Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in Pakistan.

Background: The Enterics for Global Health (EFGH) Shigella surveillance study is a longitudinal multicountry study that aims to estimate incidence rates and document consequences of Shigella diarrhea within 7 countries in Africa, Asia, and Latin America. In addition to a high incidence of childhood diarrhea, Pakistan is facing a problem of antimicrobial resistance in urban and peri-urban areas of Karachi. Methods: In Pakistan, EFGH will be conducted in Karachi, which is one of the metropolitan cities bordering the Arabian Sea and has a diverse population of 1.6 million according to the 2017 population census. The study aims to enroll 1400 children aged 6-35 months over 2 years (2022-2024) from 6 health care facilities (Abbasi Shaheed Hospital, Khidmat-e-Alam Medical Centre, Sindh Government Hospital Korangi 5, Sindh Government Hospital Ibrahim Hyderi, Ali Akbar Shah VPT Center, and Bhains Colony VPT Center) situated in Nazimabad and Bin-Qasim town. Moreover, population enumeration and health care utilization surveys from a defined catchment area of health facilities will be conducted to estimate the Shigella diarrhea incidence rates. Conclusions: The study will provide critical data to policy-makers about the burden of Shigella and antimicrobial resistance, which is essential for planning Shigella vaccine trials.

Microbiological Methods Used in the Enterics for Global Health Shigella Surveillance Study.

Background: Shigella is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting Shigella are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study is designed to determine the incidence of medically attended shigellosis in 6- to 35-month-old children in 7 resource-limited settings. Here, we describe the microbiological methods used to isolate and identify Shigella. We developed a standardized laboratory protocol for isolation and identification of Shigella by culture. This protocol was implemented across all 7 sites, ensuring consistency and comparability of results. Secondary objectives of the study are to determine the antibiotic resistance profiles of Shigella, compare isolation of Shigella from rectal swabs versus whole stool, and compare isolation of Shigella following transport of rectal swabs in Cary-Blair versus a modified buffered glycerol saline transport medium. Conclusions: Data generated from EFGH using culture methods described herein can potentially be used for microbiological endpoints in future phase 3 clinical trials to evaluate vaccines against shigellosis and for other clinical and public health studies focused on these organisms.

Evaluation of Fecal Inflammatory Biomarkers to Identify Bacterial Diarrhea Episodes: Systematic Review and Protocol for the Enterics for Global Health Shigella Surveillance Study.

Background: The measurement of fecal inflammatory biomarkers among individuals presenting to care with diarrhea could improve the identification of bacterial diarrheal episodes that would benefit from antibiotic therapy. We reviewed prior literature in this area and describe our proposed methods to evaluate 4 biomarkers in the Enterics for Global Health (EFGH) Shigella surveillance study. Methods: We systematically reviewed studies since 1970 from PubMed and Embase that assessed the diagnostic characteristics of inflammatory biomarkers to identify bacterial diarrhea episodes. We extracted sensitivity and specificity and summarized the evidence by biomarker and diarrhea etiology. In EFGH, we propose using commercial enzyme-linked immunosorbent assays to test for myeloperoxidase, calprotectin, lipocalin-2, and hemoglobin in stored whole stool samples collected within 24 hours of enrollment from participants in the Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia sites. We will develop clinical prediction scores that incorporate the inflammatory biomarkers and evaluate their ability to identify Shigella and other bacterial etiologies of diarrhea as determined by quantitative polymerase chain reaction (qPCR). Results: Forty-nine studies that assessed fecal leukocytes (n = 39), red blood cells (n = 26), lactoferrin (n = 13), calprotectin (n = 8), and myeloperoxidase (n = 1) were included in the systematic review. Sensitivities were high for identifying Shigella, moderate for identifying any bacteria, and comparable across biomarkers. Specificities varied depending on the outcomes assessed. Prior studies were generally small, identified red and white blood cells by microscopy, and used insensitive gold standard diagnostics, such as conventional bacteriological culture for pathogen detection. Conclusions: Our evaluation of inflammatory biomarkers to distinguish diarrhea etiologies as determined by qPCR will provide an important addition to the prior literature, which was likely biased by the limited sensitivity of the gold standard diagnostics used. We will determine whether point-of-care biomarker tests could be a viable strategy to inform treatment decision making and increase appropriate targeting of antibiotic treatment to bacterial diarrhea episodes.

