Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 131 Records) |
Query Trace: Feikin DR[original query] |
---|
Global impact of ten-valent and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in all ages (the PSERENADE project): a global surveillance analysis
Bennett JC , Deloria Knoll M , Kagucia EW , Garcia Quesada M , Zeger SL , Hetrich MK , Yang Y , Herbert C , Ogyu A , Cohen AL , Yildirim I , Winje BA , von Gottberg A , Viriot D , van der Linden M , Valentiner-Branth P , Suga S , Steens A , Skoczynska A , Sinkovec Zorko N , Scott JA , Savulescu C , Savrasova L , Sanz JC , Russell F , Ricketson LJ , Puentes R , Nuorti JP , Mereckiene J , McMahon K , McGeer A , Mad'arová L , Mackenzie GA , MacDonald L , Lepp T , Ladhani SN , Kristinsson KG , Kozakova J , Klein NP , Jayasinghe S , Ho PL , Hilty M , Heyderman RS , Hasanuzzaman M , Hammitt LL , Guevara M , Grgic-Vitek M , Gierke R , Georgakopoulou T , Galloway Y , Diawara I , Desmet S , De Wals P , Dagan R , Colzani E , Cohen C , Ciruela P , Chuluunbat U , Chan G , Camilli R , Bruce MG , Brandileone MC , Bigogo G , Ampofo K , O'Brien KL , Feikin DR , Hayford K . Lancet Infect Dis 2024 ![]() ![]() BACKGROUND: Pneumococcal conjugate vaccines (PCVs) that are ten-valent (PCV10) and 13-valent (PCV13) became available in 2010. We evaluated their global impact on invasive pneumococcal disease (IPD) incidence in all ages. METHODS: Serotype-specific IPD cases and population denominators were obtained directly from surveillance sites using PCV10 or PCV13 in their national immunisation programmes and with a primary series uptake of at least 50%. Annual incidence rate ratios (IRRs) were estimated comparing the incidence before any PCV with each year post-PCV10 or post-PCV13 introduction using Bayesian multi-level, mixed-effects Poisson regressions, by site and age group. All site-weighted average IRRs were estimated using linear mixed-effects regression, stratified by product and previous seven-valent PCV (PCV7) effect (none, moderate, or substantial). FINDINGS: Analyses included 32 PCV13 sites (488 758 cases) and 15 PCV10 sites (46 386 cases) in 30 countries, primarily high income (39 sites), using booster dose schedules (41 sites). By 6 years after PCV10 or PCV13 introduction, IPD due to PCV10-type serotypes and PCV10-related serotype 6A declined substantially for both products (age <5 years: 83-99% decline; ≥65 years: 54-96% decline). PCV7-related serotype 19A increases before PCV10 or PCV13 introduction were reversed at PCV13 sites (age <5 years: 61-79% decline relative to before any PCV; age ≥65 years: 7-26% decline) but increased at PCV10 sites (age <5 years: 1·6-2·3-fold; age ≥65 years: 3·6-4·9-fold). Serotype 3 IRRs had no consistent trends for either product or age group. Non-PCV13-type IPD increased similarly for both products (age <5 years: 2·3-3·3-fold; age ≥65 years: 1·7-2·3-fold). Despite different serotype 19A trends, all-serotype IPD declined similarly between products among children younger than 5 years (58-74%); among adults aged 65 years or older, declines were greater at PCV13 (25-29%) than PCV10 (4-14%) sites, but other differences between sites precluded attribution to product. INTERPRETATION: Long-term use of PCV10 or PCV13 reduced IPD substantially in young children and more moderately in older ages. Non-vaccine-type serotypes increased approximately two-fold to three-fold by 6 years after introduction of PCV10 or PCV13. Continuing serotype 19A increases at PCV10 sites and declines at PCV13 sites suggest that PCV13 use would further reduce IPD at PCV10 sites. FUNDING: Bill & Melinda Gates Foundation as part of the WHO Pneumococcal Vaccines Technical Coordination Project. |
Serotype distribution of remaining invasive pneumococcal disease after extensive use of ten-valent and 13-valent pneumococcal conjugate vaccines (the PSERENADE project): a global surveillance analysis
Garcia Quesada M , Peterson ME , Bennett JC , Hayford K , Zeger SL , Yang Y , Hetrich MK , Feikin DR , Cohen AL , von Gottberg A , van der Linden M , van Sorge NM , de Oliveira LH , de Miguel S , Yildirim I , Vestrheim DF , Verani JR , Varon E , Valentiner-Branth P , Tzanakaki G , Sinkovec Zorko N , Setchanova LP , Serhan F , Scott KJ , Scott JA , Savulescu C , Savrasova L , Reyburn R , Oishi K , Nuorti JP , Napoli D , Mwenda JM , Muñoz-Almagro C , Morfeldt E , McMahon K , McGeer A , Mad'arová L , Mackenzie GA , Eugenia León M , Ladhani SN , Kristinsson KG , Kozakova J , Kleynhans J , Klein NP , Kellner JD , Jayasinghe S , Ho PL , Hilty M , Harker-Jones MA , Hammitt LL , Grgic-Vitek M , Gilkison C , Gierke R , French N , Diawara I , Desmet S , De Wals P , Dalby T , Dagan R , Corcoran M , Colzani E , Chanto Chacón G , Castilla J , Camilli R , Ang M , Ampofo K , Almeida SCG , Alarcon P , O'Brien KL , Deloria Knoll M . Lancet Infect Dis 2024 ![]() BACKGROUND: Widespread use of pneumococcal conjugate vaccines (PCVs) has reduced vaccine-type invasive pneumococcal disease (IPD). We describe the serotype distribution of IPD after extensive use of ten-valent PCV (PCV10; Synflorix, GSK) and 13-valent PCV (PCV13; Prevenar 13, Pfizer) globally. METHODS: IPD data were obtained from surveillance sites participating in the WHO-commissioned Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project that exclusively used PCV10 or PCV13 (hereafter PCV10 and PCV13 sites, respectively) in their national immunisation programmes and had primary series uptake of at least 70%. Serotype distribution was estimated for IPD cases occurring 5 years or more after PCV10 or PCV13 introduction (ie, the mature period when the serotype distribution had stabilised) using multinomial Dirichlet regression, stratified by PCV product and age group (<5 years, 5-17 years, 18-49 years, and ≥50 years). FINDINGS: The analysis included cases occurring primarily between 2015 and 2018 from 42 PCV13 sites (63 362 cases) and 12 PCV10 sites (6806 cases) in 41 countries. Sites were mostly high income (36 [67%] of 54) and used three-dose or four-dose booster schedules (44 [81%]). At PCV10 sites, PCV10 serotypes caused 10·0% (95% CI 6·3-12·9) of IPD cases in children younger than 5 years and 15·5% (13·4-19·3) of cases in adults aged 50 years or older, while PCV13 serotypes caused 52·1% (49·2-65·4) and 45·6% (40·0-50·0), respectively. At PCV13 sites, PCV13 serotypes caused 26·4% (21·3-30·0) of IPD cases in children younger than 5 years and 29·5% (27·5-33·0) of cases in adults aged 50 years or older. The leading serotype at PCV10 sites was 19A in children younger than 5 years (30·6% [95% CI 18·2-43·1]) and adults aged 50 years or older (14·8% [11·9-17·8]). Serotype 3 was a top-ranked serotype, causing about 9% of cases in children younger than 5 years and 14% in adults aged 50 years or older at both PCV10 and PCV13 sites. Across all age and PCV10 or PCV13 strata, the proportion of IPD targeted by higher-valency PCVs beyond PCV13 was 4·1-9·7% for PCV15, 13·5-36·0% for PCV20, 29·9-53·8% for PCV21, 15·6-42·0% for PCV24, and 31·5-50·1% for PCV25. All top-ten ranked non-PCV13 serotypes are included in at least one higher-valency PCV. INTERPRETATION: The proportion of IPD due to serotypes included in PCVs in use was low in mature PCV10 and PCV13 settings. Serotype distribution differed between PCV10 and PCV13 sites and age groups. Higher-valency PCVs target most remaining IPD and are expected to extend impact. FUNDING: Bill & Melinda Gates Foundation as part of the WHO Pneumococcal Vaccines Technical Coordination Project. |
Epidemiology of human metapneumovirus among children with severe or very severe pneumonia in high pneumonia burden settings: the PERCH study experience
Miyakawa R , Zhang H , Brooks WA , Prosperi C , Baggett HC , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , O'Brien KL , Scott JAG , Thea DM , Antonio M , Awori JO , Bunthi C , Driscoll AJ , Ebruke B , Fancourt NS , Higdon MM , Karron RA , Moore DP , Morpeth SC , Mulindwa JM , Park DE , Rahman MZ , Rahman M , Salaudeen RA , Sawatwong P , Seidenberg P , Sow SO , Tapia MD , Knoll MD . Clin Microbiol Infect 2024 ![]() OBJECTIVES: After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high burden settings, which have limited data, by comparing to RSV-positive and other cases. METHODS: Children aged 1-59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (aOR) were calculated using logistic regression. Etiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics. RESULTS: HMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p≤0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR=0.18), especially RSV (aOR=0.11; all p<0.0001), and positively associated with the detection of bacteria (aORs 1.77, p=0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than other cases (9.6%). CONCLUSIONS: HMPV-associated severe pediatric pneumonia in high burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives. |
The respiratory syncytial virus vaccine and monoclonal antibody landscape: the road to global access
Terstappen J , Hak SF , Bhan A , Bogaert D , Bont LJ , Buchholz UJ , Clark AD , Cohen C , Dagan R , Feikin DR , Graham BS , Gupta A , Haldar P , Jalang'o R , Karron RA , Kragten L , Li Y , Löwensteyn YN , Munywoki PK , Njogu R , Osterhaus A , Pollard AJ , Nazario LR , Sande C , Satav AR , Srikantiah P , Stein RT , Thacker N , Thomas R , Bayona MT , Mazur NI . Lancet Infect Dis 2024 Respiratory syncytial virus (RSV) is the second most common pathogen causing infant mortality. Additionally, RSV is a major cause of morbidity and mortality in older adults (age ≥60 years) similar to influenza. A protein-based maternal vaccine and monoclonal antibody (mAb) are now market-approved to protect infants, while an mRNA and two protein-based vaccines are approved for older adults. First-year experience protecting infants with nirsevimab in high-income countries shows a major public health benefit. It is expected that the RSV vaccine landscape will continue to develop in the coming years to protect all people globally. The vaccine and mAb landscape remain active with 30 candidates in clinical development using four approaches: protein-based, live-attenuated and chimeric vector, mRNA, and mAbs. Candidates in late-phase trials aim to protect young infants using mAbs, older infants and toddlers with live-attenuated vaccines, and children and adults using protein-based and mRNA vaccines. This Review provides an overview of RSV vaccines highlighting different target populations, antigens, and trial results. As RSV vaccines have not yet reached low-income and middle-income countries, we outline urgent next steps to minimise the vaccine delay. |
Factors predicting mortality in hospitalised HIV-negative children with lower-chest-wall indrawing pneumonia and implications for management
Gallagher KE , Awori JO , Knoll MD , Rhodes J , Higdon MM , Hammitt LL , Prosperi C , Baggett HC , Brooks WA , Fancourt N , Feikin DR , Howie SRC , Kotloff KL , Tapia MD , Levine OS , Madhi SA , Murdoch DR , O'Brien KL , Thea DM , Baillie VL , Ebruke BE , Kamau A , Moore DP , Mwananyanda L , Olutunde EO , Seidenberg P , Sow SO , Thamthitiwat S , Scott JAG . PLoS One 2024 19 (3) e0297159 INTRODUCTION: In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model. METHODS: PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2. RESULTS: Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76). CONCLUSIONS: Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community. |
Clinical and laboratory findings of the first imported case of Middle East respiratory syndrome coronavirus to the United States.
