Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. METHODS: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. RESULTS: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (ß=0.02 L, 95% CI -0.02-0.06 L) or lower FEV1/FVC (ß=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income. CONCLUSION: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.

Hypertension care in demographic surveillance sites: a cross-sectional study in Bangladesh, India, Indonesia, Malaysia, Viet Nam.

Objective: To determine the proportion of adults with hypertension who reported: (i) having been previously diagnosed with hypertension; (ii) taking blood pressure-lowering medication; and (iii) having achieved hypertension control, in five health and demographic surveillance system sites across five countries in Asia. Methods: Data were collected during household surveys conducted between 2016 and 2020 in the five surveillance sites in Bangladesh, India, Indonesia, Malaysia and Viet Nam. We defined hypertension as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or taking blood pressure-lowering medication. We defined hypertension control as systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg. We disaggregated hypertension awareness, treatment and control by surveillance site, and within each site by sex, age group, education, body mass index and smoking status. Findings: Of 22 142 participants, 11 137 had hypertension (Bangladesh: 211; India: 487; Indonesia: 1641; Malaysia: 8164; and Viet Nam: 634). The mean age of participants with hypertension was 60 years (range: 19-101 years). Only in the Malaysian site were more than half of individuals with hypertension aware of their condition. Hypertension treatment ranged from 20.8% (341/1641; 95% CI: 18.8-22.8%) in the Indonesian site to 44.7% (3649/8164; 95% CI: 43.6-45.8%) in the Malaysian site. Less than one in four participants with hypertension had achieved hypertension control in any site. Hypertension awareness, treatment and control were generally higher among women and older adults. Conclusion: While hypertension awareness and treatment varied widely across surveillance sites, hypertension control was low in all sites.

Mortality risk attributable to high and low ambient temperature in Pune city, India: A time series analysis from 2004 to 2012.

BACKGROUND: Exposure to high and low ambient temperatures is associated with morbidity and mortality across the globe. Most of these studies assessing the effects of non-optimum temperatures on health and have been conducted in the developed world, whereas in India, the limited evidence on ambient temperature and health risks and has focused mostly on the effects of heat waves. Here we quantify short term association between all temperatures and mortality in urban Pune, India. METHODS: We applied a time series regression model to derive temperature-mortality associations based on daily mean temperature and all-cause mortality records of Pune city from year January 2004 to December 2012. We estimated high and low temperature-mortality relationships by using standard time series quasi-Poisson regression in conjunction with a distributed lag non-linear model (DLNM). We calculated temperature attributable mortality fractions for total heat and total cold. FINDINGS: The analysis provides estimates of the total mortality burden attributable to ambient temperature. Overall, 6∙5% [95%CI 1.76-11∙43] of deaths registered in the observational period were attributed to non-optimal temperatures, cold effect was greater 5.72% [95%CI 0∙70-10∙06] than heat 0∙84% [0∙35-1∙34]. The gender stratified analysis revealed that the highest burden among men both for heat and cold. CONCLUSION: Non-optimal temperatures are associated with a substantial mortality burden. Our findings could benefit national, and local communities in developing preparedness and prevention strategies to reduce weather-related impacts immediately due to climate change.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Strategies to adapt and implement health system guidelines and recommendations: a scoping review.

BACKGROUND: Evidence-based health system guidelines are pivotal tools to help outline the important financial, policy and service components recommended to achieve a sustainable and resilient health system. However, not all guidelines are readily translatable into practice and/or policy without effective and tailored implementation and adaptation techniques. This scoping review mapped the evidence related to the adaptation and implementation of health system guidelines in low- and middle-income countries. METHODS: We conducted a scoping review following the Joanna Briggs Institute methodology for scoping reviews. A search strategy was implemented in MEDLINE (Ovid), Embase, CINAHL, LILACS (VHL Regional Portal), and Web of Science databases in late August 2020. We also searched sources of grey literature and reference lists of potentially relevant reviews. All findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. RESULTS: A total of 41 studies were included in the final set of papers. Common strategies were identified for adapting and implementing health system guidelines, related barriers and enablers, and indicators of success. The most common types of implementation strategies included education, clinical supervision, training and the formation of advisory groups. A paucity of reported information was also identified related to adaptation initiatives. Barriers to and enablers of implementation and adaptation were reported across studies, including the need for financial sustainability. Common approaches to evaluation were identified and included outcomes of interest at both the patient and health system level. CONCLUSIONS: The findings from this review suggest several themes in the literature and identify a need for future research to strengthen the evidence base for improving the implementation and adaptation of health system guidelines in low- and middle-income countries. The findings can serve as a future resource for researchers seeking to evaluate implementation and adaptation of health system guidelines. Our findings also suggest that more effort may be required across research, policy and practice sectors to support the adaptation and implementation of health system guidelines to local contexts and health system arrangements in low- and middle-income countries.

