Publications by authors named "Maria Deloria Knoll"

91 Publications

Deep learning for classification of pediatric chest radiographs by WHO's standardized methodology.

PLoS One 2021 21;16(6):e0253239. Epub 2021 Jun 21.

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

Background: The World Health Organization (WHO)-defined radiological pneumonia is a preferred endpoint in pneumococcal vaccine efficacy and effectiveness studies in children. Automating the WHO methodology may support more widespread application of this endpoint.

Methods: We trained a deep learning model to classify pneumonia CXRs in children using the World Health Organization (WHO)'s standardized methodology. The model was pretrained on CheXpert, a dataset containing 224,316 adult CXRs, and fine-tuned on PERCH, a pediatric dataset containing 4,172 CXRs. The model was then tested on two pediatric CXR datasets released by WHO. We also compared the model's performance to that of radiologists and pediatricians.

Results: The average area under the receiver operating characteristic curve (AUC) for primary endpoint pneumonia (PEP) across 10-fold validation of PERCH images was 0.928; average AUC after testing on WHO images was 0.977. The model's classification performance was better on test images with high inter-observer agreement; however, the model still outperformed human assessments in AUC and precision-recall spaces on low agreement images.

Conclusion: A deep learning model can classify pneumonia CXR images in children at a performance comparable to human readers. Our method lays a strong foundation for the potential inclusion of computer-aided readings of pediatric CXRs in vaccine trials and epidemiology studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253239PLOS
June 2021

Global Landscape Review of Serotype-Specific Invasive Pneumococcal Disease Surveillance among Countries Using PCV10/13: The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) Project.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

National Public Health Organisation, 15123 Athens, Greece.

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon.
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http://dx.doi.org/10.3390/microorganisms9040742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066045PMC
April 2021

Serotype Distribution of Remaining Pneumococcal Meningitis in the Mature PCV10/13 Period: Findings from the PSERENADE Project.

Microorganisms 2021 Apr 1;9(4). Epub 2021 Apr 1.

Department of Clinical Microbiology, Landspitali-The National University Hospital, Hringbraut, 101 Reykjavik, Iceland.

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites ( = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites ( = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed.
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http://dx.doi.org/10.3390/microorganisms9040738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066874PMC
April 2021

Upper Respiratory Tract Co-detection of Human Endemic Coronaviruses and High-density Pneumococcus Associated With Increased Severity Among HIV-Uninfected Children Under 5 Years Old in the PERCH Study.

Pediatr Infect Dis J 2021 06;40(6):503-512

Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland.

Background: Severity of viral respiratory illnesses can be increased with bacterial coinfection and can vary by sex, but influence of coinfection and sex on human endemic coronavirus (CoV) species, which generally cause mild to moderate respiratory illness, is unknown. We evaluated CoV and pneumococcal co-detection by sex in childhood pneumonia.

Methods: In the 2011-2014 Pneumonia Etiology Research for Child Health study, nasopharyngeal and oropharyngeal (NP/OP) swabs and other samples were collected from 3981 children <5 years hospitalized with severe or very severe pneumonia in 7 countries. Severity by NP/OP detection status of CoV (NL63, 229E, OC43 or HKU1) and high-density (≥6.9 log10 copies/mL) pneumococcus (HDSpn) by real-time polymerase chain reaction was assessed by sex using logistic regression adjusted for age and site.

Results: There were 43 (1.1%) CoV+/HDSpn+, 247 CoV+/HDSpn-, 449 CoV-/HDSpn+ and 3149 CoV-/HDSpn- cases with no significant difference in co-detection frequency by sex (range 51.2%-64.0% male, P = 0.06). More CoV+/HDSpn+ pneumonia was very severe compared with other groups for both males (13/22, 59.1% versus range 29.1%-34.7%, P = 0.04) and females (10/21, 47.6% versus 32.5%-43.5%, P = 0.009), but only male CoV+/HDSpn+ required supplemental oxygen more frequently (45.0% versus 20.6%-28.6%, P < 0.001) and had higher mortality (35.0% versus 5.3%-7.1%, P = 0.004) than other groups. For females with CoV+/HDSpn+, supplemental oxygen was 25.0% versus 24.8%-33.3% (P = 0.58) and mortality was 10.0% versus 9.2%-12.9% (P = 0.69).

Conclusions: Co-detection of endemic CoV and HDSpn was rare in children hospitalized with pneumonia, but associated with higher severity and mortality in males. Findings may warrant investigation of differences in severity by sex with co-detection of HDSpn and SARS-CoV-2.
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http://dx.doi.org/10.1097/INF.0000000000003139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104011PMC
June 2021

Changes in Invasive Pneumococcal Disease Caused by Serotype 1 Following Introduction of PCV10 and PCV13: Findings from the PSERENADE Project.

Microorganisms 2021 03 27;9(4). Epub 2021 Mar 27.

