Burden of disease attributable to unsafe drinking water, sanitation, and hygiene in domestic settings: a global analysis for selected adverse health outcomes.

BACKGROUND: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels. METHODS: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH. FINDINGS: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH. INTERPRETATION: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns. FUNDING: WHO and Foreign, Commonwealth & Development Office.

Trends of global and regional aetiologies, risk factors and mortality of lower respiratory infections from 1990 to 2019: An analysis for the Global Burden of Disease Study 2019.

BACKGROUND AND OBJECTIVE: Lower respiratory infections (LRIs) are a leading cause of death worldwide. We aimed to estimate the trends of global and regional aetiologies, risk factors and mortality of LRIs from 1990 to 2019. METHODS: From the Global Burden of Disease (GBD) Study 2019, we collected relevant data, including annual LRI deaths, mortality and deaths and mortality attributable to the four high-burden aetiologies and 14 risk factors during 1990-2019. To quantify the temporal trends, estimated annual percentage changes (EAPCs) were calculated by fitting linear regression model. RESULTS: Globally, the age-standardized mortality due to LRIs decreased by an average of 2.39% (95% CI 2.33%-2.45%) per year, from 66.67 deaths per 100,000 in 1990 to 35.72 deaths per 100,000 in 2019. Low Socio-demographic Index regions, South Asia and Sub-Saharan Africa had the heaviest burden of LRIs. The age-standardized mortality decreased in 18 GBD regions, whereas increased in Southern Latin America (EAPC = 1.20, 95% CI 1.03-1.37). LRIs led to considerable deaths among children under 5 years and adults older than 70 years. Streptococcus pneumoniae was the first leading aetiology, accounting for over 50% of LRI deaths. Household air pollution from solid fuels, child wasting and ambient particulate matter pollution were the three leading risk factors for LRI mortality in 2019. CONCLUSION: LRIs remain an important health problem globally, especially in some vulnerable areas and among children under 5 and adults over 70 years. Future researches focusing on the aetiologies and risk factors for LRIs are needed to provide targeted and updated prevention strategies.

Age-sex differences in the global burden of lower respiratory infections and risk factors, 1990-2019: results from the Global Burden of Disease Study 2019.

BACKGROUND: The global burden of lower respiratory infections (LRIs) and corresponding risk factors in children older than 5 years and adults has not been studied as comprehensively as it has been in children younger than 5 years. We assessed the burden and trends of LRIs and risk factors across all age groups by sex, for 204 countries and territories. METHODS: In this analysis of data for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we used clinician-diagnosed pneumonia or bronchiolitis as our case definition for LRIs. We included International Classification of Diseases 9th edition codes 079.6, 466-469, 470.0, 480-482.8, 483.0-483.9, 484.1-484.2, 484.6-484.7, and 487-489 and International Classification of Diseases 10th edition codes A48.1, A70, B97.4-B97.6, J09-J15.8, J16-J16.9, J20-J21.9, J91.0, P23.0-P23.4, and U04-U04.9. We used the Cause of Death Ensemble modelling strategy to analyse 23 109 site-years of vital registration data, 825 site-years of sample vital registration data, 1766 site-years of verbal autopsy data, and 681 site-years of mortality surveillance data. We used DisMod-MR 2.1, a Bayesian meta-regression tool, to analyse age-sex-specific incidence and prevalence data identified via systematic reviews of the literature, population-based survey data, and claims and inpatient data. Additionally, we estimated age-sex-specific LRI mortality that is attributable to the independent effects of 14 risk factors. FINDINGS: Globally, in 2019, we estimated that there were 257 million (95% uncertainty interval [UI] 240-275) LRI incident episodes in males and 232 million (217-248) in females. In the same year, LRIs accounted for 1·30 million (95% UI 1·18-1·42) male deaths and 1·20 million (1·07-1·33) female deaths. Age-standardised incidence and mortality rates were 1·17 times (95% UI 1·16-1·18) and 1·31 times (95% UI 1·23-1·41) greater in males than in females in 2019. Between 1990 and 2019, LRI incidence and mortality rates declined at different rates across age groups and an increase in LRI episodes and deaths was estimated among all adult age groups, with males aged 70 years and older having the highest increase in LRI episodes (126·0% [95% UI 121·4-131·1]) and deaths (100·0% [83·4-115·9]). During the same period, LRI episodes and deaths in children younger than 15 years were estimated to have decreased, and the greatest decline was observed for LRI deaths in males younger than 5 years (-70·7% [-77·2 to -61·8]). The leading risk factors for LRI mortality varied across age groups and sex. More than half of global LRI deaths in children younger than 5 years were attributable to child wasting (population attributable fraction [PAF] 53·0% [95% UI 37·7-61·8] in males and 56·4% [40·7-65·1] in females), and more than a quarter of LRI deaths among those aged 5-14 years were attributable to household air pollution (PAF 26·0% [95% UI 16·6-35·5] for males and PAF 25·8% [16·3-35·4] for females). PAFs of male LRI deaths attributed to smoking were 20·4% (95% UI 15·4-25·2) in those aged 15-49 years, 30·5% (24·1-36·9) in those aged 50-69 years, and 21·9% (16·8-27·3) in those aged 70 years and older. PAFs of female LRI deaths attributed to household air pollution were 21·1% (95% UI 14·5-27·9) in those aged 15-49 years and 18·2% (12·5-24·5) in those aged 50-69 years. For females aged 70 years and older, the leading risk factor, ambient particulate matter, was responsible for 11·7% (95% UI 8·2-15·8) of LRI deaths. INTERPRETATION: The patterns and progress in reducing the burden of LRIs and key risk factors for mortality varied across age groups and sexes. The progress seen in children younger than 5 years was clearly a result of targeted interventions, such as vaccination and reduction of exposure to risk factors. Similar interventions for other age groups could contribute to the achievement of multiple Sustainable Development Goals targets, including promoting wellbeing at all ages and reducing health inequalities. Interventions, including addressing risk factors such as child wasting, smoking, ambient particulate matter pollution, and household air pollution, would prevent deaths and reduce health disparities. FUNDING: Bill & Melinda Gates Foundation.