Kapoor M , Pringle K , Kumar A , Dearth S , Liu L , Lovchik J , Perez O , Pontones P , Richards S , Yeadon-Fagbohun J , Breakwell L , Chea N , Cohen NJ , Schneider E , Erdman D , Haynes L , Pallansch M , Tao Y , Tong S , Gerber S , Swerdlow D , Feikin DR . Clin Infect Dis 2014 59 (11) 1511-8 ![]() BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) was discovered September 2012 in the Kingdom of Saudi Arabia (KSA). The first US case of MERS-CoV was confirmed on 2 May 2014. METHODS: We summarize the clinical symptoms and signs, laboratory and radiologic findings, and MERS-CoV-specific tests. RESULTS: The patient is a 65-year-old physician who worked in a hospital in KSA where MERS-CoV patients were treated. His illness onset included malaise, myalgias, and low-grade fever. He flew to the United States on day of illness (DOI) 7. His first respiratory symptom, a dry cough, developed on DOI 10. On DOI 11, he presented to an Indiana hospital as dyspneic, hypoxic, and with a right lower lobe infiltrate on chest radiography. On DOI 12, his serum tested positive by real-time reverse transcription polymerase chain reaction (rRT-PCR) for MERS-CoV and showed high MERS-CoV antibody titers, whereas his nasopharyngeal swab was rRT-PCR negative. Expectorated sputum was rRT-PCR positive the following day, with a high viral load (5.31 × 10(6) copies/mL). He was treated with antibiotics, intravenous immunoglobulin, and oxygen by nasal cannula. He was discharged on DOI 22. The genome sequence was similar (>99%) to other known MERS-CoV sequences, clustering with those from KSA from June to July 2013. CONCLUSIONS: This patient had a prolonged nonspecific prodromal illness before developing respiratory symptoms. Both sera and sputum were rRT-PCR positive when nasopharyngeal specimens were negative. US clinicians must be vigilant for MERS-CoV in patients with febrile and/or respiratory illness with recent travel to the Arabian Peninsula, especially among healthcare workers. |
Examining bias from differential depletion of susceptibles in vaccine effectiveness estimates in settings of waning
Kahn R , Feikin DR , Wiegand RE , Lipsitch M . Am J Epidemiol 2023 193 (1) 232-234 Waning of the effectiveness of COVID-19 vaccines against SARS-CoV-2 infection and | symptomatic disease has been observed in many settings (1-3). The documented ability of | booster doses to restore vaccine effectiveness (VE) to higher levels suggests at least some of | the observed waning is real (3-4). However, differential depletion of susceptibles through | infection-induced immunity related to individuals’ vaccination status can create bias that induces | spurious waning, complicating interpretation of vaccine effectiveness estimates (5-8). | In previous work (5), we showed that spurious waning was detectable but modest in settings | without true waning where true VE was very high (0.95) and constant over time (i.e., no true | waning), and more notable in settings where true VE was lower (0.70) and constant over time. | This led us to the natural question: Is spurious waning modest or more notable in situations | where true effectiveness wanes over time? Here we examine bias that can arise in settings in | which true waning occurs. |
Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization.