National Centre for Immunisation Research and Surveillance and Discipline of Child and Adolescent Health, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Westmead, NSW 2145, Australia.

serotype 1 (ST1) was an important cause of invasive pneumococcal disease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) containing ST1 antigen. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project gathered ST1 IPD surveillance data from sites globally and aimed to estimate PCV10/13 impact on ST1 IPD incidence. We estimated ST1 IPD incidence rate ratios (IRRs) comparing the pre-PCV10/13 period to each post-PCV10/13 year by site using a Bayesian multi-level, mixed-effects Poisson regression and all-site IRRs using a linear mixed-effects regression (N = 45 sites). Following PCV10/13 introduction, the incidence rate (IR) of ST1 IPD declined among all ages. After six years of PCV10/13 use, the all-site IRR was 0.05 (95% credibility interval 0.04-0.06) for all ages, 0.05 (0.04-0.05) for <5 years of age, 0.08 (0.06-0.09) for 5-17 years, 0.06 (0.05-0.08) for 18-49 years, 0.06 (0.05-0.07) for 50-64 years, and 0.05 (0.04-0.06) for ≥65 years. PCV10/13 use in infant immunization programs was followed by a 95% reduction in ST1 IPD in all ages after approximately 6 years. Limited data availability from the highest ST1 disease burden countries using a 3+0 schedule constrains generalizability and data from these settings are needed.
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http://dx.doi.org/10.3390/microorganisms9040696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066231PMC
March 2021

Willingness to pay and financing preferences for COVID-19 vaccination in China.

Vaccine 2021 04 27;39(14):1968-1976. Epub 2021 Feb 27.

China Center for Health Development Studies, Peking University, Beijing 100083, China; Peking University Health Science Center-Chinese Center for Disease Control and Prevention Joint Center for Vaccine Economics, Beijing 100083, China; Key Laboratory of Reproductive Health National Health Commission of the People's Republic of China, Beijing 100083, China. Electronic address:

Background: The COVID-19 pandemic has caused significant diseases and economic burdens in the world. Vaccines are often considered as a cost-effective way to prevent and control infectious diseases, and the research and development of COVID-19 vaccines have been progressing unprecedently. It is needed to understand individuals' willingness to pay (WTP) among general population, which provides information about social demand, access and financing for future COVID-19 vaccination.

Objective: To investigate individuals' WTP and financing mechanism preference for COVID-19 vaccination during the pandemic period in China.

Methods: During March 1-18, 2020, we conducted a network stratified random sampling survey with 2058 respondents in China. The survey questionnaires included out-of-pocket WTP, financing mechanism preference as well as basic characteristics of the respondents; risk perception and impact of the COVID-19 pandemic; attitude for future COVID-19 vaccination. Multivariable Tobit regression was used to determine impact factors for respondents' out-of-pocket WTP.

Results: The individuals' mean WTP for full COVID-19 vaccination was CNY 254 (USD 36.8) with median of CNY 100 (USD 14.5). Most respondents believed that governments (90.9%) and health insurance (78.0%) needed to pay for some or full portions of COVID-19 vaccination, although 84.3% stated that individuals needed to pay. Annual family income, employee size in the workplace, and whether considering the COVID-19 pandemic in China in a declining trend affected respondents' WTP significantly.

Conclusion: The findings demonstrated the individuals' WTP for COVID-19 vaccination in China and their preferences for financing sources from individuals, governments and health insurance. And to suggest an effective and optimal financing strategy, the public health perspective with equal access to COVID-19 vaccination should be prioritized to ensure a high vaccination rate.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914003PMC
April 2021

The Global Burden of Meningitis in Children: Challenges with Interpreting Global Health Estimates.

Microorganisms 2021 Feb 13;9(2). Epub 2021 Feb 13.

Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.

The World Health Organization (WHO) has developed a global roadmap to defeat meningitis by 2030. To advocate for and track progress of the roadmap, the burden of meningitis as a syndrome and by pathogen must be accurately defined. Three major global health models estimating meningitis mortality as a syndrome and/or by causative pathogen were identified and compared for the baseline year 2015. Two models, (1) the WHO and the Johns Hopkins Bloomberg School of Public Health's Maternal and Child Epidemiology Estimation (MCEE) group's Child Mortality Estimation (WHO-MCEE) and (2) the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease Study (GBD 2017), identified meningitis, encephalitis and neonatal sepsis, collectively, to be the second and third largest infectious killers of children under five years, respectively. Global meningitis/encephalitis and neonatal sepsis mortality estimates differed more substantially between models than mortality estimates for selected infectious causes of death and all causes of death combined. Estimates at national level and by pathogen also differed markedly between models. Aligning modelled estimates with additional data sources, such as national or sentinel surveillance, could more accurately define the global burden of meningitis and help track progress against the WHO roadmap.
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http://dx.doi.org/10.3390/microorganisms9020377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917636PMC
February 2021

Situational assessment of adult vaccine preventable disease and the potential for immunization advocacy and policy in low- and middle-income countries.

Vaccine 2021 03 19;39(11):1556-1564. Epub 2021 Feb 19.

International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 415 N Washington St, 5(th) Floor, Baltimore, MD 21231 USA.

