Comprehensive profiling of social mixing patterns in resource poor countries: a mixed methods research protocol.

Background: Low-and-middle-income countries (LMICs) bear a disproportionate burden of communicable diseases. Social interaction data inform infectious disease models and disease prevention strategies. The variations in demographics and contact patterns across ages, cultures, and locations significantly impact infectious disease dynamics and pathogen transmission. LMICs lack sufficient social interaction data for infectious disease modeling. Methods: To address this gap, we will collect qualitative and quantitative data from eight study sites (encompassing both rural and urban settings) across Guatemala, India, Pakistan, and Mozambique. We will conduct focus group discussions and cognitive interviews to assess the feasibility and acceptability of our data collection tools at each site. Thematic and rapid analyses will help to identify key themes and categories through coding, guiding the design of quantitative data collection tools (enrollment survey, contact diaries, exit survey, and wearable proximity sensors) and the implementation of study procedures.We will create three age-specific contact matrices (physical, nonphysical, and both) at each study site using data from standardized contact diaries to characterize the patterns of social mixing. Regression analysis will be conducted to identify key drivers of contacts. We will comprehensively profile the frequency, duration, and intensity of infants' interactions with household members using high resolution data from the proximity sensors and calculating infants' proximity score (fraction of time spent by each household member in proximity with the infant, over the total infant contact time) for each household member. Discussion: Our qualitative data yielded insights into the perceptions and acceptability of contact diaries and wearable proximity sensors for collecting social mixing data in LMICs. The quantitative data will allow a more accurate representation of human interactions that lead to the transmission of pathogens through close contact in LMICs. Our findings will provide more appropriate social mixing data for parameterizing mathematical models of LMIC populations. Our study tools could be adapted for other studies.

Exploring terminology for puerperal sepsis and its symptoms in urban Karachi, Pakistan to improve communication, care-seeking, and illness recognition.

Puerperal sepsis is an important cause of maternal morbidity and mortality in developing countries. Awareness of local terminology for its signs and symptoms may improve communication about this illness, what actions to take when symptoms appear, timely care seeking, and clinical outcomes. This formative research aimed to improve recognition and management of postpartum sepsis in Pakistan by eliciting local terms used for postpartum illnesses and symptoms. We conducted 32 in-depth interviews with recently delivered women, their relatives, traditional birth attendants, and health care providers to explore postpartum experiences. Terms for symptoms and illness are used interchangeably (i.e. bukhar, the Urdu word for fever), many variations exist for the same term, and gradations of severity for each term as not associated with different types of illnesses. The lack of a designated term for postpartum sepsis in Urdu delays care-seeking and proper diagnosis, particularly at the community level. Ideally, a common lexicon for symptoms and postpartum sepsis would be developed but this may not be feasible or appropriate given the nature of the Urdu language and local understandings of postpartum illness. These insights can inform how we approach educational campaigns, the development of clinical algorithms that focus on symptoms, and counselling protocols.

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.

The COVID-19 vaccination acceptance/hesitancy rate and its determinants among healthcare workers of 91 Countries: A multicenter cross-sectional study.

The aim of this study was to investigate the COVID-19 vaccination acceptance rate and its determinants among healthcare workers in a multicenter study. This was a cross-sectional multi-center survey conducted from February 5 to April 29, 2021. The questionnaire consisted of 26 items in 6 subscales. The English version of the questionnaire was translated into seven languages and distributed through Google Forms using snowball sampling; a colleague in each country was responsible for the forward and backward translation, and also the distribution of the questionnaire. A forward stepwise logistic regression was utilized to explore the variables and questionnaire factors tied to the intention to COVID-19 vaccination. 4630 participants from 91 countries completed the questionnaire. According to the United Nations Development Program 2020, 43.6 % of participants were from low Human Development Index (HDI) regions, 48.3 % high and very high, and 8.1 % from medium. The overall vaccination hesitancy rate was 37 %. Three out of six factors of the questionnaire were significantly related to intention to the vaccination. While 'Perceived benefits of the COVID-19 vaccination' (OR: 3.82, p-value<0.001) and 'Prosocial norms' (OR: 5.18, p-value<0.001) were associated with vaccination acceptance, 'The vaccine safety/cost concerns' with OR: 3.52, p-value<0.001 was tied to vaccination hesitancy. Medical doctors and pharmacists were more willing to take the vaccine in comparison to others. Importantly, HDI with OR: 12.28, 95 % CI: 6.10-24.72 was a strong positive determinant of COVID-19 vaccination acceptance. This study highlighted the vaccination hesitancy rate of 37 % in our sample among HCWs. Increasing awareness regarding vaccination benefits, confronting the misinformation, and strengthening the prosocial norms would be the primary domains for maximizing the vaccination coverage. The study also showed that the HDI is strongly associated with the vaccination acceptance/hesitancy, in a way that those living in low HDI contexts are more hesitant to receive the vaccine.

Effectiveness of typhoid conjugate vaccine against culture-confirmed Salmonella enterica serotype Typhi in an extensively drug-resistant outbreak setting of Hyderabad, Pakistan: a cohort study.

