Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
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Query Trace: Saha SK [original query] |
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Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes
Carey ME , Dyson ZA , Ingle DJ , Amir A , Aworh MK , Chattaway MA , Chew KL , Crump JA , Feasey NA , Howden BP , Keddy KH , Maes M , Parry CM , Van Puyvelde S , Webb HE , Afolayan AO , Alexander AP , Anandan S , Andrews JR , Ashton PM , Basnyat B , Bavdekar A , Bogoch II , Clemens JD , da Silva KE , De A , de Ligt J , Diaz Guevara PL , Dolecek C , Dutta S , Ehlers MM , Francois Watkins L , Garrett DO , Godbole G , Gordon MA , Greenhill AR , Griffin C , Gupta M , Hendriksen RS , Heyderman RS , Hooda Y , Hormazabal JC , Ikhimiukor OO , Iqbal J , Jacob JJ , Jenkins C , Jinka DR , John J , Kang G , Kanteh A , Kapil A , Karkey A , Kariuki S , Kingsley RA , Koshy RM , Lauer AC , Levine MM , Lingegowda RK , Luby SP , Mackenzie GA , Mashe T , Msefula C , Mutreja A , Nagaraj G , Nagaraj S , Nair S , Naseri TK , Nimarota-Brown S , Njamkepo E , Okeke IN , Perumal SPB , Pollard AJ , Pragasam AK , Qadri F , Qamar FN , Rahman SIA , Rambocus SD , Rasko DA , Ray P , Robins-Browne R , Rongsen-Chandola T , Rutanga JP , Saha SK , Saha S , Saigal K , Sajib MSI , Seidman JC , Shakya J , Shamanna V , Shastri J , Shrestha R , Sia S , Sikorski MJ , Singh A , Smith AM , Tagg KA , Tamrakar D , Tanmoy AM , Thomas M , Thomas MS , Thomsen R , Thomson NR , Tupua S , Vaidya K , Valcanis M , Veeraraghavan B , Weill FX , Wright J , Dougan G , Argimón S , Keane JA , Aanensen DM , Baker S , Holt KE . Elife 2023 12 BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]). | Salmonella Typhi (Typhi) is a type of bacteria that causes typhoid fever. More than 110,000 people die from this disease each year, predominantly in areas of sub-Saharan Africa and South Asia with limited access to safe water and sanitation. Clinicians use antibiotics to treat typhoid fever, but scientists worry that the spread of antimicrobial-resistant Typhi could render the drugs ineffective, leading to increased typhoid fever mortality. The World Health Organization has prequalified two vaccines that are highly effective in preventing typhoid fever and may also help limit the emergence and spread of resistant Typhi. In low resource settings, public health officials must make difficult trade-off decisions about which new vaccines to introduce into already crowded immunization schedules. Understanding the local burden of antimicrobial-resistant Typhi and how it is spreading could help inform their actions. The Global Typhoid Genomics Consortium analyzed 13,000 Typhi genomes from 110 countries to provide a global overview of genetic diversity and antimicrobial-resistant patterns. The analysis showed great genetic diversity of the different strains between countries and regions. For example, the H58 Typhi variant, which is often drug-resistant, has spread rapidly through Asia and Eastern and Southern Africa, but is less common in other regions. However, distinct strains of other drug-resistant Typhi have emerged in other parts of the world. Resistance to the antibiotic ciprofloxacin was widespread and accounted for over 85% of cases in South Africa. Around 70% of Typhi from Pakistan were extensively drug-resistant in 2020, but these hard-to-treat variants have not yet become established elsewhere. Variants that are resistant to both ciprofloxacin and ceftriaxone have been identified, and azithromycin resistance has also appeared in several different variants across South Asia. The Consortium’s analyses provide valuable insights into the global distribution and transmission patterns of drug-resistant Typhi. Limited genetic data were available fromseveral regions, but data from travel-associated cases helped fill some regional gaps. These findings may help serve as a starting point for collective sharing and analyses of genetic data to inform local public health action. Funders need to provide ongoing supportto help fill global surveillance data gaps. | eng |
Estimating typhoid incidence from community-based serosurveys: A multicohort study in Bangladesh, Nepal, Pakistan and Ghana (preprint)
Aiemjoy K , Seidman JC , Saha S , Munira SJ , Islam Sajib MS , Sium SMA , Sarkar A , Alam N , Zahan FN , Kabir MS , Tamrakar D , Vaidya K , Shrestha R , Shakya J , Katuwal N , Shrestha S , Yousafzai MT , Iqbal J , Dehraj IF , Ladak Y , Maria N , Adnan M , Pervaiz S , Carter AS , Longley AT , Fraser C , Ryan ET , Nodoushani A , Fasano A , Leonard MM , Kenyon V , Bogoch II , Jeon HJ , Haselbeck A , Park SE , Zellweger RM , Marks F , Owusu-Dabo E , Adu-Sarkodie Y , Owusu M , Teunis P , Luby SP , Garrett DO , Qamar FN , Saha SK , Charles RC , Andrews JR . medRxiv 2022 2021.10.20.21265277 Background The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.Methods We collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.Findings The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children <5 years ranged between 58.5 per 100 person-years (95% CI: 42.1 - 81.4) in Dhaka, Bangladesh to 6.6 (95% CI: 4.3-9.9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.Interpretation The approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.Funding This work was supported by the Bill and Melinda Gates Foundation (INV-000572).Evidence before this study Previous studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this study We developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidence Many a -risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by th eBill and Melinda Gates Foundation (grant INV-000572)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Boards in the United States (Centers for Disease Control and Prevention; Stanford University Institutional Review Board), Bangladesh (Bangladesh Institute of Child Health Ethical Review Committee), Nepal (Nepal Health Research Council Ethical Review Board), Pakistan (AKU Ethic Review Committee and Pakistan National Bioethics Committee), Korea (International Vaccine Institute IRB), Belgium (Institute of Tropical Medicine Antwerp Institutional Review Board) and Ghana (Komfo Anokye Teaching Hospital, Committee on Human Research, Publication and Ethics) approved the study forms and protocols.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors |
A novel mosaic tetracycline resistance gene tet(S/M) detected in a multidrug-resistant pneumococcal CC230 lineage that underwent capsular switching in South Africa (preprint)
Lo SW , Gladstone RA , van Tonder AJ , Du Plessis M , Cornick JE , Hawkins PA , Madhi SA , Nzenze SA , Kandasamy R , Ravikumar KL , Elmdaghri N , Kwambana-Adams B , Almeida SCG , Skoczynska A , Egorova E , Titov L , Saha SK , Paragi M , Everett DB , Antonio M , Klugman KP , Li Y , Metcalf BJ , Beall B , McGee L , Breiman RF , Bentley SD , von Gottberg A . bioRxiv 2019 718460 Objective We reported a novel tetracycline-resistant gene in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions.Methods We whole genome sequenced 12,254 pneumococcal isolates from twenty-nine countries on an Illumina HiSeq Sequencer. Serotypes, sequence types and antibiotic resistance were inferred from genomes. Phylogeny was built based on single-nucleotide variants. Temporal changes of spread were reconstructed using a birth-death model.Results We identified tet(S/M) in 131 pneumococcal isolates, 97 (74%) caused invasive pneumococcal diseases among young children (59% HIV-positive, where HIV status was available) in South Africa. A majority of tet(S/M)-positive isolates (129/131) belong to clonal complex (CC)230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sub-lineage that exhibited multidrug-resistance. Using the genomic data and a birth-death model, we detected an unrecognised outbreak of this sub-lineage in South Africa between 2000 and 2004 with an expected secondary infections (R) of ~2.5. R declined to ~1.0 in 2005 and <1.0 in 2012. The declining epidemic coincided and could be related to the nationwide implementation of anti-retroviral treatment (ART) for HIV-infected individuals in 2004 and PCVs in late 2000s. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sub-lineage.Conclusions The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognised outbreak of CC230 in South Africa prior to ART and PCVs. However, capsular switching in this multidrug-resistant sub-lineage highlighted its potential to continue to cause disease in the post-PCV13 era. |
In-hospital mortality risk stratification in children under 5 years old with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership To Assess WHO REcommendations (PREPARE) dataset
Hooli S , King C , McCollum ED , Colbourn T , Lufesi N , Mwansambo C , Gregory CJ , Thamthitiwat S , Cutland C , Madhi SA , Nunes MC , Gessner BD , Hazir T , Mathew JL , Addo-Yobo E , Chisaka N , Hassan M , Hibberd PL , Jeena P , Lozano JM , MacLeod WB , Patel A , Thea DM , Nguyen NTV , Zaman SM , Ruvinsky RO , Lucero M , Kartasasmita CB , Turner C , Asghar R , Banajeh S , Iqbal I , Maulen-Radovan I , Mino-Leon G , Saha SK , Santosham M , Singhi S , Awasthi S , Bavdekar A , Chou M , Nymadawa P , Pape JW , Paranhos-Baccala G , Picot VS , Rakoto-Andrianarivelo M , Rouzier V , Russomando G , Sylla M , Vanhems P , Wang J , Basnet S , Strand TA , Neuman MI , Arroyo LM , Echavarria M , Bhatnagar S , Wadhwa N , Lodha R , Aneja S , Gentile A , Chadha M , Hirve S , O'Grady KF , Clara AW , Rees CA , Campbell H , Nair H , Falconer J , Williams LJ , Horne M , Qazi SA , Nisar YB . Int J Infect Dis 2023 129 240-250 OBJECTIVES: We determined pulse oximetry benefit in pediatric pneumonia mortality-risk stratification and chest indrawing pneumonia in-hospital mortality risk factors. METHODS: We report characteristics and in-hospital pneumonia-related mortality of children 2-59-months-old included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57·5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5·8%, 95% CI 5·6-5·9% vs 2·1%, 95% CI 1·9-2·4%). One in five children with chest indrawing pneumonia was hypoxemic (19·7%, 95% CI 19·0-20·4%) and the hypoxemic CFR was 10·3% (95% CI 9·1%-11·5%). Other mortality risk factors were younger age (either 2-5 months (aOR 9·94, 95% CI 6·67-14·84) or 6-11 months (aOR 2·67, 95% CI 1·71-4·16)), moderate malnutrition (aOR 2·41, 95% CI 1·87-3·09), and female sex (aOR 1·82, 95% CI 1·43-2·32). CONCLUSIONS: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest indrawing pneumonia were hypoxemic and one in ten died. Young age and moderate malnutrition were risk factors for in-hospital chest indrawing pneumonia-related mortality. Pulse oximetry should be integrated in under-five pneumonia hospital care. |
Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications
Martin H , Falconer J , Addo-Yobo E , Aneja S , Arroyo LM , Asghar R , Awasthi S , Banajeh S , Bari A , Basnet S , Bavdekar A , Bhandari N , Bhatnagar S , Bhutta ZA , Brooks A , Chadha M , Chisaka N , Chou M , Clara AW , Colbourn T , Cutland C , D'Acremont V , Echavarria M , Gentile A , Gessner B , Gregory CJ , Hazir T , Hibberd PL , Hirve S , Hooli S , Iqbal I , Jeena P , Kartasasmita CB , King C , Libster R , Lodha R , Lozano JM , Lucero M , Lufesi N , MacLeod WB , Madhi SA , Mathew JL , Maulen-Radovan I , McCollum ED , Mino G , Mwansambo C , Neuman MI , Nguyen NTV , Nunes MC , Nymadawa P , O'Grady KF , Pape JW , Paranhos-Baccala G , Patel A , Picot VS , Rakoto-Andrianarivelo M , Rasmussen Z , Rouzier V , Russomando G , Ruvinsky RO , Sadruddin S , Saha SK , Santosham M , Singhi S , Soofi S , Strand TA , Sylla M , Thamthitiwat S , Thea DM , Turner C , Vanhems P , Wadhwa N , Wang J , Zaman SM , Campbell H , Nair H , Qazi SA , Nisar YB . J Glob Health 2022 12 04075 BACKGROUND: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. METHODS: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. RESULTS: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285839 children with pneumonia (244323 in the hospital and 41516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285839 episodes, 280998 occurred in children 0-59 months old, of which 129584 (46%) were 2-11 months of age and 152730 (54%) were males. CONCLUSIONS: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly. |
Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis
Connor NE , Islam MS , Mullany LC , Shang N , Bhutta ZA , Zaidi AKM , Soofi S , Nisar I , Panigrahi P , Panigrahi K , Satpathy R , Bose A , Isaac R , Baqui AH , Mitra DK , Sadeq-Ur Rahman Q , Hossain T , Schrag SJ , Winchell JM , Arvay ML , Diaz MH , Waller JL , Weber MW , Hamer DH , Hibberd P , Nawshad Uddin Ahmed ASM , Islam M , Hossain MB , Qazi SA , El Arifeen S , Darmstadt GL , Saha SK . BMJ Glob Health 2022 7 (11) OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials. |
Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study.
