Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
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Query Trace: Higdon M [original query] |
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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. |
Effectiveness of 2 and 3 mRNA COVID-19 Vaccines Doses against Omicron and Delta-Related Outpatient Illness among Adults, October 2021 - February 2022 (preprint)
Kim SS , Chung JR , Talbot HK , Grijalva CG , Wernli KJ , Martin ET , Monto AS , Belongia EA , McLean HQ , Gaglani M , Mamawala M , Nowalk MP , Geffel KM , Tartof SY , Florea A , Lee JS , Tenforde MW , Patel MM , Flannery B , Bentz ML , Burgin A , Burroughs M , Davis ML , Howard D , Lacek K , Madden JC , Nobles S , Padilla J , Sheth M , Arroliga A , Beeram M , Dunnigan K , Ettlinger J , Graves A , Hoffman E , Jatla M , McKillop A , Murthy K , Mutnal M , Priest E , Raiyani C , Rao A , Requenez L , Settele N , Smith M , Stone K , Thomas J , Volz M , Walker K , Zayed M , Annan E , Daley P , Kniss K , Merced-Morales A , Ayala E , Amundsen B , Aragones M , Calderon R , Hong V , Jimenez G , Kim J , Ku J , Lewin B , McDaniel A , Reyes A , Shaw S , Takhar H , Torres A , Burganowski R , Kiniry E , Moser KA , Nguyen M , Park S , Wellwood S , Wickersham B , Alvarado-Batres J , Benz S , Berger H , Bissonnette A , Blake J , Boese K , Botten E , Boyer J , Braun M , Breu B , Burbey G , Cravillion C , Delgadillo C , Donnerbauer A , Dziedzic T , Eddy J , Edgren H , Ermeling A , Ewert K , Fehrenbach C , Fernandez R , Frome W , Guzinski S , Heeren L , Herda D , Hertel M , Heuer G , Higdon E , Ivacic L , Jepsen L , Kaiser S , Karl J , Keffer B , King J , Koepel TK , Kohl S , Kohn S , Kohnhorst D , Kronholm E , Le T , Lemieux A , Marcis C , Maronde M , McCready I , McGreevey K , Meece J , Mehta N , Miesbauer D , Moon V , Moran J , Nikolai C , Olson B , Olstadt J , Ott L , Pan N , Pike C , Polacek D , Presson M , Price N , Rayburn C , Reardon C , Rotar M , Rottscheit C , Salzwedel J , Saucedo J , Scheffen K , Schug C , Seyfert K , Shrestha R , Slenczka A , Stefanski E , Strupp M , Tichenor M , Watkins L , Zachow A , Zimmerman B , Bauer S , Beney K , Cheng CK , Faraj N , Getz A , Grissom M , Groesbeck M , Harrison S , Henson K , Jermanus K , Johnson E , Kaniclides A , Kimberly A , Lamerato LE , Lauring A , Lehmann-Wandell R , McSpadden EJ , Nabors L , Truscon R , Balasubramani GK , Bear T , Bobeck J , Bowser E , Clarke K , Clarke LG , Dauer K , Deluca C , Dierks B , Haynes L , Hickey R , Johnson M , Jonsson A , Luosang N , McKown L , Peterson A , Phaturos D , Rectenwald A , Sax TM , Stiegler M , Susick M , Suyama J , Taylor L , Walters S , Weissman A , Williams JV , Blair M , Carter J , Chappell J , Copen E , Denney M , Graes K , Halasa N , Lindsell C , Liu Z , Longmire S , McHenry R , Short L , Tan HN , Vargas D , Wrenn J , Wyatt D , Zhu Y . medRxiv 2022 10 Background: We estimated SARS-CoV-2 Delta and Omicron-specific effectiveness of 2 and 3 mRNA COVID-19 vaccine doses in adults against symptomatic illness in US outpatient settings. Method(s): Between October 1, 2021, and February 12, 2022, research staff consented and enrolled eligible participants who had fever, cough, or loss of taste or smell and sought outpatient medical care or clinical SARS-CoV-2 testing within 10 days of illness onset. Using the test-negative design, we compared the odds of receiving 2 or 3 mRNA COVID-19 vaccine doses among SARS-CoV-2 cases versus controls using logistic regression. Regression models were adjusted for study site, age, onset week, and prior