. Results. A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%–0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as “possibly related” to the procedure. Conclusions. The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.

Effectiveness of pneumococcal conjugate vaccine against presumed bacterial pneumonia hospitalisation in HIV-uninfected South African children: a case–control study

Introduction We evaluated pneumococcal conjugate vaccine (PCV) effectiveness against hospitalisation for presumed bacterial pneumonia (PBP) in HIV-uninfected South African children. 7-valent PCV was introduced in April 2009 using a 2+1 schedule (doses at age 6, 14 and 39 weeks), superseded with 13-valent PCV in May 2011. Methods A matched case–control study was conducted at three public hospitals (Soweto, Cape Town and KwaZulu-Natal) between April 2009 and August 2012. PBP cases had either WHO defined radiographically confirmed pneumonia or ‘other infiltrate’ on chest radiograph with C-reactive protein ≥40 mg/L. Hospitalised controls were children admitted with a disease unlikely to be pneumococcal and matched for case age, site and HIV infection status. Age-matched community controls were enrolled from Soweto. Adjusted vaccine effectiveness (aVE) was estimated using conditional logistic regression. Results Of 1444 HIV-uninfected enrolled PBP cases, 1326 had ≥1 hospital controls (n=2075). Overall, aVE of an up-to-date PCV schedule was 20.1% (95% CI −9.3% to 41.6%) in children aged ≥8 weeks and 39.2% (95% CI 8.46% to 59.6%) among children 16–103 weeks of age. There were 889 PBP cases in Soweto with hospital controls and ≥1 community control (n=2628). The aVE using community controls was similar compared with hospital controls in Soweto, including 32.1% (95% CI 4.6% to 51.6%) and 38.4% (95% CI 7.7% to 58.8%), respectively, in age group ≥8 weeks and 52.7% (95% CI 25.7% to 69.9%) and 53.8% (95% CI 19.5% to 73.5%), respectively, in age group 16–103 weeks. Conclusions PCV implemented using a 2+1 schedule in the routine infant immunisation programme was effective at preventing PBP in HIV-uninfected children. Effectiveness estimates were similar to efficacy measured by earlier randomised controlled trials using different vaccination schedules.

Impact of the antiretroviral treatment program on the burden of hospitalization for culture-confirmed tuberculosis in South African children: a time-series analysis.

Background: The HIV epidemic increased the burden of tuberculosis (TB) in sub-Saharan Africa. We evaluated the impact that scaling-up of the public-funded antiretroviral treatment (ART) program had on incidence of hospitalization for culture-confirmed and overall-TB in HIV-infected and HIV-uninfected children from 2005 to 2009. Methods: The study was undertaken in Soweto, South Africa, where ART coverage of HIV-infected children increased from 43% in 2005 to 84% by 2009. Trends in incidence of hospitalization for clinically diagnosed and culture-confirmed TB in children 3 months to <15 years of age, identified through laboratory and electronic databases, were analyzed by comparing crude incidence and regression analysis. Results: The incidence (per 100,000) of culture-confirmed TB declined by 63.1% from 2005 (69.8) compared with 2009 (25.8; P < 0.0001). This included a 70.6% reduction between 2005 and 2009 among HIV-infected children (incidence: 1566.3 versus 460.7, respectively; P < 0.0001) and 41.3% decrease in HIV-uninfected children (18.7 versus 11.0, respectively; P = 0.0003). The month-by-month rate of decline of culture-confirmed TB was 2.3% in HIV-infected and 1.1% in HIV-uninfected children over the study period. The residual burden of TB remained 42-fold greater in HIV-infected children, 78% of whom were severely immune compromised, compared with HIV-uninfected children by 2009. Conclusion: Increase in ART coverage was associated with significant decline in TB hospitalizations in HIV-infected children. This reduction may also in part have been due to reduced Mycobacterium tuberculosis transmission resulting from increased ART access among HIV-infected adults, which may have contributed to the reduction of culture-confirmed TB in HIV-uninfected children.

Respiratory viral and pneumococcal coinfection of the respiratory tract: implications of pneumococcal vaccination.

The interactions between Streptococcus pneumoniae and other respiratory pathogens have been studied in vitro, in animal models and in humans – including epidemiologic and vaccine probe studies. Interactions of pneumococcus with respiratory viruses are common, and many mechanisms have been suggested to explain this phenomenon. The aim of this review is to explore pneumococcal interactions with respiratory viruses and consider the potential role that the pneumococcal polysaccharide–protein conjugate vaccine may play in modifying pneumococcal–respiratory viral interactions.

Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study

Summary In the Pneumonia Etiology Research for Child Health study, abnormal chest radiographs (CXRs) in cases were associated with hypoxemia, crackles, tachypnea, and fever. Overall, 54% of CXRs were abnormal (site range, 35%–64%). Consolidation on CXR was associated with an increased risk of mortality.

Standardized interpretation of chest radiographs in cases of pediatric pneumonia from the PERCH study

Abstract Background. Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. Methods. The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1–59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. Results. A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (κ = 0.50) and between arbitrators was 84% (κ = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (κ = 0.25) and 48.5% (κ = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). Conclusions. Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process.

Density of Upper Respiratory Colonization With Streptococcus pneumoniae and Its Role in the Diagnosis of Pneumococcal Pneumonia Among Children Aged <5 Years in the PERCH Study

Upper airway pneumococcal colonization density among children hospitalized with World Health Organization–defined pneumonia was associated with microbiologically confirmed pneumococcal pneumonia (MCPP). The optimal colonization density threshold for discriminating MCPP from non-MCPP was ≥7 log10 copies/mL (sensitivity, 64.3%, specificity, 92.2%).