Feikin DR , Higdon MM , Andrews N , Collie S , Deloria Knoll M , Kwong JC , Link-Gelles R , Pilishvili T , Patel MK . Vaccine 2023 41 (14) 2329-2338 ![]() Emerging in November 2021, the SARS-CoV-2 Omicron variant of concern exhibited marked immune evasion resulting in reduced vaccine effectiveness against SARS-CoV-2 infection and symptomatic disease. Most vaccine effectiveness data on Omicron are derived from the first Omicron subvariant, BA.1, which caused large waves of infection in many parts of the world within a short period of time. BA.1, however, was replaced by BA.2 within months, and later by BA.4 and BA.5 (BA.4/5). These later Omicron subvariants exhibited additional mutations in the spike protein of the virus, leading to speculation that they might result in even lower vaccine effectiveness. To address this question, the World Health Organization hosted a virtual meeting on December 6, 2022, to review available evidence for vaccine effectiveness against the major Omicron subvariants up to that date. Data were presented from South Africa, the United Kingdom, the United States, and Canada, as well as the results of a review and meta-regression of studies that evaluated the duration of the vaccine effectiveness for multiple Omicron subvariants. Despite heterogeneity of results and wide confidence intervals in some studies, the majority of studies showed vaccine effectiveness tended to be lower against BA.2 and especially against BA.4/5, compared to BA.1, with perhaps faster waning against severe disease caused by BA.4/5 after a booster dose. The interpretation of these results was discussed and both immunological factors (i.e., more immune escape with BA.4/5) and methodological issues (e.g., biases related to differences in the timing of subvariant circulation) were possible explanations for the findings. COVID-19 vaccines still provide some protection against infection and symptomatic disease from all Omicron subvariants for at least several months, with greater and more durable protection against severe disease. |
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis
Li Y , Wang X , Blau DM , Caballero MT , Feikin DR , Gill CJ , Madhi SA , Omer SB , Simões EAF , Campbell H , Pariente AB , Bardach D , Bassat Q , Casalegno JS , Chakhunashvili G , Crawford N , Danilenko D , Do LAH , Echavarria M , Gentile A , Gordon A , Heikkinen T , Huang QS , Jullien S , Krishnan A , Lopez EL , Markić J , Mira-Iglesias A , Moore HC , Moyes J , Mwananyanda L , Nokes DJ , Noordeen F , Obodai E , Palani N , Romero C , Salimi V , Satav A , Seo E , Shchomak Z , Singleton R , Stolyarov K , Stoszek SK , von Gottberg A , Wurzel D , Yoshida LM , Yung CF , Zar HJ , Nair H . Lancet 2022 399 (10340) 2047-2064 BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU). |
Etiology and clinical characteristics of severe pneumonia among young children in Thailand: Pneumonia Etiology Research for Child Health (PERCH) case-control study findings, 2012-2013
Bunthi C , Rhodes J , Thamthitiwat S , Higdon MM , Chuananon S , Amorninthapichet T , Paveenkittiporn W , Chittaganpitch M , Sawatwong P , Hammitt LL , Feikin DR , Murdoch DR , Deloria-Knoll M , O'Brien KL , Prosperi C , Maloney SA , Baggett HC , Akarasewi P . Pediatr Infect Dis J 2021 40 S91-s100 ![]() BACKGROUND: Pneumonia remains the leading cause of death among children <5 years of age beyond the neonatal period in Thailand. Using data from the Pneumonia Etiology Research for Child Health (PERCH) Study, we provide a detailed description of pneumonia cases and etiology in Thailand to inform local treatment and prevention strategies in this age group. METHODS: PERCH, a multi-country case-control study, evaluated the etiology of hospitalized cases of severe and very severe pneumonia among children 1-59 months of age. The Thailand site enrolled children for 24 consecutive months during January 2012-February 2014 with staggered start dates in 2 provinces. Cases were children hospitalized with pre-2013 WHO-defined severe or very severe pneumonia. Community controls were randomly selected from health services registries in each province. Analyses were restricted to HIV-negative cases and controls. We calculated adjusted odds ratios (ORs) and 95% CIs comparing organism prevalence detected by nasopharyngeal/oropharyngeal (NP/OP) polymerase chain reaction between cases and controls. The PERCH Integrated Analysis (PIA) used Bayesian latent variable analysis to estimate pathogen-specific etiologic fractions and 95% credible intervals. RESULTS: Over 96% of both cases (n = 223) and controls (n = 659) had at least 1 organism detected; multiple organisms were detected in 86% of cases and 88% of controls. Among 98 chest Radiograph positive (CXR+) cases, respiratory syncytial virus (RSV) had the highest NP/OP prevalence (22.9%) and the strongest association with case status (OR 20.5; 95% CI: 10.2, 41.3) and accounted for 34.6% of the total etiologic fraction. Tuberculosis (TB) accounted for 10% (95% CrI: 1.6-26%) of the etiologic fraction among CXR+ cases. DISCUSSION: More than one-third of hospitalized cases of severe and very severe CXR+ pneumonia among children 1-59 months of age in Thailand were attributable to RSV. TB accounted for 10% of cases, supporting evaluation for TB among children hospitalized with pneumonia in high-burden settings. Similarities in pneumonia etiology in Thailand and other PERCH sites suggest that global control strategies based on PERCH study findings are relevant to Thailand and similar settings. |
Introduction to the site-specific etiologic results from the Pneumonia Etiology Research for Child Health (PERCH) Study
Deloria Knoll M , Prosperi C , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Madhi SA , Murdoch DR , Scott JAG , Thea DM , O'Brien KL . Pediatr Infect Dis J 2021 40 S1-s6 The Pneumonia Etiology Research for Child Health (PERCH) study evaluated the etiology of severe and very severe pneumonia in children hospitalized in 7 African and Asian countries. Here, we summarize the highlights of in-depth site-specific etiology analyses published separately in this issue, including how etiology varies by age, mortality status, malnutrition, severity, HIV status, and more. These site-specific results impart important lessons that can inform disease control policy implications. |
Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study
Baillie VL , Moore DP , Mathunjwa A , Baggett HC , Brooks A , Feikin DR , Hammitt LL , Howie SRC , Knoll MD , Kotloff KL , Levine OS , O'Brien KL , Scott AG , Thea DM , Antonio M , Awori JO , Driscoll AJ , Fancourt NSS , Higdon MM , Karron RA , Morpeth SC , Mulindwa JM , Murdoch DR , Park DE , Prosperi C , Rahman MZ , Rahman M , Salaudeen RA , Sawatwong P , Somwe SW , Sow SO , Tapia MD , Simões EAF , Madhi SA . Viruses 2021 13 (7) Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1-59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3-1.6). This association was driven by the children aged 12-59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8-2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4-2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing. |
Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.