SARS-CoV-2 infection. Vaccine effectiveness (VE) was calculated as (1 - adjusted odds ratio) x 100%. Result(s): Among 3847 participants included for analysis, 574 (32%) of 1775 tested positive for SARS-CoV-2 during the Delta predominant period and 1006 (56%) of 1794 participants tested positive during the Omicron predominant period. When Delta predominated, VE against symptomatic illness in outpatient settings was 63% (95% CI: 51% to 72%) among mRNA 2-dose recipients and 96% (95% CI: 93% to 98%) for 3-dose recipients. When Omicron predominated, VE was 21% (95% CI: -6% to 41%) among 2-dose recipients and 62% (95% CI: 48% to 72%) among 3-dose recipients. Conclusion(s): In this adult population, 3 mRNA COVID-19 vaccine doses provided substantial protection against symptomatic illness in outpatient settings when the Omicron variant became the predominant cause of COVID-19 in the U.S. These findings support the recommendation for a 3rd mRNA COVID-19 vaccine dose. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study
Pneumonia Etiology Research for Child Health Study Group , O'Brien Katherine L , Levine Orin S , Knoll Maria Deloria , Feikin Daniel R , DeLuca Andrea N , Driscoll Amanda J , Fancourt Nicholas , Fu Wei , Haddix Meredith , Hammitt Laura L , Higdon Melissa M , Kagucia E Wangeci , Karron Ruth A , Li Mengying , Park Daniel E , Prosperi Christine , Shi Qiyuan , Wu Zhenke , Zeger Scott L , Watson Nora L , Crawley Jane , Murdoch David R , Brooks W Abdullah , Endtz Hubert P , Zaman Khalequ , Goswami Doli , Hossain Lokman , Jahan Yasmin , Chisti Mohammod Jobayer , Howie Stephen R C , Ebruke Bernard E , Antonio Martin , McLellan Jessica L , Machuka Eunice M , Shamsul Arifin , Zaman Syed M A , Mackenzie Grant , Scott J Anthony G , Awori Juliet O , Morpeth Susan C , Kamau Alice , Kazungu Sidi , Ominde Micah Silaba , Kotloff Karen L , Tapia Milagritos D , Sow Samba O , Sylla Mamadou , Tamboura Boubou , Onwuchekwa Uma , Kourouma Nana , Toure Aliou , Sissoko Seydou , Madhi Shabir A , Moore David P , Adrian Peter V , Baillie Vicky L , Kuwanda Locadiah , Mudau Azwifarwi , Groome Michelle J , Mahomed Nasreen , Simões Eric A F , Baggett Henry C , Thamthitiwat Somsak , Maloney Susan A , Bunthi Charatdao , Rhodes Julia , Sawatwong Pongpun , Akarasewi Pasakorn , Thea Donald M , Mwananyanda Lawrence , Chipeta James , Seidenberg Phil , Mwansa James , Somwe Somwe Wa , Kwenda Geoffrey , Anderson Trevor P , Mitchell Joanne L . Lancet 2019 394 (10200) 757-779 BACKGROUND: Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. METHODS: We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1-59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. FINDINGS: Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6-97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3-65·6) of causes, whereas bacteria accounted for 27·3% (23·3-31·6) and Mycobacterium tuberculosis for 5·9% (3·9-8·3). Viruses were less common (54·5%, 95% CrI 47·4-61·5 vs 68·0%, 62·7-72·7) and bacteria more common (33·7%, 27·2-40·8 vs 22·8%, 18·3-27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4-34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus-enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. INTERPRETATION: In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. FUNDING: Bill & Melinda Gates Foundation. |
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. |
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. |
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. |
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. |
