Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
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Query Trace: Longley AT[original query] |
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Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis
Commons RJ , Rajasekhar M , Edler P , Abreha T , Awab GR , Baird JK , Barber BE , Chu CS , Cui L , Daher A , Gonzalez-Ceron L , Grigg MJ , Hwang J , Karunajeewa H , Lacerda MVG , Ladeia-Andrade S , Lidia K , Llanos-Cuentas A , Longley RJ , Pereira DB , Pasaribu AP , Pukrittayakamee S , Rijal KR , Sutanto I , Taylor WRJ , Thanh PV , Thriemer K , Vieira JLF , Watson JA , Zuluaga-Idarraga LM , White NJ , Guerin PJ , Simpson JA , Price RN . Lancet Infect Dis 2023 BACKGROUND: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. FINDINGS: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. INTERPRETATION: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture. |
Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis
Mehdipour P , Rajasekhar M , Dini S , Zaloumis S , Abreha T , Adam I , Awab GR , Baird JK , Brasil LW , Chu CS , Cui L , Daher A , do Socorro MGomes M , Gonzalez-Ceron L , Hwang J , Karunajeewa H , Lacerda MVG , Ladeia-Andrade S , Leslie T , Ley B , Lidia K , Llanos-Cuentas A , Longley RJ , Monteiro WM , Pereira DB , Rijal KR , Saravu K , Sutanto I , Taylor WRJ , Thanh PV , Thriemer K , Vieira JLF , White NJ , Zuluaga-Idarraga LM , Guerin PJ , Price RN , Simpson JA , Commons RJ . Malar J 2023 22 (1) 306 BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence. |
Establishing vaccine pregnancy registries and active surveillance studies in low-and middle-income countries: Experience from an observational cohort surveillance project in The Gambia
Kochhar S , Okomo U , Nkereuwem O , Shaum A , Gidudu JF , Bittaye M , Fofana S , Marena M , Kaira MJ , Kampmann B , Longley AT . Vaccine 2023 41 (44) 6453-6455 Despite significant advances in child survival, infectious diseases continue to be among the leading causes of neonatal deaths [1]. Maternal immunization is a well-recognized public health intervention to reduce vaccine-preventable disease-related morbidity and mortality in the pregnant woman, her foetus, and infant from tetanus, pertussis, seasonal influenza, and COVID-19 [2]. The development of new maternal vaccines against respiratory syncytial virus (RSV) and group B streptococcus (GBS) may significantly decrease the morbidity and mortality from these diseases in neonates and infants [2], with the U.S. Food and Drug Administration (FDA) approval for licensure of an RSV vaccine to be administered in pregnancy occurring in August 2023 [3]. | | Ongoing safety assessment of novel vaccines administered during pregnancy requires well-functioning passive and active surveillance systems to collect and assess adverse maternal and neonatal outcomes [4]. In high-income countries (HICs), regulatory authorities, such as the European Medicines Agency (EMA) and the U.S. FDA, require extensive post-authorization safety monitoring activities for products used during pregnancy, including active surveillance for safety-related events through pregnancy registries and observational cohort studies [4], [5], [6]. However, safety surveillance for vaccines used in pregnancy in many low- and middle-income countries (LMICs) currently relies on passive surveillance systems whose output cannot be interpreted appropriately due to lack of information on background rates of adverse events in pregnancy in general and lack of data on the number of pregnant women vaccinated as the relevant specific comparator [4], [5], [6]. |
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 |
CDC's COVID-19 international vaccine implementation and evaluation program and lessons from earlier vaccine introductions
Soeters HM , Doshi RH , Fleming M , Adegoke OJ , Ajene U , Aksnes BN , Bennett S , Blau EF , Carlton JG , Clements S , Conklin L , Dahlke M , Duca LM , Feldstein LR , Gidudu JF , Grant G , Hercules M , Igboh LS , Ishizumi A , Jacenko S , Kerr Y , Konne NM , Kulkarni S , Kumar A , Lafond KE , Lam E , Longley AT , McCarron M , Namageyo-Funa A , Ortiz N , Patel JC , Perry RT , Prybylski D , Reddi P , Salman O , Sciarratta CN , Shragai T , Siddula A , Sikare E , Tchoualeu DD , Traicoff D , Tuttle A , Victory KR , Wallace A , Ward K , Wong MKA , Zhou W , Schluter WW , Fitter DL , Mounts A , Bresee JS , Hyde TB . Emerg Infect Dis 2022 28 (13) S208-s216 The US Centers for Disease Control and Prevention (CDC) supports international partners in introducing vaccines, including those against SARS-CoV-2 virus. CDC contributes to the development of global technical tools, guidance, and policy for COVID-19 vaccination and has established its COVID-19 International Vaccine Implementation and Evaluation (CIVIE) program. CIVIE supports ministries of health and their partner organizations in developing or strengthening their national capacities for the planning, implementation, and evaluation of COVID-19 vaccination programs. CIVIE's 7 priority areas for country-specific technical assistance are vaccine policy development, program planning, vaccine confidence and demand, data management and use, workforce development, vaccine safety, and evaluation. We discuss CDC's work on global COVID-19 vaccine implementation, including priorities, challenges, opportunities, and applicable lessons learned from prior experiences with Ebola, influenza, and meningococcal serogroup A conjugate vaccine introductions. |