By 2050, the number of adults over 65 years of age will be double the under-5 population, and heavily concentrated in low- and middle-income countries. Population growth and increasing life expectancies call for effective healthy aging strategies inclusive of immunization to reduce the burden of vaccine-preventable diseases, improve quality of life, and mitigate antimicrobial resistance. Based on a review of available literature on the pneumococcal disease, influenza, and herpes zoster epidemiology and economic burden, and the health systems and policy barriers for adult immunization, we identified evidence gaps and considerations for prioritizing adult immunization. The body of evidence for adult immunization and the health and economic burden of adult disease is heavily concentrated in high-income countries. The few countries reporting adult immunization policies generally focus on high-risk groups. Despite robust child immunization programs in most countries, adult immunization programs and policies lag far behind and there is a general lack of appropriate delivery platforms. Global adult disease burden and economic costs are substantial but evidence from low- and middle-income countries is limited. There is a need for a strengthened evidence base and political commitment to drive a comprehensive, global technical consensus on adult immunization.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960636PMC
March 2021

An affordable pneumococcal conjugate vaccine after 20 years.

Lancet Infect Dis 2021 06 28;21(6):751-753. Epub 2021 Jan 28.

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/S1473-3099(21)00002-5DOI Listing
June 2021

Oxford-AstraZeneca COVID-19 vaccine efficacy.

Lancet 2021 01 8;397(10269):72-74. Epub 2020 Dec 8.

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21231 USA.

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http://dx.doi.org/10.1016/S0140-6736(20)32623-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832220PMC
January 2021

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2021 01 26;9(1):e33-e43. Epub 2020 Nov 26.

Fogarty International Center, National Institutes of Health, Bethesda, MD, USA.

Background: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years.

Methods: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths.

Findings: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries.

Interpretation: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(20)30393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783516PMC
January 2021

Acceptance of COVID-19 Vaccination during the COVID-19 Pandemic in China.

Vaccines (Basel) 2020 Aug 27;8(3). Epub 2020 Aug 27.

China Center for Health Development Studies, Peking University, Beijing 100083, China.

Background: Faced with the coronavirus disease 2019 (COVID-19) pandemic, the development of COVID-19 vaccines has been progressing at an unprecedented rate. This study aimed to evaluate the acceptance of COVID-19 vaccination in China and give suggestions for vaccination strategies and immunization programs accordingly.

Methods: In March 2020, an anonymous cross-sectional survey was conducted online among Chinese adults. The questionnaire collected socio-demographic characteristics, risk perception, the impact of COVID-19, attitudes, acceptance and attribute preferences of vaccines against COVID-19 during the pandemic. Multivariate logistic regression was performed to identify the influencing factors of vaccination acceptance.

Results: Of the 2058 participants surveyed, 1879 (91.3%) stated that they would accept COVID-19 vaccination after the vaccine becomes available, among whom 980 (52.2%) wanted to get vaccinated as soon as possible, while others (47.8%) would delay the vaccination until the vaccine's safety was confirmed. Participants preferred a routine immunization schedule (49.4%) to emergency vaccination (9.0%) or either of them (41.6%). Logistic regression showed that being male, being married, perceiving a high risk of infection, being vaccinated against influenza in the past season, believing in the efficacy of COVID-19 vaccination or valuing doctor's recommendations could increase the probability of accepting COVID-19 vaccination as soon as possible, while having confirmed or suspected cases in local areas, valuing vaccination convenience or vaccine price in decision-making could hinder participants from immediate vaccination.

Conclusion: During the pandemic period, a strong demand for and high acceptance of COVID-19 vaccination has been shown among the Chinese population, while concerns about vaccine safety may hinder the promotion of vaccine uptake. To expand vaccination coverage, immunization programs should be designed to remove barriers in terms of vaccine price and vaccination convenience, and health education and communication from authoritative sources are important ways to alleviate public concerns about vaccine safety.
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http://dx.doi.org/10.3390/vaccines8030482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565574PMC
August 2020

Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children.

Pediatr Pulmonol 2020 11 11;55(11):3197-3208. Epub 2020 Sep 11.

Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia.

Background: Whether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low-income and middle-income countries is unknown. We sought to address these knowledge gaps.

Methods: We enrolled 1 to 59monthold children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and classified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)-defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata.

Results: Among children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI): 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR: 2.13, 95% CI: 0.91, 4.96) or any wheeze (with or without crackle) (aOR: 0.63, 95% CI: 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends toward greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs. 9.1%, p = .03).

Conclusions: Among lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care.
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http://dx.doi.org/10.1002/ppul.25046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692889PMC
November 2020

National, regional, and state-level pneumonia and severe pneumonia morbidity in children in India: modelled estimates for 2000 and 2015.

Lancet Child Adolesc Health 2020 09;4(9):678-687

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Background: The absolute number of pneumonia deaths in India has declined substantially since 2000. However, pneumonia remains a major cause of morbidity in children in the country. We used a risk factor-based model to estimate pneumonia and severe pneumonia morbidity in Indian states in 2000 and 2015.

Methods: In this modelling study, we estimated the burden of pneumonia and severe pneumonia in children younger than 5 years using a risk factor-based model. We did a systematic literature review to identify published data on the incidence of pneumonia from community-based longitudinal studies and calculated summary estimates. We estimated state-specific incidence rates for WHO-defined clinical pneumonia between 2000 and 2015 using Poisson regression and the prevalence of risk factors in each state was obtained from National Family Health Surveys. From clinical pneumonia studies, we identified studies reporting the proportion of clinical pneumonia cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases. We used the estimate of the proportion of cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases for each state.