Forecasting influenza activity using machine-learned mobility map
Venkatramanan S , Sadilek A , Fadikar A , Barrett CL , Biggerstaff M , Chen J , Dotiwalla X , Eastham P , Gipson B , Higdon D , Kucuktunc O , Lieber A , Lewis BL , Reynolds Z , Vullikanti AK , Wang L , Marathe M . Nat Commun 2021 12 (1) 726 Human mobility is a primary driver of infectious disease spread. However, existing data is limited in availability, coverage, granularity, and timeliness. Data-driven forecasts of disease dynamics are crucial for decision-making by health officials and private citizens alike. In this work, we focus on a machine-learned anonymized mobility map (hereon referred to as AMM) aggregated over hundreds of millions of smartphones and evaluate its utility in forecasting epidemics. We factor AMM into a metapopulation model to retrospectively forecast influenza in the USA and Australia. We show that the AMM model performs on-par with those based on commuter surveys, which are sparsely available and expensive. We also compare it with gravity and radiation based models of mobility, and find that the radiation model's performance is quite similar to AMM and commuter flows. Additionally, we demonstrate our model's ability to predict disease spread even across state boundaries. Our work contributes towards developing timely infectious disease forecasting at a global scale using human mobility datasets expanding their applications in the area of infectious disease epidemiology. |
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. |
Pneumococcal colonization prevalence and density among Thai children with severe pneumonia and community controls
Piralam B , Prosperi C , Thamthitiwat S , Bunthi C , Sawatwong P , Sangwichian O , Higdon MM , Watson NL , Deloria Knoll M , Paveenkittiporn W , Chara C , Hurst CP , Akarasewi P , Rhodes J , Maloney SA , O'Brien KL , Baggett HC . PLoS One 2020 15 (4) e0232151 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. |
Detection of Pneumococcal DNA in Blood by Polymerase Chain Reaction for Diagnosing Pneumococcal Pneumonia in Young Children From Low- and Middle-Income Countries.
Morpeth SC , Deloria Knoll M , Scott JAG , Park DE , Watson NL , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , O'Brien KL , Thea DM , Adrian PV , Ahmed D , Antonio M , Bunthi C , DeLuca AN , Driscoll AJ , Githua LP , Higdon MM , Kahn G , Karani A , Karron RA , Kwenda G , Makprasert S , Mazumder R , Moore DP , Mwansa J , Nyongesa S , Prosperi C , Sow SO , Tamboura B , Whistler T , Zeger SL , Murdoch DR . Clin Infect Dis 2017 64 S347-s356 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. |
Evaluation of Pneumococcal Load in Blood by Polymerase Chain Reaction for the Diagnosis of Pneumococcal Pneumonia in Young Children in the PERCH Study.
Deloria Knoll M , Morpeth SC , Scott JAG , Watson NL , Park DE , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , O'Brien KL , Thea DM , Ahmed D , Antonio M , Awori JO , Baillie VL , Chipeta J , Deluca AN , Dione M , Driscoll AJ , Higdon MM , Jatapai A , Karron RA , Mazumder R , Moore DP , Mwansa J , Nyongesa S , Prosperi C , Seidenberg P , Siludjai D , Sow SO , Tamboura B , Zeger SL , Murdoch DR , Madhi SA . Clin Infect Dis 2017 64 S357-s367 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 x 103 vs 0.19 x 103 copies/mL), but overlapped substantially (range, 0.16-989.9 x 103 copies/mL and 0.01-551.9 x 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. |
Colonization Density of the Upper Respiratory Tract as a Predictor of Pneumonia-Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii.