A survey of the training and working arrangements of general practitioners providing asthma and chronic obstructive pulmonary disease care in a rural area of Maharashtra State.

Background: Chronic respiratory diseases (CRD), especially asthma and chronic obstructive pulmonary disease (COPD), are common public health problems resulting in a substantial burden of disease for individuals. There is a need to understand the perceptions and practices of primary care physicians ("general practitioners [GPs]") who provide most of the health care in rural India. We surveyed all private and public practitioners listed as practising in a rural area of Western India with the aim of identifying GPs (GPs: graduates, registered and allowed to practice in India) to understand their training, working arrangements, and asthma/COPD workload. Methodology: We administered a short questionnaire at educational meetings or via e-mail to all private and public practitioners listed as providing community-based services in the Junnar block, Pune district, Maharashtra. The survey asked about qualifications, experience, and working arrangements, and about current asthma and COPD workload. A descriptive analysis was performed. Results: We approached 474 practitioners (434 from private sector and 40 from public sector). Eighty-eight were no longer practising in the study area. The response rate was 330/354 (93.2%) of private and 28/32 (87.5%) of public sector practitioners. We excluded 135 nonrespiratory hospital specialists and 23 private practitioners whose highest qualification was a diploma. Our final sample of 200 GPs (70% males) was 177 from private sector and 23 from public sector. The private GPs had more experience in clinical practice in comparison to public GPs (18.6 vs. 12.8 years). Eighty-four percent of GPs from the private sector only had Ayurveda, Yoga, Naturopathy, Unani, Siddha, and Homoeopathy (AYUSH) qualifications, though >90% provided "modern medicine" services. In the public sector, 43.5% GPs only had AYUSH qualifications, though all provided "modern medicine" services. A minority (9% of private GPs and 16% of public GPs) provided both services. Nearly two-thirds (62%) of private GPs had inpatient facilities compared to only 9% of public sector GPs. In both sectors, more GPs stated that they managed people with asthma than treated COPD (Private: 97% vs. 75%; Public 87% vs. 57%). Conclusion: Many GPs practising "modern medicine" only had qualifications in Ayurveda/Homeopathy and fewer GPs are involved in the management of COPD as compared to asthma. These are important factors that form the context for initiatives seeking to improve the quality of community-based care for people with CRD in Maharashtra state in India.

Chronic airflow obstruction and ambient particulate air pollution.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.

Disruptions in oral and nasal microbiota in biomass and tobacco smoke associated chronic obstructive pulmonary disease.

Chronic exposures to tobacco and biomass smoke are the most prevalent risk factors for COPD development. Although microbial diversity in tobacco smoke-associated COPD (TSCOPD) has been investigated, microbiota in biomass smoke-associated COPD (BMSCOPD) is still unexplored. We aimed to compare the nasal and oral microbiota between healthy, TSCOPD, and BMSCOPD subjects from a rural population in India. Nasal swabs and oral washings were collected from healthy (n = 10), TSCOPD (n = 11), and BMSCOPD (n = 10) subjects. The downstream analysis was performed using QIIME pipeline (v1.9). In nasal and oral microbiota no overall differences were noted, but there were key taxa that had differential abundance in either Healthy vs COPD and/or TSCOPD vs. BMSCOPD. Genera such as Actinomyces, Actinobacillus, Megasphaera, Selenomonas, and Corynebacterium were significantly higher in COPD subjects. This study suggests that microbial community undergoes dysbiosis which may further contribute to the progression of disease. Thus, it is important to identify etiological agents for such a polymicrobial alterations which contribute highly to the disease manifestation.

