Bareng A. S. Nonyane

Estimating the Burden of Pneumococcal Pneumonia among Adults: A Systematic Review and Meta-Analysis of Diagnostic Techniques

Background Pneumococcal pneumonia causes significant morbidity and mortality among adults. Given limitations of diagnostic tests for non-bacteremic pneumococcal pneumonia, most studies report the incidence of bacteremic or invasive pneumococcal disease (IPD), and thus, grossly underestimate the pneumococcal pneumonia burden. We aimed to develop a conceptual and quantitative strategy to estimate the non-bacteremic disease burden among adults with community-acquired pneumonia (CAP) using systematic study methods and the availability of a urine antigen assay. Methods and Findings We performed a systematic literature review of studies providing information on the relative yield of various diagnostic assays (BinaxNOW® S. pneumoniae urine antigen test (UAT) with blood and/or sputum culture) in diagnosing pneumococcal pneumonia. We estimated the proportion of pneumococcal pneumonia that is bacteremic, the proportion of CAP attributable to pneumococcus, and the additional contribution of the Binax UAT beyond conventional diagnostic techniques, using random effects meta-analytic methods and bootstrapping. We included 35 studies in the analysis, predominantly from developed countries. The estimated proportion of pneumococcal pneumonia that is bacteremic was 24.8% (95% CI: 21.3%, 28.9%). The estimated proportion of CAP attributable to pneumococcus was 27.3% (95% CI: 23.9%, 31.1%). The Binax UAT diagnosed an additional 11.4% (95% CI: 9.6, 13.6%) of CAP beyond conventional techniques. We were limited by the fact that not all patients underwent all diagnostic tests and by the sensitivity and specificity of the diagnostic tests themselves. We address these resulting biases and provide a range of plausible values in order to estimate the burden of pneumococcal pneumonia among adults. Conclusions Estimating the adult burden of pneumococcal disease from bacteremic pneumococcal pneumonia data alone significantly underestimates the true burden of disease in adults. For every case of bacteremic pneumococcal pneumonia, we estimate that there are at least 3 additional cases of non-bacteremic pneumococcal pneumonia.

Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults.

Objective:In settings of high HIV prevalence, tuberculosis control and patient management are hindered by lack of accurate, rapid tuberculosis diagnostic tests that can be performed at point-of-care. The Determine TB LAM Ag (TB LAM) test is a lateral flow immunochromatographic test for detection of mycobacterial lipoarabinomannan (LAM) in urine. Our objective was to determine sensitivity and specificity of the TB LAM test for tuberculosis diagnosis. Design:Prospective diagnostic accuracy study. Setting:Hospital and outpatient settings in Uganda and South Africa. Participants:HIV-infected adults with tuberculosis symptoms and/or signs. Methods:Participants provided a fresh urine specimen for TB LAM testing, blood for mycobacterial culture, and 2 respiratory specimens for smear microscopy and mycobacterial culture. Main Outcome Measures:For the TB LAM test, sensitivity in participants with culture-positive tuberculosis and specificity in participants without tuberculosis. Results:A total of 1013 participants were enrolled. Among culture-positive tuberculosis patients, the TB LAM test identified 136/367 (37.1%) overall and 116/196 (59.2%) in the group with CD4 ⩽100 cells per cubic millimeter. The test was specific in 559/573 (97.6%) patients without tuberculosis. Sensitivity of the urine TB LAM test plus sputum smear microscopy was 197/367 (53.7%) overall and 133/196 (67.9%) among those with CD4 ⩽100. CD4 ⩽50 [adjusted odds ratio (AOR), 6.2; P < 0.001] or 51–100 (AOR, 7.1; P < 0.001), mycobacteremia (AOR, 6.1; P < 0.01) and hospitalization (AOR, 2.6; P = 0.03) were independently associated with a positive TB LAM test. Conclusions:In HIV-positive adults with CD4 ⩽100, the TB LAM urine test detected over half of culture-positive tuberculosis patients, in <30 minutes and without the need for equipment or reagents.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Immunogenicity