Findings: Between 2000 and 2015, the estimated number of pneumonia cases in Indian HIV-uninfected children younger than 5 years decreased from 83·8 million cases (95% uncertainty interval [UI] 14·0-300·8) to 49·8 million cases (9·1-174·2), representing a 41% reduction in pneumonia cases. The incidence of pneumonia in children younger than 5 years in India was 657 cases per 1000 children (95% UI 110-2357) in 2000 and 403 cases per 1000 children (74-1408) in 2015. The estimated national pneumonia case fatality rate in 2015 was 0·38% (95% UI 0·11-2·10). In 2015, the estimated number of severe pneumonia cases was 8·4 million (95% UI 1·2-31·7), with an incidence of 68 cases per 1000 children (9-257) and a case fatality ratio of 2·26% (0·60-16·30). In 2015, the estimated number of pneumonia cases in HIV-uninfected children was highest in Uttar Pradesh (12·4 million [95% UI 2·1-45·0]), Bihar (7·3 million [1·3-26·1]), and Madhya Pradesh (4·6 million [0·7-17·0]). Between 2000 and 2015, the greatest reduction in pneumonia cases was observed in Kerala (82% reduction). In 2015, pneumonia incidence was greater than 500 cases per 1000 children in two states: Uttar Pradesh (565 cases per 1000 children [95% UI 94-2047]) and Madhya Pradesh (563 cases per 1000 children [88-2084]).

Interpretation: The estimated number of pneumonia and severe pneumonia cases among children younger than 5 years in India decreased between 2000 and 2015. Improvements in socioeconomic indicators and specific government initiatives are likely to have contributed to declines in the prevalence of pneumonia risk factors in many states. However, pneumonia incidence in many states remains high. The introduction of new vaccines that target pneumonia pathogens and reduce risk factors will help further reduce the burden of pneumonia in the country.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2352-4642(20)30129-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457699PMC
September 2020

Urinary arsenic is associated with wasting and underweight status in young children in rural Bangladesh.

Environ Res 2021 04 10;195:110025. Epub 2020 Aug 10.

Department of International Health, Program in Global Disease Epidemiology and Control, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background: Deficits in child growth are associated with poor cognitive outcomes and an increased risk for infection and mortality globally. One hundred forty million people are chronically exposed to arsenic from contaminated drinking water worldwide. While arsenic exposure has been associated with cognitive developmental delays in children, there is limited research on the association between arsenic exposure and growth deficits in young children.

Purpose: The objective of this study was to assess the association between chronic arsenic exposure and deficits in growth among children under 5 years in a rural setting in Bangladesh.

Methods: Urinary arsenic measurements were collected from 465 children between the ages of 28 days-59 months in rural Matlab, Bangladesh, and analyzed by graphite furnace atomic absorption. Height and weight measurements were collected from children according to World Health Organization child growth standards. A z-score cutoff2 standard deviations below the mean was used to define stunting (height-for-age z-score), underweight (weight-for-age z-score), and wasting (weight-for-height z-score).

Results: Children under 5 years with urinary arsenic concentrations in the third tertile (greater than 31 μg per liter (μg/L)) had a two times higher odds of being underweight after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (Odds Ratio (OR): 2.29 (95% Confidence Interval (CI): 1.16, 4.52)). Children under 2 years of age had a two times higher odds of being wasted after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (OR: 2.85 (95% CI: 1.18, 6.89)).

Conclusions: These findings suggest that arsenic exposure is associated with an increased odds of being wasted and underweight among young children in rural Bangladesh.
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http://dx.doi.org/10.1016/j.envres.2020.110025DOI Listing
April 2021

The Aetiology of pneumonia from analysis of Lung aspirate and Pleural fluid samples: Findings from the PERCH study.

Clin Infect Dis 2020 Jul 25. Epub 2020 Jul 25.

Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Background: An improved understanding of childhood pneumonia aetiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study.

Methods: The PERCH study enrolled children aged 1-59 months hospitalized with World Health Organization defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous trans-thoracic lung (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or pleural fluid in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative PCR and routine microbiologic culture were applied to clinical specimens.

Results: Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but one of the cases with a virus identified were co-infected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogen identified in LA and PF, respectively.

Conclusions: Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or pleural fluid, with S. pneumoniae and S. aureus the leading pathogens identified.
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http://dx.doi.org/10.1093/cid/ciaa1032DOI Listing
July 2020

A global agenda for older adult immunization in the COVID-19 era: A roadmap for action.

Vaccine 2020 Jul 3. Epub 2020 Jul 3.

Department of Health Sciences, University of Florence, Florence, Italy.