Park DE , Baggett HC , Howie SRC , Shi Q , Watson NL , Brooks WA , Deloria Knoll M , Hammitt LL , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , O'Brien KL , Scott JAG , Thea DM , Ahmed D , Antonio M , Baillie VL , DeLuca AN , Driscoll AJ , Fu W , Gitahi CW , Olutunde E , Higdon MM , Hossain L , Karron RA , Maiga AA , Maloney SA , Moore DP , Morpeth SC , Mwaba J , Mwenechanya M , Prosperi C , Sylla M , Thamthitiwat S , Zeger SL , Feikin DR . Clin Infect Dis 2017 64 S328-s336 Background.: There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.: In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens. Results.: Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)-positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii. Conclusions.: There is evidence for an association between H. influenzae colonization density and H. influenzae-confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings. |
Limited Utility of Polymerase Chain Reaction in Induced Sputum Specimens for Determining the Causes of Childhood Pneumonia in Resource-Poor Settings: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.
Thea DM , Seidenberg P , Park DE , Mwananyanda L , Fu W , Shi Q , Baggett HC , Brooks WA , Feikin DR , Howie SRC , Knoll MD , Kotloff KL , Levine OS , Madhi SA , O'Brien KL , Scott JAG , Antonio M , Awori JO , Baillie VL , DeLuca AN , Driscoll AJ , Higdon MM , Hossain L , Jahan Y , Karron RA , Kazungu S , Li M , Moore DP , Morpeth SC , Ofordile O , Prosperi C , Sangwichian O , Sawatwong P , Sylla M , Tapia MD , Zeger SL , Murdoch DR , Hammitt LL . Clin Infect Dis 2017 64 S289-s300 Background.: Sputum examination can be useful in diagnosing the cause of pneumonia in adults but is less well established in children. We sought to assess the diagnostic utility of polymerase chain reaction (PCR) for detection of respiratory viruses and bacteria in induced sputum (IS) specimens from children hospitalized with severe or very severe pneumonia. Methods.: Among children aged 1-59 months, we compared organism detection by multiplex PCR in IS and nasopharyngeal/oropharyngeal (NP/OP) specimens. To assess whether organism presence or density in IS specimens was associated with chest radiographic evidence of pneumonia (radiographic pneumonia), we compared prevalence and density in IS specimens from children with radiographic pneumonia and children with suspected pneumonia but without chest radiographic changes or clinical or laboratory findings suggestive of pneumonia (nonpneumonia group). Results.: Among 4232 cases with World Health Organization-defined severe or very severe pneumonia, we identified 1935 (45.7%) with radiographic pneumonia and 573 (13.5%) with nonpneumonia. The organism detection yield was marginally improved with IS specimens (96.2% vs 92.4% for NP/OP specimens for all viruses combined [P = .41]; 96.9% vs 93.3% for all bacteria combined [P = .01]). After accounting for presence in NP/OP specimens, no organism was detected more frequently in the IS specimens from the radiographic pneumonia compared with the nonpneumonia cases. Among high-quality IS specimens, there were no statistically significant differences in organism density, except with cytomegalovirus, for which there was a higher quantity in the IS specimens from cases with radiographic pneumonia compared with the nonpneumonia cases (median cycle threshold value, 27.9 vs 28.5, respectively; P = .01). Conclusions.: Using advanced molecular methods with IS specimens provided little additional diagnostic information beyond that obtained with NP/OP swab specimens. |
Density of Upper Respiratory Colonization With Streptococcus pneumoniae and Its Role in the Diagnosis of Pneumococcal Pneumonia Among Children Aged <5 Years in the PERCH Study.