Interplaying role of healthcare activist and homemaker: a mixed-methods exploration of the workload of community health workers (Accredited Social Health Activists) in India.

BACKGROUND: Globally, community health workers (CHWs) are integral contributors to many health systems. In India, Accredited Social Health Activists (ASHAs) have been deployed since 2005. Engaged in multiple health care activities, they are a key link between the health system and population. ASHAs are expected to participate in new health programmes prompting interest in their current workload from the perspective of the health system, community and their family. METHODS: This mixed-methods design study was conducted in rural and tribal Primary Health Centers (PHCs), in Pune district, Western Maharashtra, India. All ASHAs affiliated with these PHCs were invited to participate in the quantitative study, those agreeing to contribute in-depth interviews (IDI) were enrolled in an additional qualitative study. Key informants' interviews were conducted with the Auxiliary Nurse Midwife (ANM), Block Facilitators (BFF) and Medical Officers (MO) of the same PHCs. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed thematically. RESULTS: We recruited 67 ASHAs from the two PHCs. ASHAs worked up to 20 h/week in their village of residence, serving populations of approximately 800-1200, embracing an increasing range of activities, despite a workload that contributed to feelings of being rushed and tiredness. They juggled household work, other paid jobs and their ASHA activities. Practical problems with travel added to time involved, especially in tribal areas where transport is lacking. Their sense of benefiting the community coupled with respect and recognition gained in village brought happiness and job satisfaction. They were willing to take on new tasks. ASHAs perceived themselves as 'voluntary community health workers' rather than as 'health activists". CONCLUSIONS: ASHAs were struggling to balance their significant ASHA work and domestic tasks. They were proud of their role as CHWs and willing to take on new activities. Strategies to recruit, train, skills enhancement, incentivise, and retain ASHAs, need to be prioritised. Evolving attitudes to the advantages/disadvantages of current voluntary status and role of ASHAs need to be understood and addressed if ASHAs are to be remain a key component in achieving universal health coverage in India.

Normal spirometry predictive values for the Western Indian adult population.

Interpretation of spirometry involves comparing lung function parameters with predicted values to determine the presence/severity of the disease. The Global Lung Function Initiative (GLI) derived reference equations for healthy individuals aged 3-95 years from multiple populations but highlighted India as a "particular group" for whom further data are needed. We aimed to derive predictive equations for spirometry in a rural Western Indian adult population.We used spirometry data previously collected (2008-2012) from 1258 healthy adults (aged 18 years and over) by the Vadu Health and Demographic Surveillance System. We constructed sex-stratified prediction equations for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC using the Generalised Additive Model for Location, Scale and Shape (GAMLSS) method to derive the best fitting model of each outcome as a function of age and height.When compared with GLI Ethnicity Codes 1 (White Caucasian) and 5 (Other/Mixed), the Western Indian adult population appears to have lower lung volumes on average, though the FEV1/FVC ratio is comparable. Both age and height were predictive of mean FEV1 and FVC; and for females, the variability of response was also dependent on age. FEV1/FVC appears to have a very strong age effect, highlighting the limitations of using a fixed 0.7 cut-off value.The use of GLI normal values may result in overdiagnosis of lung disease in this population. We recommend that the values and equations generated from this study should be used by physicians in their routine practice for diagnosing disease and its severity in adults from the Western Indian population.

Phenotypic comparison between smoking and non-smoking chronic obstructive pulmonary disease.