Given our global interconnectedness, the COVID-19 pandemic highlights the urgency of building a global system that can support both routine and pandemic/epidemic adult immunization. As such, a framework to recommend vaccines and build robust platforms to deliver them to protect the rapidly expanding demographic of older adults is needed. Adult immunization as a strategy has the broad potential to preserve and improve medical, social, and economic outcomes, including maintaining functional ability that benefits older adults, their families, communities, and countries. While we will soon have multiple vaccines against COVID-19, we must recognize that we already have a variety of vaccines against other pathogens that can keep adults healthier. They can prevent simultaneous co-infection with COVID-19, and may favorably impact- the outcome of a COVID-19 illness. Further, administering a vaccine against COVID-19 requires planning now to determine delivery strategies impacting how older adults will be immunized in a timely manner. A group of international experts with various backgrounds from health and aging disciplines met to discuss the evidence case for adult immunization and crucial knowledge gaps that must be filled in order to implement effective policies and programs for older adult immunization. This group, coming together as the International Council on Adult Immunization (ICAI), outlined a high-level roadmap to catalyze action, provide policy guidance, and envision a global adult immunization platform that can be adapted by countries to fit their local contexts. Further meetings centered around the value of adult immunization, particularly in the context of COVID-19. There was agreement that programs to deliver existing influenza, pneumococcal, herpes zoster vaccines, and future COVID-19 vaccines to over a billion older adults who are at substantially higher risk of death and disability due to vaccine-preventable diseases are more urgent than ever before. Here we present a proposed framework for delivering routine and pandemic vaccines. We call upon the global community and governments to prioritize action for integrating robust adult immunization programs into the public health agenda.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332930PMC
July 2020

Use of seasonal influenza and pneumococcal polysaccharide vaccines in older adults to reduce COVID-19 mortality.

Vaccine 2020 07 19;38(34):5398-5401. Epub 2020 Jun 19.

Centre for Mathematical Modelling of Infectious Disease, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

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http://dx.doi.org/10.1016/j.vaccine.2020.06.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303659PMC
July 2020

Pneumococcal colonization prevalence and density among Thai children with severe pneumonia and community controls.

PLoS One 2020 29;15(4):e0232151. Epub 2020 Apr 29.

Division of Global Health Protection, Thailand Ministry of Public Health-US Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand.

Background: Pneumococcal colonization prevalence and colonization density, which has been associated with invasive disease, can offer insight into local pneumococcal ecology and help inform vaccine policy discussions.

Methods: The Pneumonia Etiology Research for Child Health Project (PERCH), a multi-country case-control study, evaluated the etiology of hospitalized cases of severe and very severe pneumonia among children aged 1-59 months. The PERCH Thailand site enrolled children during January 2012-February 2014. We determined pneumococcal colonization prevalence and density, and serotype distribution of colonizing isolates.

Results: We enrolled 224 severe/very severe pneumonia cases and 659 community controls in Thailand. Compared to controls, cases had lower colonization prevalence (54.5% vs. 62.5%, p = 0.12) and lower median colonization density (42.1 vs. 210.2 x 103 copies/mL, p <0.0001); 42% of cases had documented antibiotic pretreatment vs. 0.8% of controls. In no sub-group of assessed cases did pneumococcal colonization density exceed the median for controls, including cases with no prior antibiotics (63.9x103 copies/mL), with consolidation on chest x-ray (76.5x103 copies/mL) or with pneumococcus detected in whole blood by PCR (9.3x103 copies/mL). Serotype distribution was similar among cases and controls, and a high percentage of colonizing isolates from cases and controls were serotypes included in PCV10 (70.0% and 61.8%, respectively) and PCV13 (76.7% and 67.9%, respectively).

Conclusions: Pneumococcal colonization is common among children aged <5 years in Thailand. However, colonization density was not higher among children with severe pneumonia compared to controls. These results can inform discussions about PCV introduction and provide baseline data to monitor PCV impact after introduction in Thailand.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232151PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190126PMC
July 2020

National, regional, and state-level burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in India: modelled estimates for 2000-15.

Lancet Glob Health 2019 06;7(6):e735-e747

INCLEN Trust International, New Delhi, India.

Background: India accounts for a disproportionate burden of global childhood illnesses. To inform policies and measure progress towards achieving child health targets, we estimated the annual national and state-specific childhood mortality and morbidity attributable to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) between 2000 and 2015.

Methods: In this modelling study, we used vaccine clinical trial data to estimate the proportion of pneumonia deaths attributable to pneumococcus and Hib. The proportion of meningitis deaths attributable to each pathogen was derived from pathogen-specific meningitis case fatality and bacterial meningitis case data from surveillance studies. We applied these proportions to modelled state-specific pneumonia and meningitis deaths from 2000 to 2015 prepared by the WHO Maternal and Child Epidemiology Estimation collaboration (WHO/MCEE) on the basis of verbal autopsy studies from India. The burden of clinical and severe pneumonia cases attributable to pneumococcus and Hib was ascertained with vaccine clinical trial data and state-specific all-cause pneumonia case estimates prepared by WHO/MCEE by use of risk factor prevalence data from India. Pathogen-specific meningitis cases were derived from state-level modelled pathogen-specific meningitis deaths and state-level meningitis case fatality estimates. Pneumococcal and Hib morbidity due to non-pneumonia, non-meningitis (NPNM) invasive syndromes were derived by applying the ratio of pathogen-specific NPNM cases to pathogen-specific meningitis cases to the state-level pathogen-specific meningitis cases. Mortality due to pathogen-specific NPNM was calculated with the ratio of pneumococcal and Hib meningitis case fatality to pneumococcal and Hib meningitis NPNM case fatality. Census data from India provided the population at risk.