Lo SW , Mellor K , Cohen R , Alonso AR , Belman S , Kumar N , Hawkins PA , Gladstone RA , von Gottberg A , Veeraraghavan B , Ravikumar KL , Kandasamy R , Pollard SAJ , Saha SK , Bigogo G , Antonio M , Kwambana-Adams B , Mirza S , Shakoor S , Nisar I , Cornick JE , Lehmann D , Ford RL , Sigauque B , Turner P , Moïsi J , Obaro SK , Dagan R , Diawara I , Skoczyńska A , Wang H , Carter PE , Klugman KP , Rodgers G , Breiman RF , McGee L , Bentley SD , Almagro CM , Varon E . Lancet Microbe 2022 3 (10) e735-e743 BACKGROUND: Serotype 24F is one of the emerging pneumococcal serotypes after the introduction of pneumococcal conjugate vaccine (PCV). We aimed to identify lineages driving the increase of serotype 24F in France and place these findings into a global context. METHODS: Whole-genome sequencing was performed on a collection of serotype 24F pneumococci from asymptomatic colonisation (n=229) and invasive disease (n=190) isolates among individuals younger than 18 years in France, from 2003 to 2018. To provide a global context, we included an additional collection of 24F isolates in the Global Pneumococcal Sequencing (GPS) project database for analysis. A Global Pneumococcal Sequence Cluster (GPSC) and a clonal complex (CC) were assigned to each genome. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted using the same 24F collection and supplemented with a global collection of genomes belonging to the lineage of interest from the GPS project database (n=25 590). FINDINGS: Serotype 24F was identified in numerous countries mainly due to the clonal spread of three lineages: GPSC10 (CC230), GPSC16 (CC156), and GPSC206 (CC7701). GPSC10 was the only multidrug-resistant lineage. GPSC10 drove the increase in 24F in France and had high invasive disease potential. The international dataset of GPSC10 (n=888) revealed that this lineage expressed 16 other serotypes, with only six included in 13-valent PCV (PCV13). All serotype 24F isolates were clustered in a single clade within the GPSC10 phylogeny and long-range transmissions were detected from Europe to other continents. Spatiotemporal analysis showed GPSC10-24F took 3-5 years to spread across France and a rapid change of serotype composition from PCV13 serotype 19A to 24F during the introduction of PCV13 was observed in neighbouring country Spain. INTERPRETATION: Our work reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases. FUNDING: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. |
Infectious aetiologies of neonatal illness in South Asia classified using WHO definitions: a primary analysis of the ANISA study
Arvay ML , Shang N , Qazi SA , Darmstadt GL , Islam MS , Roth DE , Liu A , Connor NE , Hossain B , Sadeq-Ur Rahman Q , El Arifeen S , Mullany LC , Zaidi AKM , Bhutta ZA , Soofi SB , Shafiq Y , Baqui AH , Mitra DK , Panigrahi P , Panigrahi K , Bose A , Isaac R , Westreich D , Meshnick SR , Saha SK , Schrag SJ . Lancet Glob Health 2022 10 (9) e1289-e1297 BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation. |
Estimating typhoid incidence from community-based serosurveys: a multicohort study
Aiemjoy K , Seidman JC , Saha S , Munira SJ , Islam Sajib MS , Sium SMA , Sarkar A , Alam N , Zahan FN , Kabir MS , Tamrakar D , Vaidya K , Shrestha R , Shakya J , Katuwal N , Shrestha S , Yousafzai MT , Iqbal J , Dehraj IF , Ladak Y , Maria N , Adnan M , Pervaiz S , Carter AS , Longley AT , Fraser C , Ryan ET , Nodoushani A , Fasano A , Leonard MM , Kenyon V , Bogoch II , Jeon HJ , Haselbeck A , Park SE , Zellweger RM , Marks F , Owusu-Dabo E , Adu-Sarkodie Y , Owusu M , Teunis P , Luby SP , Garrett DO , Qamar FN , Saha SK , Charles RC , Andrews JR . Lancet Microbe 2022 3 (8) e578-e587 BACKGROUND: The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence. METHODS: We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys. FINDINGS: The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates. INTERPRETATION: The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time. FUNDING: Bill & Melinda Gates Foundation. TRANSLATIONS: For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section. |
Incidence of typhoid and paratyphoid fever in Bangladesh, Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia Project
Garrett DO , Longley AT , Aiemjoy K , Yousafzai MT , Hemlock C , Yu AT , Vaidya K , Tamrakar D , Saha S , Bogoch II , Date K , Saha S , Islam MS , Sayeed KMI , Bern C , Shakoor S , Dehraj IF , Mehmood J , Sajib MSI , Islam M , Thobani RS , Hotwani A , Rahman N , Irfan S , Naga SR , Memon AM , Pradhan S , Iqbal K , Shrestha R , Rahman H , Hasan MM , Qazi SH , Kazi AM , Saddal NS , Jamal R , Hunzai MJ , Hossain T , Marks F , Carter AS , Seidman JC , Qamar FN , Saha SK , Andrews JR , Luby SP . Lancet Glob Health 2022 10 (7) e978-e988 BACKGROUND: Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric Fever in Asia Project (SEAP) to inform these strategies. METHODS: From September, 2016, to September, 2019, we conducted prospective clinical surveillance for Salmonella enterica serotype Typhi (S Typhi) and Paratyphi (S Paratyphi) A, B, and C at health facilities in predetermined catchment areas in Dhaka, Bangladesh; Kathmandu and Kavrepalanchok, Nepal; and Karachi, Pakistan. Patients eligible for inclusion were outpatients with 3 or more consecutive days of fever in the last 7 days; inpatients with suspected or confirmed enteric fever; patients with blood culture-confirmed enteric fever from the hospital laboratories not captured by inpatient or outpatient enrolment and cases from the laboratory network; and patients with non-traumatic ileal perforation under surgical care. We used a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of health-care use. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. We additionally calculated incidence of hospitalisation due to typhoid and paratyphoid. FINDINGS: A total of 34 747 patients were enrolled across 23 facilitates (six tertiary hospitals, surgical wards of two additional hospitals, and 15 laboratory network sites) during the study period. Of the 34 303 blood cultures performed on enrolled patients, 8705 (26%) were positive for typhoidal Salmonella. Adjusted incidence rates of enteric fever considered patients in the six tertiary hospitals. Adjusted incidence of S Typhi, expressed per 100 000 person-years, was 913 (95% CI 765-1095) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (230-480) in Kathmandu and 268 (202-362) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 176 (144-216) and 103 (85-126). The adjusted incidence rates of paratyphoid (of which all included cases were due to S Paratyphi A) were 128 (107-154) in Bangladesh, 46 (34-62) and 81 (56-118) in the Nepal sites, and 23 (19-29) and 1 (1-1) in the Pakistan sites. Adjusted incidence of hospitalisation was high across sites, and overall, 2804 (32%) of 8705 patients with blood culture-confirmed enteric fever were hospitalised. INTERPRETATION: Across diverse communities in three south Asian countries, adjusted incidence exceeded the threshold for "high burden" of enteric fever (100 per 100 000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines. FUNDING: Bill & Melinda Gates Foundation. |
Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries
Rees CA , Colbourn T , Hooli S , King C , Lufesi N , McCollum ED , Mwansambo C , Cutland C , Madhi SA , Nunes M , Matthew JL , Addo-Yobo E , Chisaka N , Hassan M , Hibberd PL , Jeena PM , Lozano JM , MacLeod WB , Patel A , Thea DM , Nguyen NTV , Kartasasmita CB , Lucero M , Awasthi S , Bavdekar A , Chou M , Nymadawa P , Pape JW , Paranhos-Baccala G , Picot VS , Rakoto-Andrianarivelo M , Rouzier V , Russomando G , Sylla M , Vanhems P , Wang J , Asghar R , Banajeh S , Iqbal I , Maulen-Radovan I , Mino-Leon G , Saha SK , Santosham M , Singhi S , Basnet S , Strand TA , Bhatnagar S , Wadhwa N , Lodha R , Aneja S , Clara AW , Campbell H , Nair H , Falconer J , Qazi SA , Nisar YB , Neuman MI . BMJ Glob Health 2022 7 (4) INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality. |
A Streptococcus pneumoniae lineage usually associated with pneumococcal conjugate vaccine (PCV) serotypes is the most common cause of serotype 35B invasive disease in South Africa, following routine use of PCV.