Quantifying the Cost of Shigella Diarrhea in the Enterics for Global Health (EFGH) Shigella Surveillance Study.

Background: Comparative costs of public health interventions provide valuable data for decision making. However, the availability of comprehensive and context-specific costs is often limited. The Enterics for Global Health (EFGH) Shigella surveillance study-a facility-based diarrhea surveillance study across 7 countries-aims to generate evidence on health system and household costs associated with medically attended Shigella diarrhea in children. Methods: EFGH working groups comprising representatives from each country (Bangladesh, Kenya, Malawi, Mali, Pakistan, Peru, and The Gambia) developed the study methods. Over a 24-month surveillance period, facility-based surveys will collect data on resource use for the medical treatment of an estimated 9800 children aged 6-35 months with diarrhea. Through these surveys, we will describe and quantify medical resources used in the treatment of diarrhea (eg, medication, supplies, and provider salaries), nonmedical resources (eg, travel costs to the facility), and the amount of caregiver time lost from work to care for their sick child. To assign costs to each identified resource, we will use a combination of caregiver interviews, national medical price lists, and databases from the World Health Organization and the International Labor Organization. Our primary outcome will be the estimated cost per inpatient and outpatient episode of medically attended Shigella diarrhea treatment across countries, levels of care, and illness severity. We will conduct sensitivity and scenario analysis to determine how unit costs vary across scenarios. Conclusions: Results from this study will contribute to the existing body of literature on diarrhea costing and inform future policy decisions related to investments in preventive strategies for Shigella.

Population Enumeration and Household Utilization Survey Methods in the Enterics for Global Health (EFGH): Shigella Surveillance Study.

Background: Accurate estimation of diarrhea incidence from facility-based surveillance requires estimating the population at risk and accounting for case patients who do not seek care. The Enterics for Global Health (EFGH) Shigella surveillance study will characterize population denominators and healthcare-seeking behavior proportions to calculate incidence rates of Shigella diarrhea in children aged 6-35 months across 7 sites in Africa, Asia, and Latin America. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will use a hybrid surveillance design, supplementing facility-based surveillance with population-based surveys to estimate population size and the proportion of children with diarrhea brought for care at EFGH health facilities. Continuous data collection over a 24 month period captures seasonality and ensures representative sampling of the population at risk during the period of facility-based enrollments. Study catchment areas are broken into randomized clusters, each sized to be feasibly enumerated by individual field teams. Conclusions: The methods presented herein aim to minimize the challenges associated with hybrid surveillance, such as poor parity between survey area coverage and facility coverage, population fluctuations, seasonal variability, and adjustments to care-seeking behavior.

Efficacy of typhoid vaccines against culture-confirmed Salmonella Typhi in typhoid endemic countries: a systematic review and meta-analysis.