Findings: Between 2000 and 2015, estimates of pneumococcal deaths in Indian children aged 1-59 months fell from 166 000 (uncertainty range [UR] 110 000-198 000) to 68 700 (44 600-86 000), while Hib deaths fell from 82 600 (52 300-112 000) to 15 600 (9800-21 500), representing a 58% (UR 22-78) decline in pneumococcal deaths and an 81% (59-91) decline in Hib deaths. In 2015, national mortality rates in children aged 1-59 months were 56 (UR 37-71) per 100 000 for pneumococcal infection and 13 (UR 8-18) per 100 000 for Hib. Uttar Pradesh (18 900 [UR 12 300-23 600]) and Bihar (8600 [5600-10 700]) had the highest numbers of pneumococcal deaths in 2015. Uttar Pradesh (9300 [UR 5900-12 700]) and Odisha (1100 [700-1500]) had the highest numbers of Hib deaths in 2015. Less conservative assumptions related to the proportion of pneumonia deaths attributable to pneumococcus indicate that as many as 118 000 (UR 69 000-140 000) total pneumococcal deaths could have occurred in 2015 in India.

Interpretation: Pneumococcal and Hib mortality have declined in children aged 1-59 months in India since 2000, even before nationwide implementation of conjugate vaccines. Introduction of the Hib vaccine in several states corresponded with a more rapid reduction in morbidity and mortality associated with Hib infection. Rapid scale-up and widespread use of the pneumococcal conjugate vaccine and sustained use of the Hib vaccine could help accelerate achievement of child survival targets in India.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(19)30081-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527518PMC
June 2019

Effect of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease and nasopharyngeal carriage in Kenya: a longitudinal surveillance study.

Lancet 2019 May 15;393(10186):2146-2154. Epub 2019 Apr 15.

Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine-Coast, Kilifi, Kenya; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; INDEPTH Network, Accra, Ghana.

Background: Ten-valent pneumococcal conjugate vaccine (PCV10), delivered at 6, 10, and 14 weeks of age was introduced in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. Coverage with at least two PCV10 doses in children aged 2-11 months was 80% in 2011 and 84% in 2016; coverage with at least one dose in children aged 12-59 months was 66% in 2011 and 87% in 2016. We aimed to assess PCV10 effect against nasopharyngeal carriage and invasive pneumococcal disease (IPD) in children and adults in Kilifi County.

Methods: This study was done at the KEMRI-Wellcome Trust Research Programme among residents of the Kilifi Health and Demographic Surveillance System, a rural community on the Kenyan coast covering an area of 891 km. We linked clinical and microbiological surveillance for IPD among admissions of all ages at Kilifi County Hospital, Kenya, which serves the community, to the Kilifi Health and Demographic Surveillance System from 1999 to 2016. We calculated the incidence rate ratio (IRR) comparing the prevaccine (Jan 1, 1999-Dec 31, 2010) and postvaccine (Jan 1, 2012-Dec 31, 2016) eras, adjusted for confounding, and reported percentage reduction in IPD as 1 minus IRR. Annual cross-sectional surveys of nasopharyngeal carriage were done from 2009 to 2016.

Findings: Surveillance identified 667 cases of IPD in 3 211 403 person-years of observation. Yearly IPD incidence in children younger than 5 years reduced sharply in 2011 following vaccine introduction and remained low (PCV10-type IPD: 60·8 cases per 100 000 in the prevaccine era vs 3·2 per 100 000 in the postvaccine era [adjusted IRR 0·08, 95% CI 0·03-0·22]; IPD caused by any serotype: 81·6 per 100 000 vs 15·3 per 100 000 [0·32, 0·17-0·60]). PCV10-type IPD also declined in the post-vaccination era in unvaccinated age groups (<2 months [no cases in the postvaccine era], 5-14 years [adjusted IRR 0·26, 95% CI 0·11-0·59], and ≥15 years [0·19, 0·07-0·51]). Incidence of non-PCV10-type IPD did not differ between eras. In children younger than 5 years, PCV10-type carriage declined between eras (age-standardised adjusted prevalence ratio 0·26, 95% CI 0·19-0·35) and non-PCV10-type carriage increased (1·71, 1·47-1·99).

Interpretation: Introduction of PCV10 in Kenya, accompanied by a catch-up campaign, resulted in a substantial reduction in PCV10-type IPD in children and adults without significant replacement disease. Although the catch-up campaign is likely to have brought forward the benefits by several years, the study suggests that routine infant PCV10 immunisation programmes will provide substantial direct and indirect protection in low-income settings in tropical Africa.

Funding: Gavi, The Vaccine Alliance and The Wellcome Trust of Great Britain.
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http://dx.doi.org/10.1016/S0140-6736(18)33005-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548991PMC
May 2019

Effect of 10-valent pneumococcal conjugate vaccine on the incidence of radiologically-confirmed pneumonia and clinically-defined pneumonia in Kenyan children: an interrupted time-series analysis.

Lancet Glob Health 2019 03;7(3):e337-e346

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Oxford University, Oxford, UK; INDEPTH Network, Accra, Ghana. Electronic address:

Background: Pneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes, but the burden of pneumococcal disease in low-income and middle-income countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the effect of 10-valent PCV on the incidence of pneumonia in Kenya.