Ndlangisa KM , du Plessis M , Lo S , de Gouveia L , Chaguza C , Antonio M , Kwambana-Adams B , Cornick J , Everett DB , Dagan R , Hawkins PA , Beall B , Corso A , Grassi Almeida SC , Ochoa TJ , Obaro S , Shakoor S , Donkor ES , Gladstone RA , Ho PL , Paragi M , Doiphode S , Srifuengfung S , Ford R , Moïsi J , Saha SK , Bigogo G , Sigauque B , Eser Ö K , Elmdaghri N , Titov L , Turner P , Kumar KLR , Kandasamy R , Egorova E , Ip M , Breiman RF , Klugman KP , McGee L , Bentley SD , von Gottberg A , The Global Pneumococcal Sequencing Consortium . Microb Genom 2022 8 (4) Pneumococcal serotype 35B is an important non-conjugate vaccine (non-PCV) serotype. Its continued emergence, post-PCV7 in the USA, was associated with expansion of a pre-existing 35B clone (clonal complex [CC] 558) along with post-PCV13 emergence of a non-35B clone previously associated with PCV serotypes (CC156). This study describes lineages circulating among 35B isolates in South Africa before and after PCV introduction. We also compared 35B isolates belonging to a predominant 35B lineage in South Africa (GPSC5), with isolates belonging to the same lineage in other parts of the world. Serotype 35B isolates that caused invasive pneumococcal disease in South Africa in 2005-2014 were characterized by whole-genome sequencing (WGS). Multi-locus sequence types and global pneumococcal sequence clusters (GPSCs) were derived from WGS data of 63 35B isolates obtained in 2005-2014. A total of 262 isolates that belong to GPSC5 (115 isolates from South Africa and 147 from other countries) that were sequenced as part of the global pneumococcal sequencing (GPS) project were included for comparison. Serotype 35B isolates from South Africa were differentiated into seven GPSCs and GPSC5 was most common (49 %, 31/63). While 35B was the most common serotype among GPSC5/CC172 isolates in South Africa during the PCV13 period (66 %, 29/44), 23F was the most common serotype during both the pre-PCV (80 %, 37/46) and PCV7 period (32 %, 8/25). Serotype 35B represented 15 % (40/262) of GPSC5 isolates within the global GPS database and 75 % (31/40) were from South Africa. The predominance of the GPSC5 lineage within non-vaccine serotype 35B, is possibly unique to South Africa and warrants further molecular surveillance of pneumococci. |
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. |
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. |
Diagnostic value of clinical features to distinguish enteric fever from other febrile illnesses in Bangladesh, Nepal, and Pakistan
Aiemjoy K , Tamrakar D , Saha S , Naga SR , Yu AT , Longley A , Date K , Hemlock C , Qamar FN , Saha SK , Luby SP , Garrett DO , Andrews JR , Bogoch II . Clin Infect Dis 2020 71 S257-s265 BACKGROUND: Enteric fever, a bacterial infection caused by Salmonella enterica serotypes Typhi and Paratyphi A, frequently presents as a nonlocalizing febrile illness that is difficult to distinguish from other infectious causes of fever. Blood culture is not widely available in endemic settings and, even when available, results can take up to 5 days. We evaluated the diagnostic performance of clinical features, including both reported symptoms and clinical signs, of enteric fever among patients participating in the Surveillance for Enteric Fever in Asia Project (SEAP), a 3-year surveillance study in Bangladesh, Nepal, and Pakistan. METHODS: Outpatients presenting with ≥3 consecutive days of reported fever and inpatients with clinically suspected enteric fever from all 6 SEAP study hospitals were eligible to participate. We evaluated the diagnostic performance of select clinical features against blood culture results among outpatients using mixed-effect regression models with a random effect for study site hospital. We also compared the clinical features of S. Typhi to S. Paratyphi A among both outpatients and inpatients. RESULTS: We enrolled 20 899 outpatients, of whom 2116 (10.1%) had positive blood cultures for S. Typhi and 297 (1.4%) had positive cultures for S. Paratyphi A. The sensitivity of absence of cough was the highest among all evaluated features, at 65.5% (95% confidence interval [CI], 55.0-74.7), followed by measured fever at presentation at 59.0% (95% CI, 51.6-65.9) and being unable to complete normal activities for 3 or more days at 51.0% (95% CI, 23.8-77.6). A combined case definition of 3 or more consecutive days of reported fever and 1 or more of the following (a) either the absence of cough, (b) fever at presentation, or (c) 3 or more consecutive days of being unable to conduct usual activity--yielded a sensitivity of 94.6% (95% CI, 93.4-95.5) and specificity of 13.6% (95% CI, 9.8-17.5). CONCLUSIONS: Clinical features do not accurately distinguish blood culture-confirmed enteric fever from other febrile syndromes. Rapid, affordable, and accurate diagnostics are urgently needed, particularly in settings with limited or no blood culture capacity. |
Healthcare utilization patterns for acute febrile illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project
Andrews JR , Vaidya K , Saha S , Yousafzai MT , Hemlock C , Longley A , Aiemjoy K , Yu AT , Bogoch II , Tamrakar D , Date K , Saha SK , Garrett DO , Luby SP , Qamar F . Clin Infect Dis 2020 71 S248-s256 BACKGROUND: Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data. METHODS: We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever. RESULTS: We enrolled 31 841 households (53 926 children) in Bangladesh, 25 510 households (84 196 children and adults) in Nepal, and 21 310 households (108 031 children and adults) in Pakistan. Children <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever. CONCLUSIONS: Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence. |
Utilization of blood culture in South Asia for the diagnosis and treatment of febrile illness