Baggett HC , Watson NL , Deloria Knoll M , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Antonio M , Awori JO , Baillie VL , DeLuca AN , Driscoll AJ , Duncan J , Ebruke BE , Goswami D , Higdon MM , Karron RA , Moore DP , Morpeth SC , Mulindwa JM , Park DE , Paveenkittiporn W , Piralam B , Prosperi C , Sow SO , Tapia MD , Zaman K , Zeger SL , O'Brien KL . Clin Infect Dis 2017 64 S317-s327 Background.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. Methods.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. Results.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 x 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 x 106) and controls (0.60 x 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (≥4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein ≥40 mg/L, and lack of antibiotic pretreatment (all P< .001). Conclusions.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting. |
Safety of induced sputum collection in children hospitalized with severe or very severe pneumonia
DeLuca AN , Hammitt LL , Kim J , Higdon MM , Baggett HC , Brooks WA , Howie SRC , Deloria Knoll M , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Amornintapichet T , Awori JO , Chuananon S , Driscoll AJ , Ebruke BE , Hossain L , Jahan Y , Kagucia EW , Kazungu S , Moore DP , Mudau A , Mwananyanda L , Park DE , Prosperi C , Seidenberg P , Sylla M , Tapia MD , Zaman SMA , O'Brien KL . Clin Infect Dis 2017 64 S301-s308 Background.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. Results.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as "possibly related" to the procedure. Conclusions.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety. |
Should controls with respiratory symptoms be excluded from case-control studies of pneumonia etiology? Reflections from the PERCH Study
Higdon MM , Hammitt LL , Deloria Knoll M , Baggett HC , Brooks WA , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Driscoll AJ , Karron RA , Park DE , Prosperi C , Zeger SL , O'Brien KL , Feikin DR . Clin Infect Dis 2017 64 S205-s212 Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias. |
Microscopic analysis and quality assessment of induced sputum from children with pneumonia in the PERCH Study
Murdoch DR , Morpeth SC , Hammitt LL , Driscoll AJ , Watson NL , Baggett HC , Brooks WA , Deloria Knoll M , Feikin DR , Kotloff KL , Levine OS , Madhi SA , O'Brien KL , Scott JAG , Thea DM , Ahmed D , Awori JO , DeLuca AN , Ebruke BE , Higdon MM , Jorakate P , Karron RA , Kazungu S , Kwenda G , Hossain L , Makprasert S , Moore DP , Mudau A , Mwaba J , Panchalingam S , Park DE , Prosperi C , Salaudeen R , Toure A , Zeger SL , Howie SRC . Clin Infect Dis 2017 64 S271-s279 Background.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. Methods.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. Results.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. Conclusions.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia. |
The effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumonia
Driscoll AJ , Deloria Knoll M , Hammitt LL , Baggett HC , Brooks WA , Feikin DR , Kotloff KL , Levine OS , Madhi SA , O'Brien KL , Scott JAG , Thea DM , Howie SRC , Adrian PV , Ahmed D , DeLuca AN , Ebruke BE , Gitahi C , Higdon MM , Kaewpan A , Karani A , Karron RA , Mazumder R , McLellan J , Moore DP , Mwananyanda L , Park DE , Prosperi C , Rhodes J , Saifullah M , Seidenberg P , Sow SO , Tamboura B , Zeger SL , Murdoch DR . Clin Infect Dis 2017 64 S368-s377 Background.: Antibiotic exposure and specimen volume are known to affect pathogen detection by culture. Here we assess their effects on bacterial pathogen detection by both culture and polymerase chain reaction (PCR) in children. Methods.: PERCH (Pneumonia Etiology Research for Child Health) is a case-control study of pneumonia in children aged 1-59 months investigating pathogens in blood, nasopharyngeal/oropharyngeal (NP/OP) swabs, and induced sputum by culture and PCR. Antibiotic exposure was ascertained by serum bioassay, and for cases, by a record of antibiotic treatment prior to specimen collection. Inoculated blood culture bottles were weighed to estimate volume. Results.: Antibiotic exposure ranged by specimen type from 43.5% to 81.7% in 4223 cases and was detected in 2.3% of 