Patel MK , Bergeri I , Bresee JS , Cowling BJ , Crowcroft NS , Fahmy K , Hirve S , Kang G , Katz MA , Lanata CF , L'Azou Jackson M , Joshi S , Lipsitch M , Mwenda JM , Nogareda F , Orenstein WA , Ortiz JR , Pebody R , Schrag SJ , Smith PG , Srikantiah P , Subissi L , Valenciano M , Vaughn DW , Verani JR , Wilder-Smith A , Feikin DR . Vaccine 2021 39 (30) 4013-4024 ![]() Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results. |
Global Landscape Review of Serotype-Specific Invasive Pneumococcal Disease Surveillance among Countries Using PCV10/13: The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) Project
Deloria Knoll M , Bennett JC , Garcia Quesada M , Kagucia EW , Peterson ME , Feikin DR , Cohen AL , Hetrich MK , Yang Y , Sinkevitch JN , Ampofo K , Aukes L , Bacci S , Bigogo G , Brandileone MC , Bruce MG , Camilli R , Castilla J , Chan G , Chanto Chacón G , Ciruela P , Cook H , Corcoran M , Dagan R , Danis K , de Miguel S , De Wals P , Desmet S , Galloway Y , Georgakopoulou T , Hammitt LL , Hilty M , Ho PL , Jayasinghe S , Kellner JD , Kleynhans J , Knol MJ , Kozakova J , Kristinsson KG , Ladhani SN , Lara CS , León ME , Lepp T , Mackenzie GA , Mad'arová L , McGeer A , Mungun T , Mwenda JM , Nuorti JP , Nzoyikorera N , Oishi K , De Oliveira LH , Paragi M , Pilishvili T , Puentes R , Rafai E , Saha SK , Savrasova L , Savulescu C , Scott JA , Scott KJ , Serhan F , Setchanova LP , Sinkovec Zorko N , Skoczyńska A , Swarthout TD , Valentiner-Branth P , van der Linden M , Vestrheim DF , von Gottberg A , Yildirim I , Hayford K , Pserenade Team . Microorganisms 2021 9 (4) 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. |
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.
Park DE , Higdon MM , Prosperi C , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , O'Brien KL , Scott JAG , Thea DM , Antonio M , Awori JO , Baillie VL , Bunthi C , Kwenda G , Mackenzie GA , Moore DP , Morpeth SC , Mwananyanda L , Paveenkittiporn W , Ziaur Rahman M , Rahman M , Rhodes J , Sow SO , Tapia MD , Deloria Knoll M . Pediatr Infect Dis J 2021 40 (6) 503-512 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. |
Serotype distribution of remaining pneumococcal meningitis in the mature PCV10/13 period: Findings from the PSERENADE Project
Garcia Quesada M , Yang Y , Bennett JC , Hayford K , Zeger SL , Feikin DR , Peterson ME , Cohen AL , Almeida SCG , Ampofo K , Ang M , Bar-Zeev N , Bruce MG , Camilli R , Chacón GC , Ciruela P , Cohen C , Corcoran M , Dagan R , De Wals P , Desmet S , Diawara I , Gierke R , Guevara M , Hammitt LL , Hilty M , Ho PL , Jayasinghe S , Kleynhans J , Kristinsson KG , Ladhani SN , McGeer A , Mwenda JM , Pekka Nuorti J , Oishi K , Ricketson LJ , Sanz JC , Savrasova L , Setchanova LP , Smith A , Valentiner-Branth P , Valenzuela MT , van der Linden M , van Sorge NM , Varon E , Winje BA , Yildirim I , Zintgraff J , Knoll MD . Microorganisms 2021 9 (4) 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 (N = 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 (N = 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. |
Changes in invasive pneumococcal disease caused by streptococcus pneumoniae serotype 1 following introduction of pcv10 and pcv13: Findings from the PSERENADE project
Bennett JC , Hetrich MK , Quesada MG , Sinkevitch JN , Knoll MD , Feikin DR , Zeger SL , Kagucia EW , Cohen AL , Ampofo K , Brandileone MCC , Bruden D , Camilli R , Castilla J , Chan G , Cook H , Cornick JE , Dagan R , Dalby T , Danis K , de Miguel S , De Wals P , Desmet S , Georgakopoulou T , Gilkison C , Grgic‐vitek M , Hammitt LL , Hilty M , Ho PL , Jayasinghe S , Kellner JD , Kleynhans J , Knol MJ , Kozakova J , Kristinsson KG , Ladhani SN , Macdonald L , Mackenzie GA , Mad’arová L , McGeer A , Mereckiene J , Morfeldt E , Mungun T , Muñoz‐almagro C , Nuorti JP , Paragi M , Pilishvili T , Puentes R , Saha SK , Khan AS , Savrasova L , Scott JA , Skoczyńska A , Suga S , Linden M , Verani JR , von Gottberg A , Winje BA , Yildirim I , Zerouali K , Hayford K , Pserenade Team . Microorganisms 2021 9 (4) ![]() Streptococcus pneumoniae serotype 1 (ST1) was an important cause of invasive pneumococ-cal disease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) con-taining ST1 antigen. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERE‐ NADE) 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) compar-ing 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. |
Limited added value of oropharyngeal swabs for detecting pneumococcal carriage in adults