Assessment of a cellular host response test to risk-stratify suspected COVID-19 patients in the Emergency Department setting.

OBJECTIVE: Assess the IntelliSep Index (ISI) for risk stratification of patients presenting to the Emergency Department (ED) with respiratory symptoms suspected of COVID-19 during the pandemic. METHODS: An observational single-center study of prospective cohort of patients presenting to the ED during the early COVID-19 pandemic with respiratory symptoms and a CBC drawn within 4.5 hours of initial vital signs. A sample of this blood was aliquoted for performance of the ISI, and patients were followed for clinical outcomes. The study required no patient-centered activity beyond standard of care and treating clinicians were unaware of study enrollment and ISI test results. MAIN FINDINGS: 282 patients were included. The ISI ranges 0.1 to 10.0, with three interpretation bands indicating risk of adverse outcome: low (green), 0.1-4.9; intermediate (yellow), 5.0-6.2; and high (red), 6.3-10.0. Of 193 (68.4%) tested for SARS-CoV-2, 96 (49.7%) were positive. The ISI resulted in 182 (64.5%) green, 54 (18.1%) yellow, and 46 (15.6%) red band patients. Green band patients had a 1.1% (n = 2) 3-day mortality, while yellow and red band had 3.7% (n = 2, p > .05) and 10.9% (n = 5, p < .05) 3-day mortalities, respectively. Fewer green band patients required admission (96 [52.7%]) vs yellow (44 [81.5%]) and red (43 [93.5%]). Green band patients had more hospital free days (median 23 (Q1-Q3 20-25) than yellow (median 22 [Q1-Q3 0-23], p < 0.05) and red (median 21 [Q1-Q3 0-24], p < 0.01). SOFA increased with interpretation band: green (2, [Q1-Q3 0-4]) vs yellow (4, [Q1-Q3 2-5], p < 0.001) and red (5, [Q1-Q3 3-6]) p < 0.001). CONCLUSIONS: The ISI rapidly risk-stratifies patients presenting to the ED during the early COVID-19 pandemic with signs or suspicion of respiratory infection.

Assessment of nasopharyngeal Streptococcus pneumoniae colonization does not permit discrimination between Canadian children with viral and bacterial respiratory infection: a matched-cohort cross-sectional study.