BACKGROUND: Typhoid is a serious public health threat in many low-income and middle-income countries. Several vaccines for typhoid have been recommended by WHO for typhoid prevention in endemic countries. This study aimed to review the efficacy of typhoid vaccines against culture-confirmed Salmonella enterica serovar Typhi. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for studies published in English between Jan 1, 1986 and Nov 2, 2023. We included randomised controlled trials (RCTs) comparing typhoid vaccines with a placebo or another vaccine. This meta-analysis evaluated the efficacy and safety of several typhoid vaccines, including live attenuated oral Ty21a vaccine, Vi capsular polysaccharide (Vi-PS), Vi polysaccharide conjugated to recombinant Pseudomonas aeruginosa exotoxin A vaccine (Vi-rEPA), and Vi-tetanus toxoid conjugate vaccine (TCV). The certainty of evidence for key outcomes was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations methodology. The outcome of interest was typhoid fever confirmed by the isolation of Salmonella enterica serovar Typhi in blood and adverse events following immunisation. This study is registered with PROSPERO (CRD42021241043). FINDINGS: We included 14 RCTs assessing four different vaccines (Ty21a: four trials; Vi-PS: five trials; Vi-rEPA: one trial; TCV: four trials) involving 585 253 participants. All trials were conducted in typhoid endemic countries and the age of participants ranged from 6 months to 50 years. The pooled efficacy against typhoid fever was 45% (95% CI 33-55%; four trials; 247 649 participants; I2 59%; moderate certainty) for Ty21a and 58% (44-69%; five trials; 214 456 participants; I2 34%; moderate certainty) for polysaccharide Vi-PS. The cumulative efficacy of two doses of Vi-rEPA vaccine at 2 years was 91% (88-96%; one trial; 12 008 participants; moderate certainty). The pooled efficacy of a single shot of TCV at 2 years post-immunisation was 83% (77-87%; four trials; 111 130 participants; I2 0%; moderate certainty). All vaccines were safe, with no serious adverse effects reported in the trials. INTERPRETATION: The existing data from included trials provide promising results regarding the efficacy and safety of the four recommended typhoid vaccines. TCV and Vi-rEPA were found to have the highest efficacy at 2 years post-immunisation. However, follow-up data for Vi-rEPA are scarce and only TCV is pre-qualified by WHO. Therefore, roll-out of TCV into routine immunisation programmes in typhoid endemic settings is highly recommended. FUNDING: There was no funding source for this study.

Data Management in Multicountry Consortium Studies: The Enterics For Global Health (EFGH) Shigella Surveillance Study Example.

Background: Rigorous data management systems and planning are essential to successful research projects, especially for large, multicountry consortium studies involving partnerships across multiple institutions. Here we describe the development and implementation of data management systems and procedures for the Enterics For Global Health (EFGH) Shigella surveillance study-a 7-country diarrhea surveillance study that will conduct facility-based surveillance concurrent with population-based enumeration and a health care utilization survey to estimate the incidence of Shigella--associated diarrhea in children 6 to 35 months old. Methods: The goals of EFGH data management are to utilize the knowledge and experience of consortium members to collect high-quality data and ensure equity in access and decision-making. During the planning phase before study initiation, a working group of representatives from each EFGH country site, the coordination team, and other partners met regularly to develop the data management systems for the study. Results: This resulted in the Data Management Plan, which included selecting REDCap and SurveyCTO as the primary database systems. Consequently, we laid out procedures for data processing and storage, study monitoring and reporting, data quality control and assurance activities, and data access. The data management system and associated real-time visualizations allow for rapid data cleaning activities and progress monitoring and will enable quicker time to analysis. Conclusions: Experiences from this study will contribute toward enriching the sparse landscape of data management methods publications and serve as a case study for future studies seeking to collect and manage data consistently and rigorously while maintaining equitable access to and control of data.

Diarrhea Case Surveillance in the Enterics for Global Health Shigella Surveillance Study: Epidemiologic Methods.

Background: Shigella is a leading cause of acute watery diarrhea, dysentery, and diarrhea-attributed linear growth faltering, a precursor to stunting and lifelong morbidity. Several promising Shigella vaccines are in development and field efficacy trials will require a consortium of potential vaccine trial sites with up-to-date Shigella diarrhea incidence data. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will employ facility-based enrollment of diarrhea cases aged 6-35 months with 3 months of follow-up to establish incidence rates and document clinical, anthropometric, and financial consequences of Shigella diarrhea at 7 country sites (Mali, Kenya, The Gambia, Malawi, Bangladesh, Pakistan, and Peru). Over a 24-month period between 2022 and 2024, the EFGH study aims to enroll 9800 children (1400 per country site) between 6 and 35 months of age who present to local health facilities with diarrhea. Shigella species (spp.) will be identified and serotyped from rectal swabs by conventional microbiologic methods and quantitative polymerase chain reaction. Shigella spp. isolates will undergo serotyping and antimicrobial susceptibility testing. Incorporating population and healthcare utilization estimates from contemporaneous household sampling in the catchment areas of enrollment facilities, we will estimate Shigella diarrhea incidence rates. Conclusions: This multicountry surveillance network will provide key incidence data needed to design Shigella vaccine trials and strengthen readiness for potential trial implementation. Data collected in EFGH will inform policy makers about the relative importance of this vaccine-preventable disease, accelerating the time to vaccine availability and uptake among children in high-burden settings.