BACKGROUND: Although COPD among non-smokers (NS-COPD) is common, little is known about this phenotype. We compared NS-COPD subjects with smoking COPD (S-COPD) patients in a rural Indian population using a variety of clinical, physiological, radiological, sputum cellular and blood biomarkers. METHODS: Two hundred ninety subjects (118 healthy, 79 S-COPD, 93 NS-COPD) performed pre- and post-bronchodilator spirometry and were followed for 2 years to study the annual rate of decline in lung function. Body plethysmography, impulse oscillometry, inspiratory-expiratory HRCT, induced sputum cellular profile and blood biomarkers were compared between 49 healthy, 45 S-COPD and 55 NS-COPD subjects using standardized methods. Spirometric response to oral corticosteroids was measured in 30 female NS-COPD patients. RESULTS: Compared to all male S-COPD subjects, 47% of NS-COPD subjects were female, were younger by 3.2 years, had greater body mass index, a slower rate of decline in lung function (80 vs 130 mL/year), more small airways obstruction measured by impulse oscillometry (p < 0.001), significantly less emphysema (29% vs 11%) on CT scans, lower values in lung diffusion parameters, significantly less neutrophils in induced sputum (p < 0.05) and tended to have more sputum eosinophils. Hemoglobin and red cell volume were higher and serum insulin lower in S-COPD compared to NS-COPD. Spirometric indices, symptoms and quality of life were similar between S-COPD and NS-COPD. There was no improvement in spirometry in NS-COPD patients after 2 weeks of an oral corticosteroid. CONCLUSIONS: Compared to S-COPD, NS-COPD is seen in younger subjects with equal male-female predominance, is predominantly a small-airway disease phenotype with less emphysema, preserved lung diffusion and a slower rate of decline in lung function.

Incentivizing Elimination of Biomass Cooking Fuels with a Reversible Commitment and a Spare LPG Cylinder.

In India, approximately 480,000 deaths occur annually from exposure to household air pollution from the use of biomass cooking fuels. Displacing biomass use with clean fuels, such as liquefied petroleum gas (LPG), can help reduce these deaths. Through government initiatives, most Indian households now own an LPG stove and one LPG cylinder. Many households, however, continue to regularly use indoor biomass-fueled mud stoves (chulhas) alongside LPG. Focusing on this population in rural Maharashtra, India, this study (N = 186) tests the effects of conditioning a sales offer for a spare LPG cylinder on a reversible commitment requiring initially disabling indoor chulhas. We find that almost all relevant households (>98%) were willing to accept this commitment. Indoor chulha use decreased by 90% (95% CI = 80% to 101%) when the sales offer included the commitment, compared to a 23% decrease (95% CI = 14% to 32%) without it. For both treatment groups, we find that 80% purchased the spare cylinder at the end of the study.

Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass smoke-related COPD.

Lower airway colonisation with species of potentially pathogenic bacteria (PPB) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco smoke-associated chronic obstructive pulmonary disease (S-COPD) subjects. In the developing world, COPD among nonsmokers is largely due to biomass smoke (BMS) exposure; however, little is known about PPB colonisation and its association with impaired innate immunity in these subjects.We investigated the PPB load (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa) in BMS-exposed COPD (BMS-COPD) subjects compared with S-COPD and spirometrically normal subjects. We also examined the association between PPB load and phagocytic activity of MDMs and lung function. Induced sputum and peripheral venous blood samples were collected from 18 healthy nonsmokers, 15 smokers without COPD, 16 BMS-exposed healthy subjects, 19 S-COPD subjects and 23 BMS-COPD subjects. PPB load in induced sputum and MDM phagocytic activity were determined using quantitative PCR and fluorimetry, respectively.Higher bacterial loads of S. pneumoniae, H. influenzae and P. aeruginosa were observed in BMS-COPD subjects. Increased PPB load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs and spirometric lung function indices (p<0.05).Increased PPB load in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function.

Airflow Obstruction and Use of Solid Fuels for Cooking or Heating: BOLD Results.

RATIONALE: Evidence supporting the association of COPD or airflow obstruction with use of solid fuels is conflicting and inconsistent. OBJECTIVE: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. METHODS: We analysed 18,554 adults from the BOLD study, who had provided acceptable post-bronchodilator spirometry measurements and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analysed. We carried out similar analyses for spirometric restriction, chronic cough and chronic phlegm. MEASUREMENTS AND MAIN RESULTS: We found no association between airflow obstruction and use of solid fuels for cooking or heating (ORmen=1.20, 95%CI 0.94-1.53; ORwomen=0.88, 95%CI 0.67-1.15). This was true for low/middle and high income sites. Among never smokers there was also no evidence of an association of airflow obstruction with use of solid fuels (ORmen=1.00, 95%CI 0.57-1.76; ORwomen=1.00, 95%CI 0.76-1.32). Overall, we found no association of spirometric restriction, chronic cough or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never smokers and those who had been exposed for ≥20 years. CONCLUSION: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Unemployment in chronic airflow obstruction around the world: results from the BOLD study.