BACKGROUND: Readily-available diagnostics do not reliably discriminate between viral and bacterial pediatric uncomplicated pneumonia, both of which are common. Some have suggested that assessment of pneumococcal carriage could be used to identify those children with bacterial pneumonia. The objective of this study was to determine if nasopharyngeal pneumococcal colonization patterns differed between children with definite viral disease, definite bacterial disease, and respiratory disease of indeterminate etiology. METHODS: Three groups of subjects were recruited: children with critical respiratory illness, previously healthy children with respiratory illness admitted to the ward, and previously healthy children diagnosed in the emergency department with non-severe pneumonia. Subjects were categorized as follows: a) viral infection syndrome (eg. bronchiolitis), b) bacterial infection syndrome (ie. pneumonia complicated by effusion/empyema), or c) 'indeterminate' pneumonia. Subjects' nasopharyngeal swabs underwent quantitative PCR testing for S. pneumoniae. Associations between categorical variables were determined with Fisher's exact, chi-square, or logistic regression, as appropriate. Associations between quantitative genomic load and categorical variables was determined by linear regression. RESULTS: There were 206 children in Group 1, 122 children in Group 2, and 179 children in Group 3. Only a minority (227/507, 45%) had detectable pneumococcal carriage; in those subjects, there was no association of quantitative genomic load with age, recruitment group, or disease category. In multivariate logistic regression, pneumococcal colonization > 3 log copies/mL was associated with younger age and recruitment group, but not with disease category. CONCLUSIONS: The nasopharyngeal S. pneumoniae colonization patterns of subjects with definite viral infection were very similar to colonization patterns of those with definite bacterial infection or indeterminate pneumonia. Assessment and quantification of nasopharyngeal pneumococcal colonization does not therefore appear useful to discriminate between acute viral and bacterial respiratory disease; consequently, this diagnostic testing is unlikely to reliably determine which children with indeterminate pneumonia have a bacterial etiology and/or require antibiotic treatment.

Association of Respiratory Tract Infection after Gastroenterological Surgery with Postoperative Duration of Hospitalization and Medical Expenses: Subanalysis of Data from a Multicenter Study.

BACKGROUND: Postoperative infections can be classified as surgical site infections and remote infections. Postoperative respiratory tract infections (PRTI) are a type of remote infection and may be associated with prolonged hospitalization and increased medical expenses. This study compared postoperative duration of hospitalization and medical expenses between patients with and without PRTI after gastrointestinal surgery. METHODS: We retrospectively analyzed data from a multicenter study of centers affiliated with the Japan Society for Surgical Infection and used 1-to-1 matching analysis to evaluate 86 patients who underwent gastrointestinal surgery during the period from March 1, 2014 through February 29, 2016. RESULTS: Duration of postoperative hospitalization was significantly longer for patients with PRTI (38.6 days) than for those without PRTI (16.1 days), and postoperative medical expenses were significantly higher for patients with PRTI (1388.2 USD) than for those without PRTI (629.4 USD). CONCLUSIONS: Duration of hospitalization is longer and medical expenses are higher for patients that develop surgical site infections. This study found that this was also the case for patients with PRTI after gastrointestinal surgery. However, further studies are needed in order to confirm these results.

Lessons from an active surveillance pilot to assess the pneumonia of unknown etiology surveillance system in China, 2016: the need to increase clinician participation in the detection and reporting of emerging respiratory infectious diseases.

BACKGROUND: We sought to assess reporting in China's Pneumonia of Unknown Etiology (PUE) passive surveillance system for emerging respiratory infections and to identify ways to improve the PUE surveillance system's detection of respiratory infections of public health significance. METHODS: From February 29-May 29, 2016, we actively identified and enrolled patients in two hospitals with acute respiratory infections (ARI) that met all PUE case criteria. We reviewed medical records for documented exposure history associated with respiratory infectious diseases, collected throat samples that were tested for seasonal and avian influenza, and interviewed clinicians regarding reasons for reporting or not reporting PUE cases. We described and analyzed the proportion of PUE cases reported and clinician awareness of and practices related to the PUE system. RESULTS: Of 2619 ARI admissions in two hospitals, 335(13%) met the PUE case definition; none were reported. Of 311 specimens tested, 18(6%) were seasonal influenza virus-positive; none were avian influenza-positive. < 10% PUE case medical records documented whether or not there were exposures to animals or others with respiratory illness. Most commonly cited reasons for not reporting cases were no awareness of the PUE system (76%) and not understanding the case definition (53%). CONCLUSIONS: Most clinicians have limited awareness of and are not reporting to the PUE system. Exposures related to respiratory infections are rarely documented in medical records. Increasing clinicians' awareness of the PUE system and including relevant exposure items in standard medical records may increase reporting.

[Prognostic value of procalcitonin and C-reactive protein combined with sequential organ failure assessment score in elderly patients with sepsis induced by pulmonary infection].