Exploring Natural Immune Responses to Shigella Exposure Using Multiplex Bead Assays on Dried Blood Spots in High-Burden Countries: Protocol From a Multisite Diarrhea Surveillance Study.

Background: Molecular diagnostics on human fecal samples have identified a larger burden of shigellosis than previously appreciated by culture. Evidence of fold changes in immunoglobulin G (IgG) to conserved and type-specific Shigella antigens could be used to validate the molecular assignment of type-specific Shigella as the etiology of acute diarrhea and support polymerase chain reaction (PCR)-based microbiologic end points for vaccine trials. Methods: We will test dried blood spots collected at enrollment and 4 weeks later using bead-based immunoassays for IgG to invasion plasmid antigen B and type-specific lipopolysaccharide O-antigen for Shigella flexneri 1b, 2a, 3a, and 6 and Shigella sonnei in Shigella-positive cases and age-, site-, and season-matched test-negative controls from all sites in the Enterics for Global Health (EFGH) Shigella surveillance study. Fold antibody responses will be compared between culture-positive, culture-negative but PCR-attributable, and PCR-positive but not attributable cases and test-negative controls. Age- and site-specific seroprevalence distributions will be identified, and the association between baseline antibodies and Shigella attribution will be estimated. Conclusions: The integration of these assays into the EFGH study will help support PCR-based attribution of acute diarrhea to type-specific Shigella, describe the baseline seroprevalence of conserved and type-specific Shigella antibodies, and support correlates of protection for immunity to Shigella diarrhea. These insights can help support the development and evaluation of Shigella vaccine candidates.

Shigella Detection and Molecular Serotyping With a Customized TaqMan Array Card in the Enterics for Global Health (EFGH): Shigella Surveillance Study.

Background: Quantitative polymerase chain reaction (qPCR) targeting ipaH has been proven to be highly efficient in detecting Shigella in clinical samples compared to culture-based methods, which underestimate Shigella burden by 2- to 3-fold. qPCR assays have also been developed for Shigella speciation and serotyping, which is critical for both vaccine development and evaluation. Methods: The Enterics for Global Health (EFGH) Shigella surveillance study will utilize a customized real-time PCR-based TaqMan Array Card (TAC) interrogating 82 targets, for the detection and differentiation of Shigella spp, Shigella sonnei, Shigella flexneri serotypes, other diarrhea-associated enteropathogens, and antimicrobial resistance (AMR) genes. Total nucleic acid will be extracted from rectal swabs or stool samples, and assayed on TAC. Quantitative analysis will be performed to determine the likely attribution of Shigella and other particular etiologies of diarrhea using the quantification cycle cutoffs derived from previous studies. The qPCR results will be compared to conventional culture, serotyping, and phenotypic susceptibility approaches in EFGH. Conclusions: TAC enables simultaneous detection of diarrheal etiologies, the principal pathogen subtypes, and AMR genes. The high sensitivity of the assay enables more accurate estimation of Shigella-attributed disease burden, which is critical to informing policy and in the design of future clinical trials.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

Coverage survey of typhoid conjugate vaccine among children aged 6 months to 15 years in an urban slum settlement of Lyari Town Karachi, Pakistan.