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. |
Evaluation of vaccine safety after the first public sector introduction of typhoid conjugate vaccine - Navi Mumbai, India, 2018
Longley AT , Date K , Luby SP , Bhatnagar P , Bentsi-Enchill AD , Goyal V , Shimpi R , Katkar A , Yewale V , Jayaprasad N , Horng L , Kunwar A , Harvey P , Haldar P , Dutta S , Gidudu J . Clin Infect Dis 2021 73 (4) e927-e933 BACKGROUND: In December 2017, the World Health Organization (WHO) prequalified the first typhoid conjugate vaccine (TCV) (Typbar-TCV). While no safety concerns were identified in pre- and post-licensure studies, WHO's Global Advisory Committee on Vaccine Safety recommended robust safety evaluation with large-scale TCV introductions. During July-August 2018, the Navi Mumbai Municipal Corporation (NMMC) launched the world's first public sector TCV introduction. Per administrative reports, 113,420 children 9 months-14 years old received TCV. METHODS: We evaluated adverse events following immunization (AEFI) using passive and active surveillance via 1) reports from the passive NMMC AEFI surveillance system, 2) telephone interviews with 5% of caregivers of vaccine recipients 48 hours and 7 days post-vaccination, and 3) chart abstraction for adverse events of special interest (AESI) among patients admitted to 5 hospitals using the Brighton Collaboration criteria followed by ascertainment of vaccination status. RESULTS: We identified 222/113,420 (0.2%) AEFI through the NMMC AEFI surveillance system: 211 (0.19%) minor, 2 (0.002%) severe, and 9 (0.008%) serious. At 48 hours post-vaccination, 1,852/5,605 (33%) caregivers reported one or more AEFI, including injection site pain (n=1,452, 26%), swelling (n=419, 7.5%), and fever (n=416, 7.4%). Of the 4,728 interviews completed at 7 days post-vaccination, the most reported AEFI included fever (n=200, 4%), pain (n=52, 1%), and headache (n=42, 1%). Among 525 hospitalized children diagnosed with an AESI, 60 were vaccinated; no AESI were causally associated with TCV. CONCLUSIONS: No unexpected safety signals were identified with TCV introduction. This provides further reassurance for the large-scale use of Typbar-TCV among children 9 months-14 years old. |
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. |
Spatial heterogeneity of enteric fever in 2 diverse communities in Nepal
Tamrakar D , Vaidya K , Yu AT , Aiemjoy K , Naga SR , Cao Y , Bern C , Shrestha R , Karmacharya BM , Pradhan S , Qamar FN , Saha S , Date K , Longley AT , Hemlock C , Luby S , Garrett DO , Bogoch II , Andrews JR . Clin Infect Dis 2020 71 S205-s213 BACKGROUND: Typhoid fever is endemic in the urban Kathmandu Valley of Nepal; however, there have been no population-based studies of typhoid outside of this community in the past 3 decades. Whether typhoid immunization should be prioritized in periurban and rural communities has been unclear. METHODS: We performed population-based surveillance for enteric fever in 1 urban catchment (Kathmandu) and 1 periurban and rural catchment (Kavrepalanchok) as part of the Surveillance for Enteric Fever in Asia Project (SEAP). We recruited individuals presenting to outpatient and emergency departments at 2 study hospitals with suspected enteric fever and performed blood cultures. Additionally, we conducted a household survey in each catchment area to characterize care seeking for febrile illness. We evaluated spatial heterogeneity in febrile illness, care seeking, and enteric fever incidence. RESULTS: Between September 2016 and September 2019, we enrolled 5736 participants with suspected enteric fever at 2 study hospitals. Among these, 304 (5.3%) were culture positive for Salmonella Typhi (249 [81.9%]) or Paratyphi A (55 [18.1%]). Adjusted typhoid incidence in Kathmandu was 484 per 100 000 person-years and in Kavrepalanchok was 615 per 100 000 person-years. While all geographic areas for which estimates could be made had incidence >200 per 100 000 person-years, we observed spatial heterogeneity with up to 10-fold variation in incidence between communities. CONCLUSIONS: In urban, periurban, and rural communities in and around Kathmandu, we measured a high but heterogenous incidence of typhoid. These findings provide some support for the introduction of conjugate vaccines in Nepal, including outside urban areas, alongside other measures to prevent enteric fever. |
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. |
A cluster-based, spatial-sampling method for assessing household healthcare utilization patterns in resource-limited settings