OBJECTIVE: To investigate the prognostic value of procalcitonin (PCT) and C-reactive protein (CRP) combined with sequential organ failure assessment (SOFA) score in elderly patients with sepsis induced by pulmonary infection. METHODS: A retrospective study was conducted. The elderly patients aged over 60 years old with sepsis induced by pulmonary infection admitted to Guangdong Provincial Hospital of Chinese Medicine from October 2015 to December 2018 were enrolled. The PCT, CRP and SOFA scores of patients within 24 hours after admission and 28-day prognosis were recorded. The patients were divided into groups according to the severity of the disease and 28-day prognosis. The differences in above parameters among all the groups were compared. Receiver operator characteristic (ROC) curve was drawn to analyze the prognostic value of the above indicators in elderly patients with sepsis induced by pulmonary infection alone or in combination. RESULTS: A total of 265 patients were enrolled in the study. According to the severity of the disease, the patients were divided into sepsis group (n = 194) and septic shock group (n = 71). According to the 28-day prognosis, the patients were divided into survival group (n = 186) and non-survival group (n = 79). Compared with the sepsis group, the PCT, CRP and SOFA scores of patients in the septic shock group were significantly increased [PCT (µg/L): 6.16 (1.94, 19.60) vs. 1.56 (0.34, 7.32), CRP (mg/L): 128.90 (54.93, 198.70) vs. 91.45 (30.15, 175.30), SOFA score: 9.0 (7.0, 12.0) vs. 4.0 (3.0, 5.0)] with significant differences (all P < 0.05). Compared with the survival group, the PCT, CRP and SOFA scores of sepsis patients in the non-survival group were significantly increased [PCT (µg/L): 4.80 (1.06, 19.60) vs. 1.82 (0.34, 7.24), CRP (mg/L): 135.20 (58.10, 225.50) vs. 91.45 (31.50, 172.53), SOFA score: 7.0 (4.0, 11.0) vs. 4.0 (3.0, 6.0)] with significant differences (all P < 0.01). ROC curve analysis showed that the area under the ROC curve (AUC) of PCT, CRP, SOFA score and CRP+PCT+SOFA score was 0.641, 0.607, 0.697, and 0.712, indicating that above parameters had certain predictive value for 28-day prognosis of elderly patients with sepsis induced by pulmonary infection, and the combined predictive value of them was the greatest with the sensitivity of 55.1% and the specificity of 80.1%. CONCLUSIONS: PCT, CRP and SOFA score are commonly used to evaluate the prognosis of the elderly patients with sepsis induced by pulmonary infection, and the combination of them has higher evaluation value.

The Association between Respiratory Infection and Air Pollution in the Setting of Air Quality Policy and Economic Change.

RATIONALE: Fine particulate matter air pollution of 2.5 µm or less in diameter (PM2.5) has been associated with an increased risk of respiratory disease, but assessments of specific respiratory infections in adults are lacking. OBJECTIVES: To estimate the rate of respiratory infection healthcare encounters in adults associated with acute increases in PM2.5 concentrations. METHODS: Using case-crossover methods, we studied 498,118 adult New York State residents with a primary diagnosis of influenza, bacterial pneumonia, or culture-negative pneumonia upon hospitalization or emergency department (ED) visit (2005-2016). We estimated the relative rate of healthcare encounters associated with increases in PM2.5 in the previous 1-7 days and explored differences before (2005-2007), during (2008-2013), and after (2014-2016) implementation of air quality policies and economic changes. RESULTS: Interquartile range increases in PM2.5 over the previous 7 days were associated with increased excess rates (ERs) of culture-negative pneumonia hospitalizations (2.5%; 95% confidence interval [CI], 1.7-3.2%) and ED visits (2.5%; 95% CI, 1.4-3.6%), and increased ERs of influenza ED visits (3.9%; 95% CI, 2.1-5.6%). Bacterial pneumonia hospitalizations, but not ED visits, were associated with increases in PM2.5 and, though imprecise, were of a similar magnitude to culture-negative pneumonia (Lag Day 6 ER, 2.3%; 95% CI, 0.3-4.3). Increased relative rates of influenza ED visits and culture-negative pneumonia hospitalizations were generally larger in the "after" period (P < 0.025 for both outcomes), compared with the "during" period, despite reductions in overall PM2.5 concentrations. CONCLUSIONS: Increased rates of culture-negative pneumonia and influenza were associated with increased PM2.5 concentrations during the previous week, which persisted despite reductions in PM2.5 from air quality policies and economic changes. Though unexplained, this temporal variation may reflect altered toxicity of different PM2.5 mixtures or increased pathogen virulence.

Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma.

BACKGROUND: Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking. OBJECTIVE: We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA). METHODS: COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed. RESULTS: Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0-156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies. CONCLUSION: These data support the long-term safety and efficacy of mepolizumab in patients with SEA.

C-reactive protein point of care testing in the management of acute respiratory infections in the Vietnamese primary healthcare setting - a cost benefit analysis.

Aim: We assess the cost-benefit implications of C-reactive protein (CRP) testing in reducing antibiotic prescription for acute respiratory infection in Viet Nam by comparing the incremental costs of CRP testing with the economic costs of antimicrobial resistance averted due to lower antibiotic prescribing. Findings: Patients in the CRP group and the controls incurred similar costs in managing their illness, excluding the costs of the quantitative CRP tests, provided free of charge in the trial context. Assuming a unit cost of $1 per test, the incremental cost of CRP testing was $0.93 per patient. Based on a previous modelling analysis, the 20 percentage point reduction in prescribing observed in the trial implies a societal benefit of $0.82 per patient. With the low levels of adherence to the test results observed in the trial, CRP testing would not be cost-beneficial. The sensitivity analyses showed, however, that with higher adherence to test results their use would be cost-beneficial.

Socioeconomic inequalities in exposure to environmental tobacco smoke in children in Israel.

BACKGROUND: Environmental tobacco smoke (ETS) exposure in infants and children causes more frequent and severe asthma attacks, respiratory infections, ear infections, and sudden infant death syndrome. The aim of this study was to measure ETS exposure in children in Israel (ages 4-11 years) using urinary cotinine measurements, in order to compare exposure levels to other international populations, and to assess predictors of ETS exposure in children in Israel. METHODS: A subset of children who participated in the National Health and Nutrition Survey (RAV- MABAT) in 2015-2016 were invited to participate in the Second Israel Biomonitoring Survey. We analyzed urinary cotinine and creatinine concentrations in 103 children. Parents of study participants were interviewed in person on children's exposure to ETS at home and in other environments and on sociodemographic variables. We calculated creatinine-adjusted and unadjusted urinary cotinine geometric means in children and analyzed associations in univariable and multivariable analyses, between sociodemographic variables and parental - reported exposure, and urinary cotinine concentrations. RESULTS: Based on urinary creatinine measurement, over 60% of children are exposed to ETS (compared to <40% based on parental report). Linear regression showed a positive association between urinary cotinine concentration and reported ETS exposure (p = 0.001). Mean cotinine concentration among children whose parents reported that they are exposed to ETS at home (5.1 µg/l) was significantly higher than the concentration among children whose parents reported they are not exposed to ETS at home (1.6 µg/l, p < 0.001). There was an inverse relationship between total family income and urinary cotinine concentration (p < 0.05). In a multivariable model adjusted for ethnicity and other factors, family income was a significant predictor of urinary cotinine level (p = 0.04, slope = -0.49). Geometric mean creatinine adjusted concentrations in children in the current study were higher than in children in Canada and selected European countries. CONCLUSIONS: We found evidence of widespread exposure to ETS in children in the study. There is an urgent need to protect children in Israel from exposure to ETS.

Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND: Lower respiratory infections are a leading cause of morbidity and mortality around the world. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, provides an up-to-date analysis of the burden of lower respiratory infections in 195 countries. This study assesses cases, deaths, and aetiologies spanning the past 26 years and shows how the burden of lower respiratory infection has changed in people of all ages. METHODS: We used three separate modelling strategies for lower respiratory infections in GBD 2016: a Bayesian hierarchical ensemble modelling platform (Cause of Death Ensemble model), which uses vital registration, verbal autopsy data, and surveillance system data to predict mortality due to lower respiratory infections; a compartmental meta-regression tool (DisMod-MR), which uses scientific literature, population representative surveys, and health-care data to predict incidence, prevalence, and mortality; and modelling of counterfactual estimates of the population attributable fraction of lower respiratory infection episodes due to Streptococcus pneumoniae, Haemophilus influenzae type b, influenza, and respiratory syncytial virus. We calculated each modelled estimate for each age, sex, year, and location. We modelled the exposure level in a population for a given risk factor using DisMod-MR and a spatio-temporal Gaussian process regression, and assessed the effectiveness of targeted interventions for each risk factor in children younger than 5 years. We also did a decomposition analysis of the change in LRI deaths from 2000-16 using the risk factors associated with LRI in GBD 2016. FINDINGS: In 2016, lower respiratory infections caused 652 572 deaths (95% uncertainty interval [UI] 586 475-720 612) in children younger than 5 years (under-5s), 1 080 958 deaths (943 749-1 170 638) in adults older than 70 years, and 2 377 697 deaths (2 145 584-2 512 809) in people of all ages, worldwide. Streptococcus pneumoniae was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more deaths than all other aetiologies combined in 2016 (1 189 937 deaths, 95% UI 690 445-1 770 660). Childhood wasting remains the leading risk factor for lower respiratory infection mortality among children younger than 5 years, responsible for 61·4% of lower respiratory infection deaths in 2016 (95% UI 45·7-69·6). Interventions to improve wasting, household air pollution, ambient particulate matter pollution, and expanded antibiotic use could avert one under-5 death due to lower respiratory infection for every 4000 children treated in the countries with the highest lower respiratory infection burden. INTERPRETATION: Our findings show substantial progress in the reduction of lower respiratory infection burden, but this progress has not been equal across locations, has been driven by decreases in several primary risk factors, and might require more effort among elderly adults. By highlighting regions and populations with the highest burden, and the risk factors that could have the greatest effect, funders, policy makers, and programme implementers can more effectively reduce lower respiratory infections among the world's most susceptible populations. FUNDING: Bill & Melinda Gates Foundation.

Assessment of temporally-related acute respiratory illness following influenza vaccination.

BACKGROUND: A barrier to influenza vaccination is the misperception that the inactivated vaccine can cause influenza. Previous studies have investigated the risk of acute respiratory illness (ARI) after influenza vaccination with conflicting results. We assessed whether there is an increased rate of laboratory-confirmed ARI in post-influenza vaccination periods. METHODS: We conducted a cohort sub-analysis of children and adults in the MoSAIC community surveillance study from 2013 to 2016. Influenza vaccination was confirmed through city or hospital registries. Cases of ARI were ascertained by twice-weekly text messages to household to identify members with ARI symptoms. Nasal swabs were obtained from ill participants and analyzed for respiratory pathogens using multiplex PCR. The primary outcome measure was the hazard ratio of laboratory-confirmed ARI in individuals post-vaccination compared to other time periods during three influenza seasons. RESULTS: Of the 999 participants, 68.8% were children, 30.2% were adults. Each study season, approximately half received influenza vaccine and one third experienced ≥1 ARI. The hazard of influenza in individuals during the 14-day post-vaccination period was similar to unvaccinated individuals during the same period (HR 0.96, 95% CI [0.60, 1.52]). The hazard of non-influenza respiratory pathogens was higher during the same period (HR 1.65, 95% CI [1.14, 2.38]); when stratified by age the hazard remained higher for children (HR 1·71, 95% CI [1.16, 2.53]) but not for adults (HR 0.88, 95% CI [0.21, 3.69]). CONCLUSION: Among children there was an increase in the hazard of ARI caused by non-influenza respiratory pathogens post-influenza vaccination compared to unvaccinated children during the same period. Potential mechanisms for this association warrant further investigation. Future research could investigate whether medical decision-making surrounding influenza vaccination may be improved by acknowledging patient experiences, counseling regarding different types of ARI, and correcting the misperception that all ARI occurring after vaccination are caused by influenza.

The risk of lower respiratory tract infection following influenza virus infection: A systematic and narrative review.

BACKGROUND: Lower respiratory tract infections (LRTI) are a major cause of morbidity and mortality worldwide, particularly in young children and older adults. Influenza is known to cause severe disease but the risk of developing LRTI following influenza virus infection in various populations has not been systematically reviewed. Such data are important for estimating the impact specific influenza vaccine programs would have on LRTI outcomes in a community. We sought to review the published literature to determine the risk of developing LRTI following an influenza virus infection in individuals of any age. METHODS AND FINDINGS: We conducted a systematic review to identify prospective studies that estimated the incidence of LRTI following laboratory-confirmed influenza virus infection. We searched PubMed, Medline, and Embase databases for relevant literature. We supplemented this search with a narrative review of influenza and LRTI. The systematic review identified two prospective studies that both followed children less than 5 years. We also identified one additional pediatric study from our narrative review meeting the study inclusion criteria. Finally, we summarized recent case-control studies on the etiology of pneumonia in both adults and children. CONCLUSIONS: There is a dearth of prospective studies evaluating the risk of developing LRTI following influenza virus infection. Determining the burden of severe LRTI that is attributable to influenza is necessary to estimate the benefits of influenza vaccine on this important public health outcome. Vaccine probe studies are an efficient way to evaluate these questions and should be encouraged going forward.

Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015.

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2015 provides an up-to-date analysis of the burden of lower respiratory tract infections (LRIs) in 195 countries. This study assesses cases, deaths, and aetiologies spanning the past 25 years and shows how the burden of LRI has changed in people of all ages. METHODS: We estimated LRI mortality by age, sex, geography, and year using a modelling platform shared across most causes of death in the GBD 2015 study called the Cause of Death Ensemble model. We modelled LRI morbidity, including incidence and prevalence, using a meta-regression platform called DisMod-MR. We estimated aetiologies for LRI using two different counterfactual approaches, the first for viral pathogens, which incorporates the aetiology-specific risk of LRI and the prevalence of the aetiology in LRI episodes, and the second for bacterial pathogens, which uses a vaccine-probe approach. We used the Socio-demographic Index, which is a summary indicator derived from measures of income per capita, educational attainment, and fertility, to assess trends in LRI-related mortality. The two leading risk factors for LRI disability-adjusted life-years (DALYs), childhood undernutrition and air pollution, were used in a decomposition analysis to establish the relative contribution of changes in LRI DALYs. FINDINGS: In 2015, we estimated that LRIs caused 2·74 million deaths (95% uncertainty interval [UI] 2·50 million to 2·86 million) and 103·0 million DALYs (95% UI 96·1 million to 109·1 million). LRIs have a disproportionate effect on children younger than 5 years, responsible for 704 000 deaths (95% UI 651 000-763 000) and 60.6 million DALYs (95ÙI 56·0-65·6). Between 2005 and 2015, the number of deaths due to LRI decreased by 36·9% (95% UI 31·6 to 42·0) in children younger than 5 years, and by 3·2% (95% UI -0·4 to 6·9) in all ages. Pneumococcal pneumonia caused 55·4% of LRI deaths in all ages, totalling 1 517 388 deaths (95% UI 857 940-2 183 791). Between 2005 and 2015, improvements in air pollution exposure were responsible for a 4·3% reduction in LRI DALYs and improvements in childhood undernutrition were responsible for an 8·9% reduction. INTERPRETATION: LRIs are the leading infectious cause of death and the fifth-leading cause of death overall; they are the second-leading cause of DALYs. At the global level, the burden of LRIs has decreased dramatically in the last 10 years in children younger than 5 years, although the burden in people older than 70 years has increased in many regions. LRI remains a largely preventable disease and cause of death, and continued efforts to decrease indoor and ambient air pollution, improve childhood nutrition, and scale up the use of the pneumococcal conjugate vaccine in children and adults will be essential in reducing the global burden of LRI. FUNDING: Bill & Melinda Gates Foundation.

Sleep Habits and Susceptibility to Upper Respiratory Illness: the Moderating Role of Subjective Socioeconomic Status.

BACKGROUND: Sleep is a predictor of infectious illness that may depend on one's socioeconomic status (SES). PURPOSE: This study aimed to investigate the moderating effects of objective and subjective SES on sleep-clinical cold risk link and test whether nasal inflammation serves as a plausible biological pathway. METHODS: This study combined data (n = 732) from three viral challenge studies. Measures of self-reported sleep and objective and subjective measures of SES were obtained. Participants were quarantined and administrated rhinovirus (RV) or influenza virus and monitored over 5 (RV) or 6 (influenza) days for the development of a cold. Symptom severity, including mucus production and nasal clearance time, and levels of nasal cytokines (interleukin (IL)-6 and IL-1ß) were measured prior to administration and each day during the quarantined period. RESULTS: Subjective SES, but not objective SES, moderated associations between shorter sleep duration and increased likelihood of a clinical cold. Compared to ≥8-hour sleepers, ≤6-hour sleepers with low subjective SES were at increased risk for developing a cold (OR = 2.57, 95% CI 1.10-6.02). There was no association between sleep duration and colds in high subjective SES participants. Among infected individuals who reported low subjective SES, shorter sleep duration was associated with greater mucus production. There was no evidence that markers of nasal inflammation mediated the link between sleep duration and cold susceptibility among those reporting low subjective SES. CONCLUSION: Subjective SES may reflect an important social factor for understanding vulnerability to and protection against infectious illness among short sleepers.