4863 controls. Antibiotics were associated with a 45% reduction in blood culture yield and approximately 20% reduction in yield from induced sputum culture. Reduction in yield of Streptococcus pneumoniae from NP culture was approximately 30% in cases and approximately 32% in controls. Several bacteria had significant but marginal reductions (by 5%-7%) in detection by PCR in NP/OP swabs from both cases and controls, with the exception of S. pneumoniae in exposed controls, which was detected 25% less frequently compared to nonexposed controls. Bacterial detection in induced sputum by PCR decreased 7% for exposed compared to nonexposed cases. For every additional 1 mL of blood culture specimen collected, microbial yield increased 0.51% (95% confidence interval, 0.47%-0.54%), from 2% when volume was ≤1 mL to approximately 6% for ≥3 mL. Conclusions.: Antibiotic exposure and blood culture volume affect detection of bacterial pathogens in children with pneumonia and should be accounted for in studies of etiology and in clinical management. |
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. |
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. |
Association of C-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged <5 years in the PERCH Study
Higdon MM , Le T , O'Brien KL , Murdoch DR , Prosperi C , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Scott JAG , Thea DM , Awori JO , Baillie VL , Cascio S , Chuananon S , DeLuca AN , Driscoll AJ , Ebruke BE , Endtz HP , Kaewpan A , Kahn G , Karani A , Karron RA , Moore DP , Park DE , Rahman MZ , Salaudeen R , Seidenberg P , Somwe SW , Sylla M , Tapia MD , Zeger SL , Deloria Knoll M , Madhi SA . Clin Infect Dis 2017 64 S378-s386 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. |
Chest radiograph findings in childhood pneumonia cases from the multisite PERCH Study
Fancourt N , Deloria Knoll M , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SRC , Kotloff KL , Levine OS , Madhi SA , Murdoch DR , Scott JAG , Thea DM , Awori JO , Barger-Kamate B , Chipeta J , DeLuca AN , Diallo M , Driscoll AJ , Ebruke BE , Higdon MM , Jahan Y , Karron RA , Mahomed N , Moore DP , Nahar K , Naorat S , Ominde MS , Park DE , Prosperi C , Wa Somwe S , Thamthitiwat S , Zaman SMA , Zeger SL , O'Brien KL . Clin Infect Dis 2017 64 S262-s270 Background: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge. |
Data management and data quality in PERCH, a large international case-control study of severe childhood pneumonia
Watson NL , Prosperi C , Driscoll AJ , Higdon MM , Park DE , Sanza M , DeLuca AN , Awori JO , Goswami D , Hammond E , Hossain L , Johnson C , Kamau A , Kuwanda L , Moore DP , Neyzari O , Onwuchekwa U , Parker D , Sapchookul P , Seidenberg P , Shamsul A , Siazeele K , Srisaengchai P , Sylla M , Levine OS , Murdoch DR , O'Brien KL , Wolff M , Deloria Knoll M . Clin Infect Dis 2017 64 S238-s244 The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for ≥96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity. |
The diagnostic utility of induced sputum microscopy and culture in childhood pneumonia
Murdoch DR , Morpeth SC , Hammitt LL , Driscoll AJ , Watson NL , Baggett HC , Brooks WA , Deloria Knoll M , Feikin DR , Kotloff KL , Levine OS , Madhi SA , O'Brien KL , Scott JAG , Thea DM , Adrian PV , Ahmed D , Alam M , Awori JO , DeLuca AN , Higdon MM , Karron RA , Kwenda G , Machuka EM , Makprasert S , McLellan J , Moore DP , Mwaba J , Mwarumba S , Park DE , Prosperi C , Sangwichian O , Sissoko S , Tapia MD , Zeger SL , Howie SRC . Clin Infect Dis 2017 64 S280-s288 Background.: Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.: We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1-59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results.: One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of <10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. Conclusions.: The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice. |
Pertussis-associated pneumonia in infants and children from low- and middle-income countries participating in the PERCH Study