OBJECTIVE: To estimate the coverage rate of typhoid conjugate vaccine (TCV) among children aged 6 months to 15 years in Lyari Town Karachi, Pakistan. METHODS: A cross-sectional survey was conducted to estimate the vaccine coverage of Typbar TCV in Lyari Town Karachi utilizing the World Health Organization (WHO) recommended rapid vaccine coverage assessment technique (30 clusters × 7 households). Sampling was powered at town level and multistage cluster sampling was used. Four union councils were randomly selected from a total of 11 and the survey was conducted in those union councils. After consent was obtained, parents of age-eligible children living in the selected union councils were invited to participate in the survey and information was collected on Typbar TCV vaccination status of children aged 6 months to 15 years. RESULTS: Overall, 2325 children were included in the survey. The mean age of the participants was 7.60 ± 3.84 years. The ratio of males to females was equal in the survey sample; 1163 (50.02%) were male. In the total target population, 82% children were found to be vaccinated; however, the vaccination status could be verified for 80%. The vaccine coverage of TCV was comparable among the four union councils and the overall coverage of TCV vaccine in Lyari Town was found to be 80%. The coverage was significantly lower in younger children, 5% and 17% among children aged 6 months to < 2 years and 2 years to < 5 years respectively and 78% among children aged 5 years to 15 years. CONCLUSION: The overall immunization coverage rate with TCV was found to be satisfactory. Immunization coverage was comparable among both sexes and the selected union councils but it was relatively low among children in younger age groups.

Parental acceptance of typhoid conjugate vaccine for children aged 6 months to 15 years in an outbreak setting of Lyari Town Karachi, Pakistan.

BACKGROUND: This study aimed to evaluate the parental acceptance of Typhoid Conjugate Vaccine (TCV) and to determine the predictors of TCV vaccination status among children in an outbreak setting of extensively drug resistant (XDR) typhoid fever in Karachi, Pakistan. METHODS: A cross-sectional survey using the WHO recommended rapid vaccine coverage assessment technique was conducted. Out of 11, four union councils (UCs) in Lyari Town were randomly selected. A parent or primary caretaker from the eligible household was interviewed. Data were collected using a locally validated vaccine attitudes scale (VAS). Sum of scores was calculated for VAS. A higher score denoted negative attitudes and perceptions regarding TCV and vice versa. Multivariable logistic regression was performed to determine the predictors of TCV vaccination status. RESULTS: Based on the 14-item parental VAS, 78.0 % of the parents had a score between 0 to <40 and 22 % had a score ≥40. VAS score of <40 was significantly associated with higher odds of receiving TCV during the campaign setting (adjusted Odds Ratio (aOR): 1.30; 95 % Confidence Interval (CI): 1.02, 1.66). The odds of receiving TCV vaccination were higher among children whose parents were aware of the ongoing vaccination campaign in the area (aOR: 4.57; 95 % CI: 2.93, 7.12) and expressed willingness to get their child vaccinated against typhoid fever (aOR: 2.54; 95 % CI: 1.82, 3.55). CONCLUSION: Parental awareness of the ongoing vaccination campaign, positive perception and attitudes towards vaccine were found to be significantly associated with TCV vaccination among children. Appropriately structured pre-vaccination awareness campaigns focused on childhood vaccination targeted towards parents are necessary to improve parental awareness, attitude and behavior towards vaccination.

Exploring the beliefs and experiences with regard to COVID-19 vaccine hesitancy and acceptance in a slum of Karachi, Pakistan.

The COVID-19-related misinformation and vaccine hesitancy is a widespread global concern and a recognized public health problem in Pakistan. The current research sought to explore the beliefs and experiences with regard to COVID-19, including vaccine hesitancy and acceptance, in a slum of Karachi, Pakistan. This study used an interpretivist epistemological approach for data collection and employed in-depth interviews (IDIs) and focus group discussions (FGDs) to explore the themes of interest. IDIs and FDGs were conducted in the local language (Pashtu) and Urdu, using semi-structured interview guides. A hybrid thematic analysis approach (use of both inductive and deductive coding) was used to analyze the data. We identified two key themes: the first related to vaccine hesitancy and refusal and included the role of personal belief systems, vaccine mistrust and public perceptions in hesitancy; the second related to vaccine acceptance and included knowledge and awareness about the vaccine and trusted sources of information. Religious beliefs and cultural norms influenced attitudes toward COVID-19 and vaccination. This study also found that awareness about the COVID-19 vaccine in this sample was influenced by sex, educational status and socioeconomic status. Participants with good health literacy and those from healthcare backgrounds were more likely to share views that indicated vaccine acceptance. The findings of this study are being used to co-design a comprehensive intervention to dispel COVID-19 misinformation and vaccine hesitancy across a range of stakeholders such as youths, community leaders, family members, faith leaders, schools and community-based local organizations in Pakistan.