We aimed to examine associations between chronic airflow obstruction (CAO) and unemployment across the world.Cross-sectional data from 26 sites in the Burden of Obstructive Lung Disease (BOLD) study were used to analyse effects of CAO on unemployment. Odds ratios for unemployment in subjects aged 40-65 years were estimated using a multilevel mixed-effects generalised linear model with study site as random effect. Site-by-site heterogeneity was assessed using individual participant data meta-analyses.Out of 18 710 participants, 11.3% had CAO. The ratio of unemployed subjects with CAO divided by subjects without CAO showed large site discrepancies, although these were no longer significant after adjusting for age, sex, smoking and education. The site-adjusted odds ratio (95% CI) for unemployment was 1.79 (1.41-2.27) for CAO cases, decreasing to 1.43 (1.14-1.79) after adjusting for sociodemographic factors, comorbidities and forced vital capacity. Of other covariates that were associated with unemployment, age and education were important risk factors in high-income sites (4.02 (3.53-4.57) and 3.86 (2.80-5.30), respectively), while female sex was important in low- to middle-income sites (3.23 (2.66-3.91)).In the global BOLD study, CAO was associated with increased levels of unemployment, even after adjusting for sociodemographic factors, comorbidities and lung function.

Socioenvironmental factors associated with heat and cold-related mortality in Vadu HDSS, western India: a population-based case-crossover study.

Ambient temperatures (heat and cold) are associated with mortality, but limited research is available about groups most vulnerable to these effects in rural populations. We estimated the effects of heat and cold on daily mortality among different sociodemographic groups in the Vadu HDSS area, western India. We studied all deaths in the Vadu HDSS area during 2004-2013. A conditional logistic regression model in a case-crossover design was used. Separate analyses were carried out for summer and winter season. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for total mortality and population subgroups. Temperature above a threshold of 31 °C was associated with total mortality (OR 1.48, CI = 1.05-2.09) per 1 °C increase in daily mean temperature. Odds ratios were higher among females (OR 1.93; CI = 1.07-3.47), those with low education (OR 1.65; CI = 1.00-2.75), those owing larger agricultural land (OR 2.18; CI = 0.99-4.79), and farmers (OR 1.70; CI = 1.02-2.81). In winter, per 1 °C decrease in mean temperature, OR for total mortality was 1.06 (CI = 1.00-1.12) in lag 0-13 days. High risk of cold-related mortality was observed among people occupied in housework (OR = 1.09; CI = 1.00-1.19). Our study suggests that both heat and cold have an impact on mortality particularly heat, but also, to a smaller degree, cold have an impact. The effects may differ partly by sex, education, and occupation. These findings might have important policy implications in preventing heat and cold effects on particularly vulnerable groups of the rural populations in low and middle-income countries with hot semi-arid climate.

Severity of Airflow Obstruction in Chronic Obstructive Pulmonary Disease (COPD): Proposal for a New Classification.

Current classifications of Chronic Obstructive Pulmonary Disease (COPD) severity are complex and do not grade levels of obstruction. Obstruction is a simpler construct and independent of ethnicity. We constructed an index of obstruction severity based on the FEV1/FVC ratio, with cut-points dividing the Burden of Obstructive Lung Disease (BOLD) study population into four similarly sized strata to those created by the GOLD criteria that uses FEV1. We measured the agreement between classifications and the validity of the FEV1-based classification in identifying the level of obstruction as defined by the new groupings. We compared the strengths of association of each classification with quality of life (QoL), MRC dyspnoea score and the self-reported exacerbation rate. Agreement between classifications was only fair. FEV1-based criteria for moderate COPD identified only 79% of those with moderate obstruction and misclassified half of the participants with mild obstruction as having more severe COPD. Both scales were equally strongly associated with QoL, exertional dyspnoea and respiratory exacerbations. Severity assessed using the FEV1/FVC ratio is only in moderate agreement with the severity assessed using FEV1 but is equally strongly associated with other outcomes. Severity assessed using the FEV1/FVC ratio is likely to be independent of ethnicity.