Methods: We linked prospective hospital surveillance for clinically-defined WHO severe or very severe pneumonia at Kilifi County Hospital, Kenya, from 2002 to 2015, to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45 000 children younger than 5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January, 2011. In Kilifi, there was a three-dose catch-up campaign for infants (aged <1 year) and a two-dose catch-up campaign for children aged 1-4 years, between January and March, 2011. We estimated the effect of PCV10 on the incidence of clinically-defined and radiologically-confirmed pneumonia through interrupted time-series analysis, accounting for seasonal and temporal trends.

Findings: Between May 1, 2002 and March 31, 2015, 44 771 children aged 2-143 months were admitted to Kilifi County Hospital. We excluded 810 admissions between January and March, 2011, and 182 admissions during nurses' strikes. In 2002-03, the incidence of admission with clinically-defined pneumonia was 2170 per 100 000 in children aged 2-59 months. By the end of the catch-up campaign in 2011, 4997 (61·1%) of 8181 children aged 2-11 months had received at least two doses of PCV10 and 23 298 (62·3%) of 37 416 children aged 12-59 months had received at least one dose. Across the 13 years of surveillance, the incidence of clinically-defined pneumonia declined by 0·5% per month, independent of vaccine introduction. There was no secular trend in the incidence of radiologically-confirmed pneumonia over 8 years of study. After adjustment for secular trend and season, incidence rate ratios for admission with radiologically-confirmed pneumonia, clinically-defined pneumonia, and diarrhoea (control condition), associated temporally with PCV10 introduction and the catch-up campaign, were 0·52 (95% CI 0·32-0·86), 0·73 (0·54-0·97), and 0·63 (0·31-1·26), respectively. Immediately before PCV10 was introduced, the annual incidence of clinically-defined pneumonia was 1220 per 100 000; this value was reduced by 329 per 100 000 at the point of PCV10 introduction.

Interpretation: Over 13 years, admissions to Kilifi County Hospital for clinically-defined pneumonia decreased sharply (by 27%) in association with the introduction of PCV10, as did the incidence of radiologically-confirmed pneumonia (by 48%). The burden of hospital admissions for childhood pneumonia in Kilifi, Kenya, has been reduced substantially by the introduction of PCV10.

Funding: Gavi, The Vaccine Alliance and Wellcome Trust.
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http://dx.doi.org/10.1016/S2214-109X(18)30491-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379823PMC
March 2019

Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15.

Lancet Glob Health 2018 07;6(7):e744-e757

International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Pneumococcal conjugate vaccine (PCV) and Haemophilus influenzae type b (Hib) vaccine are now used in most countries. To monitor global and regional progress towards improving child health and to inform national policies for disease prevention and treatment, we prepared global, regional, and national disease burden estimates for these pathogens in children from 2000 to 2015.

Methods: Using WHO and Maternal and Child Epidemiology Estimation collaboration country-specific estimates of pneumonia and meningitis mortality and pneumonia morbidity from 2000 to 2015, we applied pneumococcal and Hib cause-specific proportions to estimate pathogen-specific deaths and cases. Summary estimates of the proportion of pneumonia deaths and cases attributable to these pathogens were derived from four Hib vaccine and six PCV efficacy and effectiveness study values. The proportion of meningitis deaths due to each pathogen was derived from bacterial meningitis aetiology and adjusted pathogen-specific meningitis case-fatality data. Pneumococcal and Hib meningitis cases were inferred from modelled pathogen-specific meningitis deaths and literature-derived case-fatality estimates. Cases of pneumococcal and Hib syndromes other than pneumonia and meningitis were estimated using the ratio of pathogen-specific non-pneumonia, non-meningitis cases to pathogen-specific meningitis cases from the literature. We accounted for annual HIV infection prevalence, access to care, and vaccine use.

Findings: We estimated that there were 294 000 pneumococcal deaths (uncertainty range [UR] 192 000-366 000) and 29 500 Hib deaths (18 400-40 700) in HIV-uninfected children aged 1-59 months in 2015. An additional 23 300 deaths (15 300-28 700) associated with pneumococcus and fewer than 1000 deaths associated Hib were estimated to have occurred in children infected with HIV. We estimate that pneumococcal deaths declined by 51% (7-74) and Hib deaths by 90% (78-96) from 2000 to 2015. Most children who died of pneumococcus (81%) and Hib (76%) presented with pneumonia. Less conservative assumptions result in pneumococcccal death estimates that could be as high as 515 000 deaths (302 000-609 000) in 2015. Approximately 50% of all pneumococcal deaths in 2015 occurred in four countries in Africa and Asia: India (68 700 deaths, UR 44 600-86 100), Nigeria (49 000 deaths, 32 400-59 000), the Democratic Republic of the Congo (14 500 deaths, 9300-18 700), and Pakistan (14 400 deaths, 9700-17 000]). India (15 600 deaths, 9800-21 500), Nigeria (3600 deaths, 2200-5100), China (3400 deaths, 2300-4600), and South Sudan (1000 deaths, 600-1400) had the greatest number of Hib deaths in 2015. We estimated 3·7 million episodes (UR 2·7 million-4·3 million) of severe pneumococcus and 340 000 episodes (196 000-669 000) of severe Hib globally in children in 2015.