Hemlock C , Luby SP , Saha S , Qamar F , Andrews JR , Saha SK , Tamrakar D , Date K , Longley AT , Garrett DO , Bogoch II . Clin Infect Dis 2020 71 S266-s275 BACKGROUND: Blood culture is the current standard for diagnosing bacteremic illnesses, yet it is not clear how physicians in many low- and middle-income countries utilize blood culture for diagnostic purposes and to inform treatment decisions. METHODS: We screened suspected enteric fever cases from 6 hospitals in Bangladesh, Nepal, and Pakistan, and enrolled patients if blood culture was prescribed by the treating physician. We used generalized additive regression models to analyze the probability of receiving blood culture by age, and linear regression models to analyze changes by month to the proportion of febrile cases prescribed a blood culture compared with the burden of febrile illness, stratified by hospital. We used logistic regression to analyze predictors for receiving antibiotics empirically. We descriptively reviewed changes in antibiotic therapy by susceptibility patterns and coverage, stratified by country. RESULTS: We screened 30 809 outpatients resulting in 1819 enteric fever cases; 1935 additional cases were enrolled from other hospital locations. Younger outpatients were less likely to receive a blood culture. The association between the number of febrile outpatients and the proportion prescribed blood culture varied by hospital. Antibiotics prescribed empirically were associated with severity and provisional diagnoses, but 31% (1147/3754) of enteric fever cases were not covered by initial therapy; this was highest in Pakistan (50%) as many isolates were resistant to cephalosporins, which were commonly prescribed empirically. CONCLUSIONS: Understanding hospital-level communication between laboratories and physicians may improve patient care and timeliness of appropriate antibiotics, which is important considering the rise of antimicrobial resistance. |
Illness severity and outcomes among enteric fever cases from Bangladesh, Nepal, and Pakistan: Data from the Surveillance for Enteric Fever in Asia Project, 2016-2019
Longley AT , Hemlock C , Date K , Luby SP , Andrews JR , Saha SK , Bogoch II , Yousafzai MT , Garrett DO , Qamar FN . Clin Infect Dis 2020 71 S222-s231 BACKGROUND: Enteric fever can lead to prolonged hospital stays, clinical complications, and death. The Surveillance for Enteric Fever in Asia Project (SEAP), a prospective surveillance study, characterized the burden of enteric fever, including illness severity, in selected settings in Bangladesh, Nepal, and Pakistan. We assessed disease severity, including hospitalization, clinical complications, and death among SEAP participants. METHODS: We analyzed clinical and laboratory data from blood culture-confirmed enteric fever cases enrolled in SEAP hospitals and associated network laboratories from September 2016 to September 2019. We used hospitalization and duration of hospital stay as proxies for severity. We conducted a follow-up interview 6 weeks after enrollment to ascertain final outcomes. RESULTS: Of the 8705 blood culture-confirmed enteric fever cases enrolled, we identified 6 deaths (case-fatality ratio, .07%; 95% CI, .01-.13%), 2 from Nepal, 4 from Pakistan, and none from Bangladesh. Overall, 1.7% (90/5205) of patients recruited from SEAP hospitals experienced a clinical complication (Bangladesh, 0.6% [18/3032]; Nepal, 2.3% [12/531]; Pakistan, 3.7% [60/1642]). The most identified complications were hepatitis (n = 36), septic shock (n = 22), and pulmonary complications/pneumonia (n = 13). Across countries, 32% (2804/8669) of patients with hospitalization data available were hospitalized (Bangladesh, 27% [1295/4868]; Nepal, 29% [455/1595]; Pakistan, 48% [1054/2206]), with a median hospital stay of 5 days (IQR, 3-7). CONCLUSIONS: While defined clinical complications and deaths were uncommon at the SEAP sites, the high proportion of hospitalizations and prolonged hospital stays highlight illness severity and the need for enteric fever control measures, including the use of typhoid conjugate vaccines. |
Antimicrobial resistance in typhoidal Salmonella: Surveillance for enteric fever in Asia Project, 2016-2019
Qamar FN , Yousafzai MT , Dehraj IF , Shakoor S , Irfan S , Hotwani A , Hunzai MJ , Thobani RS , Rahman N , Mehmood J , Hemlock C , Memon AM , Andrews JR , Luby SP , Garrett DO , Longley AT , Date K , Saha SK . Clin Infect Dis 2020 71 S276-s284 BACKGROUND: Clinicians have limited therapeutic options for enteric as a result of increasing antimicrobial resistance, and therefore typhoid vaccination is recommended as a preventive measure. As a part of the Surveillance for Enteric Fever in Asia Project (SEAP), we investigated the extent measured the burden of antimicrobial resistance (AMR) among confirmed enteric fever cases in Bangladesh, Nepal, and Pakistan. METHODS: From September 2016-September 2019, SEAP recruited study participants of all age groups from its outpatient, inpatient, hospital laboratory, laboratory network, and surgical sites who had a diagnosis of febrile illness that was either suspected or blood culture confirmed for enteric fever. Antimicrobial resistance of isolates was determined by disc diffusion using Clinical and Laboratory Standard Institute cut-off points. We reported the frequency of multidrug resistance (MDR)(resistance to ampicillin, cotrimoxazole, and chloramphenicol), extensive drug resistance (XDR) (MDR plus non-susceptible to fluoroquinolone and any 3rd generation cephalosporins), and fluoroquinolone (FQ) and azithromycin non-susceptibility. RESULTS: We enrolled 8,705 blood culture confirmed enteric fever cases: 4,873 (56%) from Bangladesh, 1,602 (18%) from Nepal and 2,230 (26%) from Pakistan. Of these, 7,591 (87%) were Salmonella Typhi and 1114 (13%) were S. Paratyphi. MDR S. Typhi was identified in 17% (701/4065) of isolates in Bangladesh, and 1% (19/1342) in Nepal. In Pakistan, 16 % (331/2084) of S. Typhi isolates were MDR, and 64% (1319/2074) were XDR. FQ nonsusceptibility among S. Typhi isolates was 98% in Bangladesh, 87% in Nepal, and 95% in Pakistan. Azithromycin non-susceptibility was detected in 77 (2%) in Bangladesh, 9 (.67%) in Nepal and 9 (.59%) isolates in Pakistan. In Pakistan, three (2%) S. Paratyphi isolates were MDR; no MDR S. Paratyphi was reported from Bangladesh or Nepal. CONCLUSIONS: Although AMR against S. Paratyphi was low across the three countries, there was widespread drug resistance among S. Typhi, including FQ non-susceptibility and the emergence of XDR S. Typhi in Pakistan, limiting treatment options. As typhoid conjugate vaccine (TCV) is rolled out, surveillance should continue to monitor changes in AMR to inform policies and to monitor drug resistance in S. Paratyphi, for which there is no vaccine. |