Ethical Challenges and Lessons Learned During the Clinical Development of a Group A Meningococcal Conjugate Vaccine.

BACKGROUND: The group A meningococcal vaccine (PsA-TT) clinical development plan included clinical trials in India and in the West African region between 2005 and 2013. During this period, the Meningitis Vaccine Project (MVP) accumulated substantial experience in the ethical conduct of research to the highest standards. METHODS: Because of the public-private nature of the sponsorship of these trials and the extensive international collaboration with partners from a diverse setting of countries, the ethical review process was complex and required strategic, timely, and attentive communication to ensure the smooth review and approval for the clinical studies. Investigators and their site teams fostered strong community relationships prior to, during, and after the studies to ensure the involvement and the ownership of the research by the participating populations. As the clinical work proceeded, investigators and sponsors responded to specific questions of informed consent, pregnancy testing, healthcare, disease prevention, and posttrial access. RESULTS: Key factors that led to success included (1) constant dialogue between partners to explore and answer all ethical questions; (2) alertness and preparedness for emerging ethical questions during the research and in the context of evolving international ethics standards; and (3) care to assure that approaches were acceptable in the diverse community contexts. CONCLUSIONS: Many of the ethical issues encountered during the PsA-TT clinical development are familiar to groups conducting field trials in different cultural settings. The successful approaches used by the MVP clinical team offer useful examples of how these problems were resolved. CLINICAL TRIALS REGISTRATION: ISRCTN17662153 (PsA-TT-001); ISRTCN78147026 (PsA-TT-002); ISRCTN87739946 (PsA-TT-003); ISRCTN46335400 (PsA-TT-003a); ISRCTN82484612 (PsA-TT-004); CTRI/2009/091/000368 (PsA-TT-005); PACTR ATMR2010030001913177 (PsA-TT-006); PACTR201110000328305 (PsA-TT-007).

Antibody Persistence at 1 and 4 Years Following a Single Dose of MenAfriVac or Quadrivalent Polysaccharide Vaccine in Healthy Subjects Aged 2-29 Years.

BACKGROUND: Mass vaccination campaigns of the population aged 1-29 years with 1 dose of group A meningococcal (MenA) conjugate vaccine (PsA-TT, MenAfriVac) in African meningitis belt countries has resulted in the near-disappearance of MenA. The vaccine was tested in clinical trials in Africa and in India and found to be safe and highly immunogenic compared with the group A component of the licensed quadrivalent polysaccharide vaccine (PsACWY). Antibody persistence in Africa and in India was investigated. METHODS: A total of 900 subjects aged 2-29 years were followed up for 4 years in Senegal, Mali, and The Gambia (study A). A total of 340 subjects aged 2-10 years were followed up for 1 year in India (study B). In study A, subjects were randomized in a 2:1 ratio, and in study B a 1:1 ratio to receive either PsA-TT or PsACWY. Immunogenicity was evaluated by measuring MenA serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. RESULTS: In both studies, substantial SBA decay was observed at 6 months postvaccination in both vaccine groups, although more marked in the PsACWY group. At 1 year and 4 years (only for study A) postvaccination, SBA titers were relatively sustained in the PsA-TT group, whereas a slight increasing trend, more pronounced among the youngest, was observed in the participants aged <18 years in the PsACWY groups. The SBA titers were significantly higher in the PsA-TT group than in the PsACWY group at any time point, and the majority of subjects in the PsA-TT group had SBA titers ≥128 and group A-specific IgG concentrations ≥2 µg/mL at any point in time in both the African and Indian study populations. CONCLUSIONS: Four years after vaccination with a single dose of PsA-TT vaccine in Africa, most subjects are considered protected from MenA disease. CLINICAL TRIALS REGISTRATION: PsA-TT-003 (ISRCTN87739946); PsA-TT-003a (ISRCTN46335400).

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. METHODS: We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). FINDINGS: 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0-66·9; p=0·0013) and 56·4% (36·6-70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33-0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. INTERPRETATION: Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. FUNDING: Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.