Farrar JL , Odiembo H , Odoyo A , Bigogo G , Kim L , Lessa FC , Feikin DR , Breiman RF , Whitney CG , Carvalho MG , Pimenta FC . Open Forum Infect Dis 2020 7 (9) ofaa368 We compared pneumococcal isolation rates and evaluated the benefit of using oropharyngeal (OP) specimens in addition to nasopharyngeal (NP) specimens collected from adults in rural Kenya. Of 846 adults, 52.1% were colonized; pneumococci were detected from both NP and OP specimens in 23.5%, NP only in 22.9%, and OP only in 5.7%. Ten-valent pneumococcal conjugate vaccine strains were detected from both NP and OP in 3.4%, NP only in 4.1%, and OP only in 0.7%. Inclusion of OP swabs increased carriage detection by 5.7%; however, the added cost of collecting and processing OP specimens may justify exclusion from future carriage studies among adults. |
Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children
McCollum ED , Park DE , Watson NL , Fancourt NSS , Focht C , Baggett HC , Abdullah Brooks W , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Awori JO , Chipeta J , Chuananon S , DeLuca AN , Driscoll AJ , Ebruke BE , Elhilal M , Emmanouilidou D , Githua LP , Higdon MM , Hossain L , Jahan Y , Karron RA , Kyalo J , Moore DP , Mulindwa JM , Naorat S , Prosperi C , Verwey C , West JE , Knoll MD , Brien KLO , Feikin DR , Hammitt LL . Pediatr Pulmonol 2020 55 (11) 3197-3208 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 1-59 month old 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 reclassified 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 towards 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=0.03). 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. This article is protected by copyright. All rights reserved. |
Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting
Driscoll AJ , Arshad SH , Bont L , Brunwasser SM , Cherian T , Englund JA , Fell DB , Hammitt LL , Hartert TV , Innis BL , Karron RA , Langley GE , Mulholland EK , Munywoki PK , Nair H , Ortiz JR , Savitz DA , Scheltema NM , Simoes EAF , Smith PG , Were F , Zar HJ , Feikin DR . Vaccine 2020 38 (11) 2435-2448 Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies. |
Indirect effects of 10-valent pneumococcal conjugate vaccine against adult pneumococcal pneumonia in rural western Kenya
Bigogo GM , Audi A , Auko J , Aol GO , Ochieng BJ , Odiembo H , Odoyo A , Widdowson MA , Onyango C , Borgdorff MW , Feikin DR , Carvalho MDG , Whitney CG , Verani JR . Clin Infect Dis 2019 69 (12) 2177-2184 BACKGROUND: Data on pneumococcal conjugate vaccine (PCV) indirect effects in low-income countries with high HIV burden are limited. We examined adult pneumococcal pneumonia incidence before and after 10-valent PCV introduction in Kenya in 2011. METHODS: From 1/1/2008 to 12/31/2016, we conducted surveillance for acute respiratory infection (ARI) among ~12,000 adults (>/=18 years) in western Kenya, where HIV prevalence ~17%. ARI cases (cough or difficulty breathing or chest pain, plus temperature >/=38.0 C or oxygen saturation <90%) presenting to a clinic underwent blood culture and pneumococcal urine antigen testing (UAT). We calculated ARI incidence and adjusted for healthcare seeking using data from household visits. The proportion of ARI cases with pneumococcus detected among those with complete testing (blood culture and UAT) was multiplied by adjusted ARI incidence to estimate pneumococcal pneumonia incidence. RESULTS: Pre-PCV (2008-2010), crude and adjusted ARI incidence were 3.14 and 5.30/100 person-years-observation (pyo), respectively. Among ARI cases, 39.0% (340/872) had both blood culture and UAT; 21.2% (72/340) had pneumococcus detected, yielding baseline pneumococcal pneumonia incidence of 1.12/100 pyo (95% confidence interval [CI] 1.0-1.3). In each post-PCV year (2012-2016), pneumococcal pneumonia incidence was significantly lower than baseline; with incidence rate ratios (IRR) of 0.53 (95%CI 0.31-0.61) in 2012 and 0.13 (95%CI 0.09-0.17) in 2016. Similar declines were observed in HIV-infected (IRR 0.13, 95%CI 0.08-0.22), and HIV-uninfected (IRR 0.10, 95%CI 0.05-0.20). CONCLUSIONS: Adult pneumococcal pneumonia declined in western Kenya following 10-valent PCV introduction, likely reflecting vaccine indirect effects. Evidence of herd protection is critical for guiding PCV policy decisions in resource-constrained areas. |
Streptococcus infantis, Streptococcus mitis , and Streptococcus oralis Strains With Highly Similar cps5 Loci and Antigenic Relatedness to Serotype 5 Pneumococci.