Perception of first respiratory infection with Pseudomonas aeruginosa by people with cystic fibrosis and those close to them: an online qualitative study.

BACKGROUND: People with cystic fibrosis (CF) are susceptible to respiratory infection with Pseudomonas aeruginosa (PA), which may become chronic if initial eradication fails. Environmental acquisition and person-to-person transmission can occur. Respiratory PA infection is associated with increased mortality and more hospitalisations. This may cause patients and families anxiety and lead them to adopt preventive measures which may be ineffectual and intrusive. It is not possible to hold a conventional focus group to explore these issues because people with CF cannot meet together due to the risk of cross-infection. OBJECTIVE: To explore the perceptions of first respiratory infection with PA in people with CF and those close to them. DESIGN: We designed an online survey, to maximise accessibility and avoid the risk of cross-infection. This established the respondent's relationship with CF, asked 3 open questions about perceptions of PA and a final question about the prioritisation of research. Responses were analysed using a structured, iterative process. We identified keywords, analysed these incontext and derived key themes. SETTING: Promotion through social media allowed respondents from any country to participate. PARTICIPANTS: People with CF and those close to them. RESULTS: Responses were received from 393 people, including 266 parents and 97 people with CF. The key themes were the emotional burden of PA (fear in particular); the burden of treatment PA entails and the need for accurate knowledge about PA. CONCLUSIONS: Lack of knowledge and the health beliefs of individuals may promote fear of infection and inappropriate avoidance measures. Uncertainty about the implications of PA infection and the treatment required may cause anxiety. Healthcare professionals should provide clear information about how PA might be acquired and the treatment necessary, making clear the limitations of current understanding and acknowledging health beliefs.

Trends, causes, and risk factors of mortality among children under 5 in Ethiopia, 1990-2013: findings from the Global Burden of Disease Study 2013.

BACKGROUND: Ethiopia has made remarkable progress in reducing child mortality over the last two decades. However, the under-5 mortality rate in Ethiopia is still higher than the under-5 mortality rates of several low- and middle-income countries (LMIC). On the other hand, the patterns and causes of child mortality have not been well investigated in Ethiopia. The objective of this study was to investigate the mortality trend, causes of death, and risk factors among children under 5 in Ethiopia during 1990-2013. METHODS: We used Global Burden of Disease (GBD) 2013 data. Spatiotemporal Gaussian Process Regression (GPR) was applied to generate best estimates of child mortality with 95% uncertainty intervals (UI). Causes of death by age groups, sex, and year were measured using Cause of Death Ensemble modeling (CODEm). For estimation of HIV/AIDS mortality rate, the modified UNAIDS EPP-SPECTRUM suite model was used. RESULTS: Between 1990 and 2013 the under-5 mortality rate declined from 203.9 deaths/1000 live births to 74.4 deaths/1000 live births with an annual rate of change of 4.6%, yielding a total reduction of 64%. Similarly, child (1-4 years), post-neonatal, and neonatal mortality rates declined by 75%, 64%, and 52%, respectively, between 1990 and 2013. Lower respiratory tract infection (LRI), diarrheal diseases, and neonatal syndromes (preterm birth complications, neonatal encephalopathy, neonatal sepsis, and other neonatal disorders) accounted for 54% of the total under-5 deaths in 2013. Under-5 mortality rates due to measles, diarrhea, malaria, protein-energy malnutrition, and iron-deficiency anemia declined by more than two-thirds between 1990 and 2013. Among the causes of under-5 deaths, neonatal syndromes such as sepsis, preterm birth complications, and birth asphyxia ranked third to fifth in 2013. Of all risk-attributable deaths in 1990, 25% of the total under-5 deaths (112,288/435,962) and 48% (112,288/232,199) of the deaths due to diarrhea, LRI, and other common infections were attributable to childhood wasting. Similarly, 19% (43,759/229,333) of the total under-5 deaths and 45% (43,759/97,963) of the deaths due to diarrhea and LRI were attributable to wasting in 2013. Of the total diarrheal disease- and LRI-related deaths (n = 97,963) in 2013, 59% (57,923/97,963) of them were attributable to unsafe water supply, unsafe sanitation, household air pollution, and no handwashing with soap. CONCLUSIONS: LRI, diarrheal diseases, and neonatal syndromes remain the major causes of under-5 deaths in Ethiopia. These findings call for better-integrated newborn and child survival interventions focusing on the main risk factors.