This study explored the beliefs and experiences of the COVID-19 vaccine, including hesitancy and acceptance toward vaccinations, in a slum of Karachi, Pakistan. The findings of this study highlight that hesitancy was linked to personal belief systems, vaccine mistrust and public perceptions. In contrast, vaccine acceptance was linked to knowledge and awareness about the vaccine and trusted sources of information. This research identifies a clear need for co-designed health communication for vaccines to design and deliver people-centered interventions to dispel the COVID-19 misconceptions and vaccine hesitancy.

Field evaluation of typhoid conjugate vaccine in a catch-up campaign among children aged 9 months to 15 years in Sindh, Pakistan.

BACKGROUND: Typhoid conjugate vaccine (TCV) has recently been introduced in the expanded program for immunization (EPI) in Pakistan. Before its introduction in routine immunization, a onetime catchup campaign among children 9 months to 15 years old was conducted in November 2019. We performed field evaluation of TCV against culture confirmed Salmonella Typhi (S. Typhi) among 9 months to 15 years old children during the catch up campaign in Karachi and Hyderabad. METHODS: A rapid assessment of blood culture confirmed S. Typhi was performed. Age eligible cases of culture confirmed S. Typhi were identified from the laboratory networks of Aga Khan University Hospital Karachi and Hyderabad, Kharadar General Hospital Karachi, and Liaqat University of Medical & Health Sciences (LUMHS) Hyderabad. Information on sociodemographic, typhoid vaccination history and antimicrobial resistance was collected using a structured questionnaire. Patient medical records and lab reports were also reviewed to collect information on diagnosis and antimicrobial susceptibility information. Information about the population vaccination coverage during catch-up campaign was obtained from the provincial EPI office. Field performance of TCV in catchup campaign was measured by calculating the effectiveness using rapid screening method which is less resource-intensive technique of calculating vaccine effectiveness (VE). RESULTS: Overall, 968 culture confirmed typhoid cases were enrolled. Among them, 82% (793/968) were from Karachi and 18% (175/968) from Hyderabad. The average age of the participants was 5.68 years, and 54% (523/968) were male. 6% (62/968) of the culture confirmed S. Typhi cases were multidrug resistant (MDR), and 61% (586/968) were extensively drug resistant (XDR). The VE using the TCV coverage data provided by EPI was 98%. CONCLUSION: TCV is effective against culture confirmed S. Typhi among children aged 9 months to 15 years in the catch-up campaign setting. While typhoid vaccination can significantly decrease the burden of typhoid disease, improvements in sanitation and hygiene are necessary for the prevention of spread of enteric fever. Longer term follow up will be needed to assess the duration of protection and requirement for booster doses of TCV.

Estimating typhoid incidence from community-based serosurveys: a multicohort study.

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.

Risk Factors Associated with Extensively Drug-Resistant Typhoid in an Outbreak Setting of Lyari Town Karachi, Pakistan.

Typhoid fever is endemic in Pakistan, with high annual incidence rates. An outbreak of extensively drug-resistant typhoid fever that first started in the Hyderabad District, Sindh Province, in November 2016 immediately spread to the entire province. We conducted an age-matched case-control study to assess the risk factors of typhoid fever in an outbreak setting of Lyari Town, Karachi. We enrolled 82 patients with blood culture-confirmed Salmonella typhi between August 2019 to December 2019, and 82 age-matched hospital and 164 age-matched community control subjects. In a matched conditional logistic regression model, consumption of meals outside the home more than once per month was associated significantly with developing culture-confirmed typhoid fever compared with no consumption of food outside the home (odds ratio, 4.11). Hygiene of the environment in which food is prepared, practices of adult food handlers, access to clean water, and food legislation play significant roles in the spread of typhoid fever.