Background: Despite the breadth of studies demonstrating benefits of pneumococcal conjugate vaccine (PCV), uncertainty remains regarding the optimal PCV dosing schedule in infants. Methods: We conducted a systematic literature review of PCV immunogenicity published from 1994 to 2010 (supplemented post hoc with studies from 2011). Studies included for analysis evaluated ≥2 doses of 7-valent or higher product (excluding Aventis-Pasteur PCV11) administered to nonhigh-risk infants ⩽6 months of age. Impact of PCV schedule on geometric mean antibody concentration (GMC) and proportion of subjects over 0.35 mcg/mL were assessed at various time points; the GMC 1 month postdose 3 (for various dosing regimens) for serotypes 1, 5, 6B, 14, 19F and 23F was assessed in detail using random effects linear regression, adjusted for product, acellular diphtheria-tetanus-pertussis/whole-cell diphtheria- tetanus-pertussis coadministration, laboratory method, age at first dose and geographic region. Results: From 61 studies, we evaluated 13 two-dose (2+0) and 65 three-dose primary schedules (3+0) without a booster dose, 11 “2+1” (2 primary plus booster) and 42 “3+1” schedules. The GMC after the primary series was higher following 3-dose schedules compared with 2-dose schedules for all serotypes except for serotype 1. Pre- and postbooster GMCs were generally similar regardless of whether 2 or 3 primary doses were given. GMCs were significantly higher for all serotypes when dose 3 was administered in the second year (2+1) compared with ⩽6 months of age (3+0). Conclusions: While giving the third dose in the second year of life produces a higher antibody response than when given as part of the primary series in the first 6 months, the lower GMC between the 2-dose primary series and booster may result in less disease protection for infants in that interval than those who completed the 3-dose primary series. Theoretical advantages of higher antibodies induced by giving the third dose in the second year of life, such as increased protection against serotype 1 disease, longer duration of protection or more rapid induction of herd effects, need to be evaluated in practice.

Point-of-Care Lateral Flow Assays for Tuberculosis and Cryptococcal Antigenuria Predict Death in HIV Infected Adults in Uganda

Background Mortality in hospitalized, febrile patients in Sub-Saharan Africa is high due to HIV-infected, severely immunosuppressed patients with opportunistic co-infection, particularly disseminated tuberculosis (TB) and cryptococcal disease. We sought to determine if a positive lateral flow assay (LFA) result for urine lipoarabinomannan (LAM) and cryptococcal antigenuria was associated with mortality. Methods 351 hospitalized, HIV-positive adults with symptoms consistent with TB and who were able to provide both urine and sputum specimens were prospectively enrolled at Mulago National Referral Hospital in Uganda as part of a prospective accuracy evaluation of the lateral flow Determine TB LAM test. Stored frozen urine was retrospectively tested for cryptococcal antigen (CRAG) using the LFA. We fitted a multinomial logistic regression model to analyze factors associated with death within 2 months after initial presentation. Results The median CD4 of the participants was 57 (IQR: 14–179) cells/µl and 41% (145) were microbiologically confirmed TB cases. LAM LFA was positive in 38% (134), 7% (25) were CRAG positive, and 43% (151) were positive for either test in urine. Overall, 21% (75) died within the first 2 months, and a total of 32% (114) were confirmed dead by 6 months. At 2 months, 30% of LAM or CRAG positive patients were confirmed dead compared to 15.0% of those who were negative. In an adjusted model, LAM or CRAG positive results were associated with an increased risk of death (RRR 2.29, 95% CI: 1.29, 4.05; P = 0.005). Conclusions In hospitalized HIV-infected patients, LAM or CRAG LFA positivity was associated with subsequent death within 2 months. Further studies are warranted to examine the impact of POC diagnostic ‘test and treat’ approach on patient-centered outcomes.