Antibiotic use prior to hospital presentation among individuals with suspected enteric fever in Nepal, Bangladesh, and Pakistan
Vaidya K , Aiemjoy K , Qamar FN , Saha SK , Tamrakar D , Naga SR , Saha S , Hemlock C , Longley AT , Date K , Bogoch II , Garrett DO , Luby SP , Andrews JR . Clin Infect Dis 2020 71 S285-s292 BACKGROUND: Antibiotic use prior to seeking care at a hospital may reduce the sensitivity of blood culture for enteric fever, with implications for both clinical care and surveillance. The Surveillance for Enteric Fever in Asia Project (SEAP) is a prospective study of enteric fever incidence in Nepal, Bangladesh, and Pakistan. Nested within SEAP, we evaluated the accuracy of self-reported antibiotic use and investigated the association between antibiotic use and blood culture positivity. METHODS: Between November 2016 and April 2019, we collected urine samples among a subset of SEAP participants to test for antibiotic use prior to the hospital visit using an antibacterial activity assay. All participants were asked about recent antibiotic use and had a blood culture performed. We used mixed-effect logit models to evaluate the effect of antimicrobial use on blood culture positivity, adjusted for markers of disease severity. RESULTS: We enrolled 2939 patients with suspected enteric fever. Antibiotics were detected in 39% (1145/2939) of urine samples. The correlation between measured and reported antibiotic use was modest (κ = 0.72). After adjusting for disease severity, patients with antibiotics in their urine were slightly more likely to be blood culture positive for enteric fever; however, the effect was not statistically significant (prevalence ratio, 1.22 [95% confidence interval, .99-1.50]). CONCLUSIONS: The reliability of self-reported prior antibiotic use was modest among individuals presenting with fever to tertiary hospitals. While antibiotics are likely to reduce the sensitivity of blood culture, our findings indicate that there is still considerable value in performing blood culture for individuals reporting antibiotic use. |
The Surveillance for Enteric Fever in Asia Project (SEAP), Severe Typhoid Fever Surveillance in Africa (SETA), Surveillance of Enteric Fever in India (SEFI), and Strategic Typhoid Alliance Across Africa and Asia (STRATAA) Population-based Enteric Fever Studies: A review of methodological similarities and differences
Carey ME , MacWright WR , Im J , Meiring JE , Gibani MM , Park SE , Longley A , Jeon HJ , Hemlock C , Yu AT , Soura A , Aiemjoy K , Owusu-Dabo E , Terferi M , Islam S , Lunguya O , Jacobs J , Gordon M , Dolecek C , Baker S , Pitzer VE , Yousafzai MT , Tonks S , Clemens JD , Date K , Qadri F , Heyderman RS , Saha SK , Basnyat B , Okeke IN , Qamar FN , Voysey M , Luby S , Kang G , Andrews J , Pollard AJ , John J , Garrett D , Marks F . Clin Infect Dis 2020 71 S102-s110 Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to microbiologically safe water and improved sanitation. These differences in part reflect the heterogeneity of the epidemiology of invasive salmonellosis globally, and thus enable generation of data that are useful to policymakers in decision-making for the introduction of typhoid conjugate vaccines (TCVs). Moreover, each study is evaluating the large-scale deployment of TCVs, and may ultimately be used to assess post-introduction vaccine impact. The data generated by these studies will also be used to refine global disease burden estimates. It is important to ensure that lessons learned from these studies not only inform vaccination policy, but also are incorporated into sustainable, low-cost, integrated vaccine-preventable disease surveillance systems. |
Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study
Wang X , Li Y , O'Brien KL , Madhi SA , Widdowson MA , Byass P , Omer SB , Abbas Q , Ali A , Amu A , Azziz-Baumgartner E , Bassat Q , Abdullah Brooks W , Chaves SS , Chung A , Cohen C , Echavarria M , Fasce RA , Gentile A , Gordon A , Groome M , Heikkinen T , Hirve S , Jara JH , Katz MA , Khuri-Bulos N , Krishnan A , de Leon O , Lucero MG , McCracken JP , Mira-Iglesias A , Moisi JC , Munywoki PK , Ourohire M , Polack FP , Rahi M , Rasmussen ZA , Rath BA , Saha SK , Simoes EA , Sotomayor V , Thamthitiwat S , Treurnicht FK , Wamukoya M , Yoshida LM , Zar HJ , Campbell H , Nair H . Lancet Glob Health 2020 8 (4) e497-e510 BACKGROUND: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018. METHODS: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries. FINDINGS: In 2018, among children under 5 years globally, there were an estimated 109.5 million influenza virus episodes (uncertainty range [UR] 63.1-190.6), 10.1 million influenza-virus-associated ALRI cases (6.8-15.1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries. INTERPRETATION: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries. FUNDING: WHO; Bill & Melinda Gates Foundation. |
A mosaic tetracycline resistance gene tet(S/M) detected in an MDR pneumococcal CC230 lineage that underwent capsular switching in South Africa.