Pimenta F , Gertz RE Jr , Park SH , Kim E , Moura I , Milucky J , Rouphael N , Farley MM , Harrison LH , Bennett NM , Bigogo G , Feikin DR , Breiman R , Lessa FC , Whitney CG , Rajam G , Schiffer J , da Gloria Carvalho M , Beall B . Front Microbiol 2018 9 3199 ![]() ![]() Streptococcus pneumoniae is a highly impactful bacterial pathogen on a global scale. The principal pneumococcal virulence factor and target of effective vaccines is its polysaccharide capsule, of which there are many structurally distinct forms. Here, we describe four distinct strains of three Mitis group commensal species (Streptococcus infantis, Streptococcus mitis, and Streptococcus oralis) recovered from upper respiratory tract specimens from adults in Kenya and the United States that were PCR-positive for the pneumococcal serotype 5 specific gene, wzy5. For each of the four strains, the 15 genes comprising the capsular polysaccharide biosynthetic gene cluster (cps5) shared the same order found in serotype 5 pneumococci, and each of the serotype 5-specific genes from the serotype 5 pneumococcal reference strain shared 76-99% sequence identity with the non-pneumococcal counterparts. Double-diffusion experiments demonstrated specific reactivity of the non-pneumococcal strains with pneumococcal serotype 5 typing sera. Antiserum raised against S. mitis strain KE67013 specifically reacted with serotype 5 pneumococci for a positive Quellung reaction and stimulated serotype 5 specific opsonophagocytic killing of pneumococci. Four additional commensal strains, identified using PCR serotyping assays on pharyngeal specimens, revealed loci highly homologous to those of pneumococci of serotypes 12F, 15A, 18C, and 33F. These data, in particular the species and strain diversity shown for serotype 5, highlight the existence of a broad non-pneumococcal species reservoir in the upper respiratory tract for the expression of capsular polysaccharides that are structurally related or identical to those corresponding to epidemiologically significant serotypes. Very little is known about the genetic and antigenic capsular diversity among the vast array of commensal streptococcal strains that represent multiple diverse species. The discovery of serotype 5 strains within three different commensal species suggests that extensive capsular serologic overlap exists between pneumococci and other members of the diverse Mitis group. These findings may have implications for our current understanding of naturally acquired immunity to S. pneumoniae and pneumococcal serotype distributions in different global regions. Further characterization of commensal strains carrying homologs of serotype-specific genes previously thought to be specific for pneumococci of known serotypes may shed light on the evolution of these important loci. |
Clinical surveillance and evaluation of suspected Ebola cases in a vaccine trial during an Ebola epidemic: The Sierra Leone Trial to Introduce a Vaccine Against Ebola
Conteh MA , Goldstein ST , Wurie HR , Gidudu J , Lisk DR , Carter RJ , Seward JF , Hampton LM , Wang D , Andersen LE , Arvay M , Schrag SJ , Dawson P , Fombah AE , Petrie CR , Feikin DR , Russell JBW , Lindblad R , Kargbo SAS , Samai M , Mahon BE . J Infect Dis 2018 217 S33-s39 Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220]. |
Effectiveness of a third dose of MMR vaccine for mumps outbreak control
Cardemil CV , Dahl RM , James L , Wannemuehler K , Gary HE , Shah M , Marin M , Riley J , Feikin DR , Patel M , Quinlisk P . N Engl J Med 2017 377 (10) 947-956 BACKGROUND: The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. METHODS: Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. RESULTS: Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. CONCLUSIONS: Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.). |
Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1–59 months enrolled in the pneumonia etiology research for child health (PERCH) case–control study
McCollum ED , Park DE , Watson NL , Buck WC , Bunthi C , Devendra A , Ebruke BE , Elhilali M , Emmanouilidou D , Garcia-Prats AJ , Githinji L , Hossain L , Madhi SA , Moore DP , Mulindwa J , Olson D , Awori JO , Vandepitte WP , Verwey C , West JE , Knoll MD , O’Brien KL , Feikin DR , Hammit LL . BMJ Open Respir Res 2017 4 (1) e000193 Introduction Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. Methods Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1–59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. Results Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/ absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. Conclusions Listening panel and case–control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries. |
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
Shi T , McAllister DA , O'Brien KL , Simoes EAF , Madhi SA , Gessner BD , Polack FP , Balsells E , Acacio S , Aguayo C , Alassani I , Ali A , Antonio M , Awasthi S , Awori JO , Azziz-Baumgartner E , Baggett HC , Baillie VL , Balmaseda A , Barahona A , Basnet S , Bassat Q , Basualdo W , Bigogo G , Bont L , Breiman RF , Brooks WA , Broor S , Bruce N , Bruden D , Buchy P , Campbell S , Carosone-Link P , Chadha M , Chipeta J , Chou M , Clara W , Cohen C , de Cuellar E , Dang DA , Dash-Yandag B , Deloria-Knoll M , Dherani M , Eap T , Ebruke BE , Echavarria M , de Freitas Lazaro Emediato CC , Fasce RA , Feikin DR , Feng L , Gentile A , Gordon A , Goswami D , Goyet S , Groome M , Halasa N , Hirve S , Homaira N , Howie SRC , Jara J , Jroundi I , Kartasasmita CB , Khuri-Bulos N , Kotloff KL , Krishnan A , Libster R , Lopez O , Lucero MG , Lucion F , Lupisan SP , Marcone DN , McCracken JP , Mejia M , Moisi JC , Montgomery JM , Moore DP , Moraleda C , Moyes J , Munywoki P , Mutyara K , Nicol MP , Nokes DJ , Nymadawa P , da Costa Oliveira MT , Oshitani H , Pandey N , Paranhos-Baccala G , Phillips LN , Picot VS , Rahman M , Rakoto-Andrianarivelo M , Rasmussen ZA , Rath BA , Robinson A , Romero C , Russomando G , Salimi V , Sawatwong P , Scheltema N , Schweiger B , Scott JAG , Seidenberg P , Shen K , Singleton R , Sotomayor V , Strand TA , Sutanto A , Sylla M , Tapia MD , Thamthitiwat S , Thomas ED , Tokarz R , Turner C , Venter M , Waicharoen S , Wang J , Watthanaworawit W , Yoshida LM , Yu H , Zar HJ , Campbell H , Nair H . Lancet 2017 390 (10098) 946-958 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. |