The Use of Indwelling Tunneled Pleural Catheters for Recurrent Pleural Effusions in Patients With Hematologic Malignancies: A Multicenter Study

BACKGROUND Malignant pleural effusion is a common complication of advanced malignancies. Indwelling tunneled pleural catheter (IPC) placement provides effective palliation but can be associated with complications, including infection. In particular, hematologic malignancy and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review outcomes in patients with hematologic malignancy undergoing IPC placement. METHODS A retrospective multicenter study of IPCs placed in patients with hematologic malignancy from January 2009 to December 2013 was performed. Inclusion criteria were recurrent, symptomatic pleural effusion and an underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, and pathology, cytology, and microbiology reports. RESULTS Ninety-one patients (mean ± SD age, 65.4 ± 15.4 years) were identified from eight institutions. The mean × SD in situ dwell time of all catheters was 89.9 ± 127.1 days (total, 8,160 catheter-days). Seven infectious complications were identified, all of the pleural space. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died of septic shock related to pleural infection. CONCLUSIONS We present, to our knowledge, the largest study examining clinical outcomes related to IPC placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality were identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present in this population. IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.

The Differential Impact of Coadministered Vaccines, Geographic Region, Vaccine Product and Other Covariates on Pneumococcal Conjugate Vaccine Immunogenicity

Background: Antipneumococcal capsular polysaccharide antibody concentrations are used as predictors of vaccine efficacy against vaccine serotype (ST) pneumococcal disease among infants. While pneumococcal conjugate vaccines (PCV) are recommended globally, factors associated with optimal PCV immune response are not well described. We aimed to systematically assess local setting factors, beyond dosing schedule, which may affect PCV antibody levels. Methods: We conducted a literature review of PCV immunogenicity, abstracting data from published reports, unpublished sources, and conference abstracts from 1994 to 2010 (and ad hoc 2011 reports). Studies included in this analysis evaluated ≥ 2 primary doses of PCV before 6 months of age in non–high-risk populations, used 7-valent or higher PCV products (excluding Aventis-Pasteur and Merck products) and provided information on geometric mean concentration (GMC) for STs 1, 5, 6B, 14, 19F or 23F. Using random effects meta-regression, we assessed the impact of geographic region, coadministered vaccines and PCV product on postprimary GMC, adjusting for dosing schedule and ELISA laboratory method. Results: Of 12,980 citations reviewed, we identified 103 vaccine study arms for this analysis. Children in studies from Asia, Africa and Latin America had significantly higher GMC responses compared with those in studies from Europe and North America. Coadministration with acellular pertussis DTP compared with whole-cell DTP had no effect on PCV immunogenicity except for ST14, where GMCs were higher when coadministered with acellular pertussis DTP. Vaccine product, number of PCV doses, dosing interval, age at first dose and ELISA laboratory method also affected the GMC. Conclusions: PCV immunogenicity is associated with geographic region and vaccine product; however, the associations and magnitude varied by ST. Consideration of these factors is essential when comparing PCV immunogenicity results between groups and should be included in the evidence base when selecting optimal PCV vaccine schedules in specific settings.

Contribution of community-based newborn health promotion to reducing inequities in healthy newborn care practices and knowledge: evidence of improvement from a three-district pilot program in Malawi

BackgroundInequities in both health status and coverage of health services are considered important barriers to achieving Millennium Development Goal 4. Community-based health promotion is a strategy that is believed to reduce inequities in rural low-income settings. This paper examines the contributions of community-based programming to improving the equity of newborn health in three districts in Malawi.MethodsThis study is a before-and-after evaluation of Malawi’s Community-Based Maternal and Newborn Care (CBMNC) program, a package of facility and community-based interventions to improve newborn health. Health Surveillance Assistants (HSAs) within the catchment area of 14 health facilities were trained to make pregnancy and postnatal home visits to promote healthy behaviors and assess women and newborns for danger signs requiring referral to a facility. “Core groups” of community volunteers were also trained to raise awareness about recommended newborn care practices. Baseline and endline household surveys measured the coverage of the intervention and targeted health behaviors for this before-and-after evaluation. Wealth indices were constructed using household asset data and concentration indices were compared between baseline and endline for each indicator.ResultsThe HSAs trained in the intervention reached 36.7% of women with a pregnancy home visit and 10.9% of women with a postnatal home visit within three days of delivery. Coverage of the intervention was slightly inequitable, with richer households more likely to receive one or two pregnancy home visits (concentration indices (CI) of 0.0786 and 0.0960), but not significantly more likely to receive a postnatal visit or know of a core group. Despite modest coverage levels for the intervention, health equity improved significantly over the study period for several indicators. Greater improvements in inequities were observed for knowledge indicators than for coverage of routine health services. At endline, a greater proportion of women from the poorest quintile knew three or more danger signs for pregnancy, delivery, and postpartum mothers than did women from the least poor quintile (change in CI: -0.1704, -0.2464, and -0.4166, respectively; p < 0.05). Equity also significantly improved for coverage of some health behaviors, including delivery at a health facility (change in CI: -0.0591), breastfeeding within the first hour (-0.0379), and delayed bathing (-0.0405).ConclusionsAlthough these results indicate promising improvements for newborn health in Malawi, the extent to which the CBMNC program contributed to these improvements in coverage and equity are not known. The strategies through which community-based programs are implemented likely play an important role in their ability to improve equity, and further research and program monitoring are needed to ensure that the poorest households are reached by community-based health programs.