Lo SW , Gladstone RA , van Tonder AJ , Du Plessis M , Cornick JE , Hawkins PA , Madhi SA , Nzenze SA , Kandasamy R , Ravikumar KL , Elmdaghri N , Kwambana-Adams B , Almeida SCG , Skoczynska A , Egorova E , Titov L , Saha SK , Paragi M , Everett DB , Antonio M , Klugman KP , Li Y , Metcalf BJ , Beall B , McGee L , Breiman RF , Bentley SD , von Gottberg A . J Antimicrob Chemother 2019 75 (3) 512-520 OBJECTIVES: We reported tet(S/M) in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions. METHODS: We whole-genome sequenced 12 254 pneumococcal isolates from 29 countries on an Illumina HiSeq sequencer. Serotype, multilocus ST and antibiotic resistance were inferred from genomes. An SNP tree was built using Gubbins. Temporal spread was reconstructed using a birth-death model. RESULTS: We identified tet(S/M) in 131 pneumococcal isolates and none carried other known tet genes. Tetracycline susceptibility testing results were available for 121 tet(S/M)-positive isolates and all were resistant. A majority (74%) of tet(S/M)-positive isolates were from South Africa and caused invasive diseases among young children (59% HIV positive, where HIV status was available). All but two tet(S/M)-positive isolates belonged to clonal complex (CC) 230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sublineage predicted to exhibit resistance to penicillin, co-trimoxazole, erythromycin and tetracycline. The birth-death model detected an unrecognized outbreak of this sublineage in South Africa between 2000 and 2004 with expected secondary infections (effective reproductive number, R) of approximately 2.5. R declined to approximately 1.0 in 2005 and <1.0 in 2012. The declining epidemic could be related to improved access to ART in 2004 and introduction of pneumococcal conjugate vaccine (PCV) in 2009. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sublineage. CONCLUSIONS: The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognized outbreak of CC230 in South Africa. Capsular switching in this MDR sublineage highlighted its potential to continue to cause disease in the post-PCV13 era. |
Precipitation and fatal motor vehicle crashes: Continental analysis with high-resolution radar data
Stevens SE , Schreck CJ , Saha SK , Bell JE , Kunkel KE . Bull Am Meteorol Soc 2019 100 (8) 1453-1461 Motor vehicle crashes remain a leading cause of accidental death in the United States, and weather is frequently cited as a contributing factor in fatal crashes. Previous studies have investigated the link between these crashes and precipitation typically using station-based observations that, while providing a good estimate of the prevailing conditions on a given day or hour, often fail to capture the conditions present at the actual time and location of a crash. Using a multiyear, high-resolution radar reanalysis and information on 125,012 fatal crashes spanning the entire continental United States over a 6-yr period, we find that the overall risk of a fatal crash increases by approximately 34% during active precipitation. The risk is significant in all regions of the continental United States, and it is highest during the morning rush hour and during the winter months. |
Vaccines for maternal immunization against Group B Streptococcus disease: WHO perspectives on case ascertainment and case definitions
Seale AC , Baker CJ , Berkley JA , Madhi SA , Ordi J , Saha SK , Schrag SJ , Sobanjo-Ter Meulen A , Vekemans J . Vaccine 2019 37 (35) 4877-4885 Group B Streptococcus (GBS) is an important cause of disease in young infants, stillbirths, pregnant and post-partum women. GBS vaccines for maternal immunization are in development aiming to reduce this burden. Standardisation of case definitions and ascertainment methodologies for GBS disease is needed to support future trials of maternal GBS vaccines. Considerations presented here may also serve to promote consistency in observational studies and surveillance, to better establish disease burden. The World Health Organization convened a working group to provide consensus guidance for case ascertainment and case definitions of GBS disease in stillbirths, infants, pregnant and post-partum women, with feedback sought from external stakeholders. In intervention studies, case capture and case ascertainment for GBS disease should be based on antenatal recruitment of women, with active follow-up, systematic clinical assessment, standardised sampling strategies and optimised laboratory methods. Confirmed cases of invasive GBS disease in stillbirths or infants should be included in a primary composite endpoint for vaccine efficacy studies, with GBS cultured from a usually sterile body site (may be post-mortem). For additional endpoints, or observational studies, confirmed cases of GBS sepsis in pregnant and post-partum women should be assessed. Culture independent diagnostic tests (CIDTs) may detect additional presumed cases, however, the use of these diagnostics needs further evaluation. Efficacy of vaccination against maternal and neonatal GBS colonisation, and maternal GBS urinary tract infection could be included as additional, separate, endpoints and/or in observational studies. Whilst the focus here is on specific GBS disease outcomes, intervention studies also present an opportunity to establish the contribution of GBS across adverse perinatal outcomes, including all-cause stillbirth, preterm birth and neonatal encephalopathy. |
Invasive pneumococcal infections in children with nephrotic syndrome in Bangladesh
Malaker R , Saha S , Hanif M , Ahmed A , Saha S , Hasanuzzaman M , Khondakar T , Islam M , Baqui AH , Santosham M , Darmstadt GL , Whitney CG , Saha SK . Pediatr Infect Dis J 2019 38 (8) 798-803 INTRODUCTION: Children with nephrotic syndrome are susceptible to invasive bacterial infections. In this study, we aimed to: (1) determine the pathogens associated with infections in children with nephrotic syndrome and (2) describe antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae to guide evidence-based treatment and prevention policies. METHODS: From June 2013 to March 2015, we collected blood and/or ascitic fluid from children hospitalized with nephrotic syndrome and suspected bacterial disease in the largest pediatric hospital of Bangladesh. We cultured all samples and performed polymerase chain reaction (PCR) and immunochromatographic test on ascitic fluid for detection of S. pneumoniae. Pneumococcal isolates were tested for antibiotic susceptibility using disc diffusion and serotyped using Quellung reaction and PCR. RESULTS: We identified 1342 children hospitalized with nephrotic syndrome. Among them, 608 children had suspected bacterial disease from whom blood and/or ascitic fluid were collected. A pathogen was identified in 8% (48/608) of cases, 94% (45/48) of which were S. pneumoniae. Most (73%, 33/45) pneumococcal infections were identified through culture of blood and ascitic fluid and 27% (12/45) through immunochromatographic test and PCR of ascitic fluid. In total, 24 different pneumococcal serotypes were detected; 51% are covered by PCV10 (+6A), 53% by PCV13 and 60% by PPSV23. All pneumococcal isolates were susceptible to penicillin. CONCLUSIONS: Because S. pneumoniae was the primary cause of invasive infections, pneumococcal vaccines may be considered as a preventive intervention in children with nephrotic syndrome. Additionally, penicillin can be used to prevent and treat pneumococcal infections in children with nephrotic syndrome in Bangladesh. |
The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations
Vekemans J , Crofts J , Baker CJ , Goldblatt D , Heath PT , Madhi SA , Le Doare K , Andrews N , Pollard AJ , Saha SK , Schrag SJ , Smith PG , Kaslow DC . Vaccine 2019 37 (24) 3190-3198 The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined. |
Effect of population-based antenatal screening and treatment of genitourinary tract infections on birth outcomes in Sylhet, Bangladesh (MIST): a cluster-randomised clinical trial
Lee AC , Mullany LC , Quaiyum M , Mitra DK , Labrique A , Christian P , Ahmed P , Uddin J , Rafiqullah I , DasGupta S , Rahman M , Koumans EH , Ahmed S , Saha SK , Baqui AH . Lancet Glob Health 2019 7 (1) e148-e159 BACKGROUND: One-third of preterm births are attributed to pregnancy infections. We implemented a community-based intervention to screen and treat maternal genitourinary tract infections, with the aim of reducing the incidence of preterm birth. METHODS: We did an unblinded cluster-randomised controlled trial in two subdistricts of Sylhet, Bangladesh. Clusters were defined as the contiguous area served by a single community health worker, and each cluster comprised several contiguous villages, contained roughly 4000 people, and had about 120 births per year. Eligible participants within clusters were all ever-married women and girls of reproductive age (ie, aged 15-49 years) who became pregnant during the study period. Clusters were randomly assigned (1:1) to the intervention or control groups via a restricted randomisation procedure. In both groups, community health workers made home visits to identify pregnant women and girls and provide antenatal and postnatal care. Between 13 and 19 weeks' gestation, participants in the intervention group received home-based screening for abnormal vaginal flora and urinary tract infections. A random 10% of the control group also received the intervention to examine the similarity of infection prevalence between groups. If present, abnormal vaginal flora (ie, Nugent score >/=4 was treated with oral clindamycin (300 mg twice daily for 5 days) and urinary tract infections with cefixime (400 mg once daily for 3 days) or oral nitrofurantoin (100 mg twice daily for 7 days). Both infections were retreated if persistent. The primary outcome was the incidence of preterm livebirths before 37 weeks' gestation among all livebirths. This trial is registered with ClinicalTrials.gov, number NCT01572532. The trial is closed to new participants, with follow-up completed. FINDINGS: Between Jan 2, 2012, and July 28, 2015, 9712 pregnancies were enrolled (4840 in the intervention group, 4391 in the control group, and 481 in the control subsample). 3818 livebirths in the intervention group and 3557 livebirths in the control group were included in the primary analysis. In the intervention group, the prevalence of abnormal vaginal flora was 16.3% (95% CI 15.1-17.6) and that of urinary tract infection was 8.6% (7.7-9.5). The effective coverage of successful treatment in the intervention group was 58% in participants with abnormal vaginal flora (ie, abnormal vaginal flora resolved in 361 [58%] of the 622 participants who initially tested positive), and 71% in those with urinary tract infections (ie, resolution in 224 [71%] of the 317 participants who initially tested positive). Overall, the incidence of preterm livebirths before 37 weeks' gestation did not differ significantly between the intervention and control groups (21.8% vs 20.6%; relative risk 1.07 [95% CI 0.91-1.24]). INTERPRETATION: A population-based antenatal screening and treatment programme for genitourinary tract infections did not reduce the incidence of preterm birth in Bangladesh. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and Saving Lives at Birth Grand Challenges. |
Prevalence of and risk factors for abnormal vaginal flora and its association with adverse pregnancy outcomes in a rural district in north-east Bangladesh
Baqui AH , Lee AC , Koffi AK , Khanam R , Mitra DK , Dasgupta SK , Uddin J , Ahmed P , Rafiqullah I , Rahman M , Quaiyum A , Koumans EH , Christian P , Saha SK , Mullany LC , Labrique A . Acta Obstet Gynecol Scand 2018 98 (3) 309-319 INTRODUCTION: The role of screening and treatment for abnormal vaginal flora (AVF) on adverse pregnancy outcomes remains unclear. Using data from women who participated in a population-based cluster randomized trial who were screened and treated for AVF, we report risk factors for AVF and association of persistent AVF with adverse perinatal outcomes. MATERIAL AND METHODS: Pregnant women (n=4,221) <19 weeks of gestation provided self-administered mid-vaginal swabs; smears were Nugent scored. AVF was treated with oral clindamycin; if AVF was present 3 weeks after treatment, persistent AVF was re-treated. We examined risk factors for AVF and the association of persistent AVF with adverse pregnancy outcomes. RESULTS: The prevalence of AVF was 16.5%; 9.8% of women had bacterial vaginosis and 6.8% had intermediate flora. Lower economic and educational status of women were associated with increased risk of AVF. One-third of women with AVF had persistent abnormal flora; these women had higher risk of a composite measure of adverse pregnancy outcomes from 20 to < 37 weeks (preterm live birth, preterm still birth, late miscarriage) [RR 1.33, 95% CI; 1.07 to 1.65)], and of late miscarriage alone [RR 4.15, 95% CI; 2.12 to 8.12)] compared to women without AVF. CONCLUSIONS: In this study in Sylhet District, Bangladesh, rates of AVF and persistent AVF were high and persistent AVF was associated with adverse pregnancy outcomes, with an especially high associated risk for late miscarriage. Further characterization of the microbiome and relative bacterial species density associated with persistent AVF is needed. This article is protected by copyright. All rights reserved. |
Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP): An overview and lessons learned
Barkume C , Date K , Saha SK , Qamar FN , Sur D , Andrews JR , Luby SP , Khan MI , Freeman A , Yousafzai MT , Garrett D . J Infect Dis 2018 218 S188-S194 Objective: The objective of Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP), a multiphase surveillance study characterizing the burden of disease in South Asia, was to inform data collection for prospective surveillance and to capture clinical aspects of disease. Methods: Through a retrospective record review conducted at hospitals in Bangladesh, India, Nepal, and Pakistan, we examined laboratory and clinical records to assess the culture positivity rate for Salmonella Typhi and Salmonella Paratyphi, age and sex distribution, and antimicrobial susceptability in each country. Results: Of all blood cultures performed in Bangladesh, India, Nepal, and Pakistan, 1.5%, 0.43%, 2%, and 1.49%, respectively, were positive for S. Typhi and 0.24%, 0.1%, 0.5%, and 0.67%, respectively, were positive for S. Paratyphi. A higher proportion of laboratory-confirmed infections in Bangladesh and Pakistan were aged </=5 years, while India and Nepal had a higher proportion of participants aged 15-25 years. In all countries, the sex of the majority of participants was male. The majority of isolates in all countries were resistant to fluoroquinolones, with a high proportion also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Discussion: Enteric fever remains endemic in South Asia. Data generated by this study can help inform strategies for implementation and evaluation of prevention and control measures. |
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