Yu AT , Shakya R , Adhikari B , Tamrakar D , Vaidya K , Maples S , Date K , Bogoch II , Bern C , Qamar F , Yousafzai MT , Garrett DO , Longley AT , Hemlock C , Luby S , Aiemjoy K , Andrews JR . Clin Infect Dis 2020 71 S239-s247 BACKGROUND: Implementation of population-based surveys is resource intensive and logistically demanding, especially in areas with rapidly changing demographics and incomplete or no enumeration of the underlying population and their residences. To remove the need for pre-enumeration and to simplify field logistics for the population healthcare utilization survey used for the Surveillance for Enteric Fever in Asia Project in Nepal, we incorporated a geographic information system-based geosurvey and field mapping system into a single-stage cluster sampling approach. METHODS: A survey was administered to ascertain healthcare-seeking behavior in individuals with recent suspected enteric fever. Catchment areas were based on residential addresses of enteric fever patients using study facilities; clusters were randomly selected from digitally created grids using available satellite images and all households within clusters were offered enrollment. A tablet-compatible geosurvey and mapping system that allowed for data-syncing and use in areas without cellular data was created using the ArcGIS suite of software. RESULTS: Between January 2017 and November 2018, we surveyed 25 521 households in Nepal (16 769 in urban Kathmandu and 8752 in periurban Kavrepalanchok), representing 84 202 individuals. Overall, the survey participation rate was 90.9%, with geographic heterogeneity in participation rates within each catchment area. Areas with higher average household wealth had lower participation rates. CONCLUSION: A geographic information system-based geosurvey and field mapping system allowed creation of a virtual household map at the same time as survey administration, enabling a single-stage cluster sampling method to assess healthcare utilization in Nepal for the Surveillance for Enteric Fever in Asia Project . This system removed the need for pre-enumeration of households in sampling areas, simplified logistics and could be replicated in future community surveys. |
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. |
Using reduced inoculum densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to prevent false-resistant results and improve accuracy: A multicenter evaluation
Morlock GP , Tyrrell FC , Baynham D , Escuyer VE , Green N , Kim Y , Longley-Olson PA , Parrish N , Pennington C , Tan D , Austin B , Posey JE . Tuberc Res Treat 2017 2017 3748163 The primary platform used for pyrazinamide (PZA) susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson). Since false-resistant results have been associated with the use of this system, we conducted a multicenter evaluation to determine the effect of using a reduced cell density inoculum on the rate of false resistance. Two reduced inoculum densities were compared with that prescribed by the manufacturer (designated as "BD" method). The reduced inoculum methods (designated as "A" and "C") were identical to the manufacturer's protocol in all aspects with the exception of the cell density of the inoculum. Twenty genetically and phenotypically characterized M. tuberculosis isolates were tested in duplicate by ten independent laboratories using the three inoculum methods. False-resistant results declined from 21.1% using the standard "BD" method to 5.7% using the intermediate ("A") inoculum and further declined to 2.8% using the most dilute ("C") inoculum method. The percentages of the resistant results that were false-resistant declined from 55.2% for the "BD" test to 28.8% and 16.0% for the "A" and "C" tests, respectively. These results represent compelling evidence that the occurrence of false-resistant MGIT PZA susceptibility test results can be mitigated through the use of reduced inoculum densities. |
Evaluation of a public-sector, provider-initiated cryptococcal antigen screening and treatment program, Western Cape, South Africa
Vallabhaneni S , Longley N , Smith M , Smith R , Osler M , Kelly N , Cross A , Boulle A , Meintjes G , Govender NP . J Acquir Immune Defic Syndr 2016 72 (2) e37-e42 BACKGROUND: Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and pre-emptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012-August 31, 2013. METHODS: We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened. RESULTS: Of 4,395 eligible patients, 26.6% (n=1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg-positive patients; nine of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (p=0.07). CONCLUSIONS: Relatively few eligible patients were screened under the WC provider-initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible. |
Cryptococcal antigen screening and preemptive therapy in patients initiating antiretroviral therapy in resource-limited settings: a proposed algorithm for clinical implementation
Jarvis JN , Govender N , Chiller T , Park BJ , Longley N , Meintjes G , Bekker LG , Wood R , Lawn SD , Harrison TS . J Int Assoc Physicians AIDS Care (Chic) 2012 11 (6) 374-9 HIV-associated cryptococcal meningitis (CM) is estimated to cause over half a million deaths annually in Africa. Many of these deaths are preventable. Screening patients for subclinical cryptococcal infection at the time of entry into antiretroviral therapy programs using cryptococcal antigen (CRAG) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with "preemptive" therapy to prevent the development of severe disease. Such CRAG screening programs are currently being implemented in a number of countries; however, a strong evidence base and clear guidance on how to manage patients with subclinical cryptococcal infection identified by screening are lacking. We review the available evidence and propose a treatment algorithm for the management of patients with asymptomatic cryptococcal antigenemia. |
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