Factors associated with delay in care-seeking for fatal neonatal illness in the Sylhet district of Bangladesh: results from a verbal and social autopsy study.

Background We conducted a social and verbal autopsy study to determine cultural–, social– and health system–related factors that were associated with the delay in formal care seeking in Sylhet district, Bangladesh. Methods Verbal and social autopsy interviews were conducted with mothers who experienced a neonatal death between October 2007 and May 2011. We fitted a semi–parametric regression model of the cumulative incidence of seeking formal care first, accounting for competing events of death or seeking informal care first. Results Three hundred and thirty–one neonatal deaths were included in the analysis and of these, 91(27.5%) sought formal care first; 26 (7.9%) sought informal care first; 59 (17.8%) sought informal care only, and 155 (46.8%) did not seek any type of care. There was lower cumulative incidence of seeking formal care first for preterm neonates (sub–hazard ratio SHR 0.61, P = 0.025), and those who delivered at home (SHR 0.52, P = 0.010); and higher cumulative incidence for those who reported less than normal activity (SHR 1.95, P = 0.048). The main barriers to seeking formal care reported by 165 mothers included cost (n = 98, 59.4%), believing the neonate was going to die anyway (n = 29, 17.7%), and believing traditional care was more appropriate (n = 26, 15.8%). Conclusions The majority of neonates died before formal care could be sought, but formal care was more likely to be sought than informal care. There were economic and social belief barriers to care–seeking. There is a need for programs that educate caregivers about well–recognized danger signs requiring timely care–seeking, particularly for preterm neonates and those who deliver at home.

Use of One-Way Intrabronchial Valves in Air Leak Management after Tube Thoracostomy Drainage

BACKGROUND A persistent air leak represents significant clinical management problems, potentially affecting morbidity, mortality, and health care costs. In 2008, a unidirectional, intrabronchial valve received humanitarian device exemption for use in managing prolonged air leak after pulmonary resection. Since its introduction, numerous reports exist but no large series describe current utilization or outcomes. Our aim was to report current use of intrabronchial valves for air leaks and review outcome data associated with its utilization. METHODS A multicenter, retrospective review of intrabronchial valve utilization from January 2013 to August 2014 was performed at eight centers. Data regarding demographics, valve utilization, and outcomes were analyzed. RESULTS We identified 112 patients undergoing evaluation for intrabronchial valve placement, with 67% (75 of 112) undergoing valve implantation. Nearly three quarters of patients underwent valve placement for off-label usage (53 of 75). A total of 195 valves were placed in 75 patients (mean 2.6 per patient; range, 1 to 8) with median time to air leak resolution of 16 days (range, 2 to 156). CONCLUSIONS We present the largest, multicenter study of patients undergoing evaluation for intrabronchial valve use for air leak management. Our data suggest the majority of intrabronchial valve placements are occurring for off-label indications. Although the use of intrabronchial valves are a minimally invasive intervention for air leak management, the lack of rigorously designed studies demonstrating efficacy remains concerning. Prospective randomized controlled studies remain warranted.

A Plasma α-Tocopherome Can Be Identified from Proteins Associated with Vitamin E Status in School-Aged Children of Nepal

BACKGROUND The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations. OBJECTIVE To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 μmol/L). METHODS Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency. RESULTS We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability. CONCLUSIONS In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271.