Barger-Kamate B , Deloria Knoll M , Kagucia EW , Prosperi C , Baggett HC , Brooks WA , Feikin DR , Hammitt LL , Howie SR , Levine OS , Madhi SA , Scott JA , Thea DM , Amornintapichet T , Anderson TP , Awori JO , Baillie VL , Chipeta J , DeLuca AN , Driscoll AJ , Goswami D , Higdon MM , Hossain L , Karron RA , Maloney S , Moore DP , Morpeth SC , Mwananyanda L , Ofordile O , Olutunde E , Park DE , Sow SO , Tapia MD , Murdoch DR , O'Brien KL , Kotloff KL . Clin Infect Dis 2016 63 S187-s196 BACKGROUND: Few data exist describing pertussis epidemiology among infants and children in low- and middle-income countries to guide preventive strategies. METHODS: Children 1-59 months of age hospitalized with World Health Organization-defined severe or very severe pneumonia in 7 African and Asian countries and similarly aged community controls were enrolled in the Pneumonia Etiology Research for Child Health study. They underwent a standardized clinical evaluation and provided nasopharyngeal and oropharyngeal swabs and induced sputum (cases only) for Bordetella pertussis polymerase chain reaction. Risk factors and pertussis-associated clinical findings were identified. RESULTS: Bordetella pertussis was detected in 53 of 4200 (1.3%) cases and 11 of 5196 (0.2%) controls. In the age stratum 1-5 months, 40 (2.3% of 1721) cases were positive, all from African sites, as were 8 (0.5% of 1617) controls. Pertussis-positive African cases 1-5 months old, compared to controls, were more often human immunodeficiency virus (HIV) uninfected-exposed (adjusted odds ratio [aOR], 2.2), unvaccinated (aOR, 3.7), underweight (aOR, 6.3), and too young to be immunized (aOR, 16.1) (all P ≤ .05). Compared with pertussis-negative African cases in this age group, pertussis-positive cases were younger, more likely to vomit (aOR, 2.6), to cough ≥14 days (aOR, 6.3), to have leukocyte counts >20 000 cells/microL (aOR, 4.6), and to have lymphocyte counts >10 000 cells/microL (aOR, 7.2) (all P ≤ .05). The case fatality ratio of pertussis-infected pneumonia cases 1-5 months of age was 12.5% (95% confidence interval, 4.2%-26.8%; 5/40); pertussis was identified in 3.7% of 137 in-hospital deaths among African cases in this age group. CONCLUSIONS: In the postneonatal period, pertussis causes a small fraction of hospitalized pneumonia cases and deaths; however, case fatality is substantial. The propensity to infect unvaccinated infants and those at risk for insufficient immunity (too young to be vaccinated, premature, HIV-infected/exposed) suggests that the role for maternal vaccination should be considered along with efforts to reduce exposure to risk factors and to optimize childhood pertussis vaccination coverage. |
Contribution of the BacT/ALERT MB mycobacteria bottle to bloodstream infection surveillance in Thailand: added yield for Burkholderia pseudomallei
Jorakate P , Higdon M , Kaewpan A , Makprasert S , Yuenprakhon S , Tawisaid K , Dejsirilert S , Whistler T , Baggett HC . J Clin Microbiol 2015 53 (3) 910-4 Community-acquired bloodstream infections cause substantial morbidity and mortality worldwide but microbiology capacity and surveillance limitations have challenged good descriptions of pathogen distribution in many regions, including Southeast Asia. Active surveillance for bloodstream infections has been conducted in two rural Thailand provinces for >7 years. Blood specimens were divided into two culture bottles: one optimized for aerobic growth (F bottle) and a second for enhanced growth of mycobacteria (MB bottle), and processed used the BactT/ALERT 3D(R) system. Because routine use of MB culture bottles is resource intensive (expensive and prolonged incubation), we assessed the added yield of MB bottles by comparing the proportion of pathogens detected by MB vs. F bottles from 2005 - 2012. Of 63,066 blood cultures, 7,296(12%) were positive for at least one pathogen, the most common pathogens were Escherichia coli (28%), Burkholderia pseudomallei (11%), Klebsiella pneumoniae (9%) and Staphylococcus aureus (6%). Two bottles improved yield overall, but added yield attributable to the MB bottles was limited to a few pathogens. In addition to mycobacteria and some fungi, MB bottles improved B. pseudomallei detection (MB 27% vs. F 8%; p-value < 0.0001) with added benefit if therapy was initiated prior to the blood draw culture. Targeted use of MB bottles is warranted for patients at risk for mycobacterial and fungal infections, as well as B. pseudomallei, a common cause of septicemia in Thailand. |