Interpretation: The widespread use of Hib vaccine and the recent introduction of PCV in countries with high child mortality is associated with reductions in Hib and pneumococcal cases and deaths. Uncertainties in the burden of pneumococcal disease are largely driven by the fraction of pneumonia deaths attributable to pneumococcus. Progress towards further reducing the global burden of Hib and pneumococcal disease burden will depend on the efforts of a few large countries in Africa and Asia.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(18)30247-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005122PMC
July 2018

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

Lancet 2017 Sep 7;390(10098):946-958. Epub 2017 Jul 7.

Arctic Investigations Program, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centres for Disease Control and Prevention, Anchorage, AK, USA.

Background: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015.

Methods: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity.

Findings: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population.

Interpretation: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group.

Funding: The Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(17)30938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592248PMC
September 2017

Association of C-Reactive Protein With Bacterial and Respiratory Syncytial Virus-Associated Pneumonia Among Children Aged <5 Years in the PERCH Study.

Clin Infect Dis 2017 Jun;64(suppl_3):S378-S386

Medical Research Council Unit, Basse, The Gambia.

Background.: Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study.

Methods.: We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases.

Results.: Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity.

Conclusions.: Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.
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http://dx.doi.org/10.1093/cid/cix150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447856PMC
June 2017

Evaluation of Pneumococcal Load in Blood by Polymerase Chain Reaction for the Diagnosis of Pneumococcal Pneumonia in Young Children in the PERCH Study.

Clin Infect Dis 2017 Jun;64(suppl_3):S357-S367

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background.: Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia.

Methods.: The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the "optimal threshold" that distinguished MCPP cases from controls.

Results.: Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 × 103 vs 0.19 × 103 copies/mL), but overlapped substantially (range, 0.16-989.9 × 103 copies/mL and 0.01-551.9 × 103 copies/mL, respectively). The proportion with high load (≥2.2 log10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high (>6.9 log10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein ≥40 mg/L (both P < .01) in nonconfirmed cases but not controls.

Conclusions.: Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies.
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http://dx.doi.org/10.1093/cid/cix149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447847PMC
June 2017

Is Higher Viral Load in the Upper Respiratory Tract Associated With Severe Pneumonia? Findings From the PERCH Study.

Clin Infect Dis 2017 Jun;64(suppl_3):S337-S346

Global Disease Detection Center, Thailand Ministry of Public Health-US Centers for Disease Control and Prevention Collaboration, Nonthaburi.

Background.: The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization-defined severe and very severe pneumonia and age-matched community controls.

Methods.: In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted.

Results.: The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses.

Conclusions.: Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia.
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http://dx.doi.org/10.1093/cid/cix148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447843PMC
June 2017

Addressing the Analytic Challenges of Cross-Sectional Pediatric Pneumonia Etiology Data.

Clin Infect Dis 2017 Jun;64(suppl_3):S197-S204

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Despite tremendous advances in diagnostic laboratory technology, identifying the pathogen(s) causing pneumonia remains challenging because the infected lung tissue cannot usually be sampled for testing. Consequently, to obtain information about pneumonia etiology, clinicians and researchers test specimens distant to the site of infection. These tests may lack sensitivity (eg, blood culture, which is only positive in a small proportion of children with pneumonia) and/or specificity (eg, detection of pathogens in upper respiratory tract specimens, which may indicate asymptomatic carriage or a less severe syndrome, such as upper respiratory infection). While highly sensitive nucleic acid detection methods and testing of multiple specimens improve sensitivity, multiple pathogens are often detected and this adds complexity to the interpretation as the etiologic significance of results may be unclear (ie, the pneumonia may be caused by none, one, some, or all of the pathogens detected). Some of these challenges can be addressed by adjusting positivity rates to account for poor sensitivity or incorporating test results from controls without pneumonia to account for poor specificity. However, no classical analytic methods can account for measurement error (ie, sensitivity and specificity) for multiple specimen types and integrate the results of measurements for multiple pathogens to produce an accurate understanding of etiology. We describe the major analytic challenges in determining pneumonia etiology and review how the common analytical approaches (eg, descriptive, case-control, attributable fraction, latent class analysis) address some but not all challenges. We demonstrate how these limitations necessitate a new, integrated analytical approach to pneumonia etiology data.
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http://dx.doi.org/10.1093/cid/cix147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447845PMC
June 2017

Detection of Pneumococcal DNA in Blood by Polymerase Chain Reaction for Diagnosing Pneumococcal Pneumonia in Young Children From Low- and Middle-Income Countries.

Clin Infect Dis 2017 Jun;64(suppl_3):S347-S356

Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.

Background.: We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries.

Methods.: We tested blood by PCR for the pneumococcal autolysin gene in children aged 1-59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization-defined severe or very severe pneumonia or were age-frequency-matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls.

Results.: In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%-11.5% among cases and 5.3%-10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus.

Discussion.: The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.
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http://dx.doi.org/10.1093/cid/cix145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447841PMC
June 2017

Bayesian Estimation of Pneumonia Etiology: Epidemiologic Considerations and Applications to the Pneumonia Etiology Research for Child Health Study.

Clin Infect Dis 2017 Jun;64(suppl_3):S213-S227

Department of Biostatistics.

In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case-control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case-control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods.
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Source
http://dx.doi.org/10.1093/cid/cix144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447849PMC
June 2017