The incremental value of repeated induced sputum and gastric aspirate samples for the diagnosis of pulmonary tuberculosis in young children with acute community-acquired pneumonia
Moore DP , Higdon MM , Hammitt LL , Prosperi C , DeLuca AN , Da Silva P , Baillie VL , Adrian PV , Mudau A , Deloria Knoll M , Feikin DR , Murdoch DR , O'Brien KL , Madhi SA . Clin Infect Dis 2017 64 S309-s316 Background.: Mycobacterium tuberculosis (Mtb) contributes to the pathogenesis of childhood acute community-acquired pneumonia in settings with a high tuberculosis burden. The incremental value of a repeated induced sputum (IS) sample, compared with a single IS or gastric aspirate (GA) sample, is not well known. Methods.: Two IS samples were obtained for Mtb culture from children enrolled as cases in the Pneumonia Etiology Research for Child Health (PERCH) study in South Africa. Nonstudy attending physicians requested GA if pulmonary tuberculosis was clinically suspected. We compared the Mtb yield of 2 IS samples to that of 1 IS sample and GA samples. Results: . Twenty-seven (3.0%) culture-confirmed pulmonary tuberculosis cases were identified among 906 children investigated with IS and GA samples for Mtb. Results from 2 IS samples were available for 719 children (79.4%). Of 12 culture-confirmed pulmonary tuberculosis cases identified among children with ≥2 IS samples, 4 (33.3%) were negative at the first IS sample. In head-to-head comparisons among children with both GA and IS samples collected, the yield of 1 GA sample (8 of 427; 1.9%) was similar to that of 1 IS sample (5 of 427, 1.2%), and the yield of 2 GA samples (10 of 300; 3.3%) was similar to that of 2 IS samples (5 of 300; 1.7%). IS samples identified 8 (42.1%) of the 19 culture-confirmed pulmonary tuberculosis cases that were identified through submission of IS and GA samples. Conclusions.: A single IS sample underestimated the presence of Mtb in children hospitalized with severe or very severe pneumonia. Detection of Mtb is enhanced by combining 2 IS with GA sample collections in young children with acute severe pneumonia. |
Introduction to the epidemiologic considerations, analytic methods, and foundational results from the Pneumonia Etiology Research for Child Health Study
O'Brien KL , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Deloria Knoll M , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Zeger SL . Clin Infect Dis 2017 64 S179-s184 Over the last 20–30 years, enormous reductions have occurred in the absolute and relative burden of pneumonia mortality in young children around the world. Only 20 years ago, when the population of young children was approximately 625 million, approximately 1.7 million young children died from pneumonia before their 5th birthday (Figure 1) [1–4]. Mortality from pneumonia among children aged <5 years fell to 921 000 in 2015, whereas the population of young children rose to >670 million [1, 2, 5]. This remarkable improvement in child survival and health has resulted from advances in social conditions and economic development [6] but has also been influenced by at least 4 pivotal innovations: (1) the development of a global vaccination program, the World Health Organization’s Expanded Program on Immunizations (begun in 1974), which created the architecture around which country investments, donor funding, program strategies, and outcome measurements could be envisioned and implemented; (2) the global consensus to focus funding, programs, and momentum on 6 development targets articulated by the United Nations General Assembly through the Millennium Development Goals (MDGs, agreed upon in 2000) with MDG4 targeting child survival; (3) the advent of large, health-focused nongovernmental organizations; and (4) the founding of the Global Alliance for Vaccines and Immunization (the Gavi Alliance, formally launched at the World Economic Forum in January 2000), a multilateral funding organization that has allowed for an unprecedented pace of introduction and expanded use of life-saving vaccines in low-income countries. In part, as a result of this multidimensional, multisectoral consensus approach enacted through critical large-scale investments in prevention, protection, and treatment, pneumonia mortality has fallen substantially in many parts of the world because the most fatal of the pathogens and the underlying conditions that put children at risk are being targeted. |
Is higher viral load in the upper respiratory tract associated with severe pneumonia? Findings From the PERCH Study
Feikin DR , Fu W , Park DE , Shi Q , Higdon MM , Baggett HC , Brooks WA , Deloria Knoll M , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Scott JAG , Thea DM , Adrian PV , Antonio M , Awori JO , Baillie VL , DeLuca AN , Driscoll AJ , Ebruke BE , Goswami D , Karron RA , Li M , Morpeth SC , Mwaba J , Mwansa J , Prosperi C , Sawatwong P , Sow SO , Tapia MD , Whistler T , Zaman K , Zeger SL , O' Brien KL , Murdoch DR . Clin Infect Dis 2017 64 S337-s346 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. |
Addressing the analytic challenges of cross-sectional pediatric pneumonia etiology data
Hammitt LL , Feikin DR , Scott JAG , Zeger SL , Murdoch DR , O'Brien KL , Deloria Knoll M . Clin Infect Dis 2017 64 S197-s204 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. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Jan 27, 2025
- Content source:
- Powered by CDC PHGKB Infrastructure