Lessons about the state and local public health system response to the 2009 H1N1 pandemic: a workshop summary
Stoto MA , Nelson C , Higdon MA , Kraemer J , Hites L , Singleton CM . J Public Health Manag Pract 2013 19 (5) 428-435 OBJECTIVE: Identify lessons about the public health emergency preparedness system from after action report/improvement plans (AAR/IPs) authored by state and local health departments following the 2009 H1N1 influenza pandemic. DESIGN: Potentially generalizable findings were collected during a workshop attended by representatives from the Centers for Disease Control and Prevention (CDC), state and local public health departments, and other organizations that prepared 2009 H1N1AAR/IPs. PARTICIPANTS: Workshop participants included state and local health department personnel who had submitted AAR/IPs to the CDC for review. MEASURES: Workshop participants were asked to consider the question: What did you hear from other jurisdictions that resonated with your own experience and could be a generalized finding? RESULTS: Workshop discussions revealed potential lessons concerning: (1) situational awareness during the initial response; (2) resource mobilization and legal authority; (3) the complexity of vaccine distribution and administration; (4) balancing emergency response and routine operations; (5) communication and coordination among the many independent actors in the public health system; and (6) incident management in a long-duration incident. CONCLUSIONS: The response to the 2009 H1N1 influenza pandemic provides an opportunity to learn about the public health system's emergency response capabilities and to identify ways to improve preparedness for future events. Perhaps the most important lessons from the 2009 H1N1 response reveal the complexity of coordinating actions among the many different actors, institutions, sectors, and disciplines involved in the public health system. While the response to the pandemic engendered creative "on the spot" solutions, continued effort is needed to better understand and manage the identified challenges. |
Learning about after action reporting from the 2009 H1N1 pandemic: a workshop summary
Stoto MA , Nelson C , Higdon MA , Kraemer J , Singleton CM . J Public Health Manag Pract 2013 19 (5) 420-7 OBJECTIVE: To analyze key variations in the after action report/improvement plan (AAR/IP) process used by state and local health departments following the 2009 H1N1 pandemic and identify ideas for improving that process. DESIGN: Workshop participants discussed their AAR findings and the methods used to prepare their reports and implications for improving the AAR/IP process in future events. PARTICIPANTS: Workshop participants included state and local health department personnel who had submitted AAR/IPs to the Centers for Disease Control and Prevention (CDC) for review. MEASURES: Workshop participants were asked to consider the question: On the basis of what you heard in this workshop, what would you do differently if you could redo your 2009 H1N1 AAR/IP? RESULTS: Workshop discussions revealed wide differences in the participants' understanding of the intended uses and users of the AAR/IPs, their scope, timing, and format, and the use of external consultants in their preparation, and on the strengths and weaknesses of various approaches. The AAR/IPs also varied in the extent to which they sought to identify root causes and the methods they used to do so. CONCLUSIONS: The AAR/IPs can be useful for both accountability and quality improvement, but these objectives require different foci and methodological approaches. Notably, the AAR/IPs can also be used as an opportunity to hold health departments accountable for conducting root cause analyses and making the improvements that follow from them. Federal agencies requiring the AAR/IPs should clarify the purpose and issues of scope and timing; develop training materials and exemplary cases of effective AAR/IPs, particularly of root cause analysis applied to public health emergency preparedness, professional guidelines, and standards for consultants; and consider developing a peer model for preparing AAR/IPs. |
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