BACKGROUND: Salmonella enterica serotype Typhi (S Typhi) is a major public health problem in low-income and middle-income countries. We aimed to investigate the effectiveness and impact of the typhoid conjugate vaccine Typbar-TCV against S Typhi among children in an outbreak setting of extensively drug-resistant (XDR) S Typhi in Pakistan. METHODS: This cohort study was done from Feb 21, 2018, to Dec 31, 2019. A census survey of all households located in the Qasimabad and Latifabad subdistricts of Hyderabad, Pakistan, was done at baseline, and 174 005 households were registered in the census. The Typbar-TCV immunisation campaign was initiated at temporary vaccination centres and 207 000 children aged 6 months to 10 years were vaccinated from Feb 21, 2018, to Dec 31, 2018. Social mobilisers informed parents about the vaccination process. Vaccination records were maintained electronically and linked with the household census surveys. Active surveillance for suspected and blood-culture-confirmed S Typhi was established in hospitals, clinics, and laboratories to assess the following outcomes: cases of suspected typhoid fever, culture-confirmed S Typhi, and antimicrobial resistance. An age-stratified cohort of 1100 vaccinated children was randomly selected from the vaccination registry, tested for Vi-IgG antibodies (data not reported), and followed up fortnightly (via telephone calls or household visits) until Dec 31, 2019, for ascertainment of outcomes during the study period. 20 847 vaccinated and unvaccinated children were randomly selected from the census registry as a quality control cohort and followed up from Oct 1 to Dec 31, 2019, for ascertainment of outcomes. Vaccine effectiveness against suspected, culture-confirmed, and XDR S Typhi was calculated. FINDINGS: 23 407 children from the census registry and surveillance system were included in the vaccine effectiveness analysis. 13 436 (57·4%) children were vaccinated, 12 214 (52·2%) were male, and 10 168 (43·4%) were aged 6-59 months. 5378 (23·0%) of 23 407 children had suspected S Typhi, among whom 775 (14·4%) had culture-confirmed S Typhi and 361 (68·6%) of 526 had XDR S Typhi. Vaccine effectiveness was 55% (95% CI 52-57) against suspected S Typhi (regardless of culture confirmation), 95% (93-96) against culture-confirmed S Typhi, and 97% (95-98) against XDR S Typhi. INTERPRETATION: Typbar-TCV is effective in protecting children against S Typhi infection in an outbreak setting, and was able, with moderate deployment, to curtail a major XDR S Typhi outbreak in a densely populated setting. The vaccine shows efficacy against S Typhi irrespective of antimicrobial resistance. FUNDING: Bill & Melinda Gates Foundation.

Ceftriaxone-resistant Salmonella Typhi Outbreak in Hyderabad City of Sindh, Pakistan: High Time for the Introduction of Typhoid Conjugate Vaccine.

BACKGROUND: The Aga Khan University clinical microbiology laboratory identified an outbreak of ceftriaxone-resistant Salmonella Typhi in Hyderabad, Pakistan, through antimicrobial resistance surveillance. An outbreak investigation was carried out to identify the risk factors and institute control measures. Here we report the preliminary findings of this outbreak investigation, using data collected from 30 November 2016 to 28 March 2017. METHODS: The design for the investigation was a case-control study that included identification of culture-proven ceftriaxone-resistant S. Typhi cases, suspected cases from the households or neighborhood of the confirmed cases, and enrollment of controls matched by age to identify the risk factors. Data were collected through face-to-face interviews using a structured questionnaire. Blood cultures were obtained from all suspected cases. Drinking water samples from each household of cases and controls were obtained for microbiological testing. Geographic Information System coordinates were obtained for all cases and controls. RESULTS: Only 2 subdistricts of Hyderabad (Latifabad and Qasimabad) were affected. A total of 101 confirmed cases of ceftriaxone-resistant S. Typhi had been reported in 4 months with the first case reported on 30 November 2016. Median age was 48 (interquartile range, 29-84) months. The majority (60% [61/101]) of the cases were 6-60 months old. More than half (56% [57/101]) of the cases were male. About 60% of the cases were admitted to hospital and treated as inpatient. More than half (57/101) of the patients developed complications related to typhoid. CONCLUSIONS: Community awareness was raised regarding chlorination of drinking water and sanitation measures in Hyderabad. These efforts were coordinated with the municipal water and sewage authority established to improve chlorination at processing plants and operationalize fecal sludge treatment plants. Outbreak investigation and control efforts have continued. Immunization of children with typhoid conjugate vaccine within Hyderabad city is planned.

Assessment and Validation of Syndromic Case Definitions for Respiratory Syncytial Virus Testing in a Low Resource Population.

Standardized case definitions are needed in decision-making regarding respiratory syncytial virus control strategies, including vaccine evaluation. A syndromic case definition comprising of "wheeze or apnea or cyanosis" could be useful for community-based surveillance of moderate respiratory syncytial virus infection among young infants particularly in resource-limited settings. However, this definition showed modest specificity (29.2%-49.6%), indicating that community-based surveillance may need augmentation with other data.

Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan.

Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and ninety-five percent of rotavirus deaths occur in Africa and Asia. Rotavirus vaccines (RVV) can dramatically reduce RV deaths, but have low efficacy in low-income settings where they are most needed. The intestinal microbiome may contribute to this decreased RVV efficacy. This pilot study hypothesizes that infants' intestinal microbiota composition correlates with RVV immune responses and that RVV responders have different gut microbiota as compared to non-responders. We conducted a nested, matched case-control study comparing the pre-vaccination intestinal microbiota composition between 10 6-week old Pakistani RVV-responders, 10 6-week old Pakistani RVV non-responders, and 10 healthy Dutch infants.  RVV response was defined as an Immunoglobulin A of ≥20 IU/mL following Rotarix™(RV1) vaccination in an infant with a pre-vaccination IgA<20. Infants were matched in a 1:1 ratio using ranked variables: RV1 dosing schedule (6/10/14; 6/10; or 10/14 weeks), RV season, delivery mode, delivery place, breastfeeding practices, age and gender. Fecal microbiota analysis was performed using a highly reproducible phylogenetic microarray. RV1 response correlated with a higher relative abundance of bacteria belonging to Clostridium cluster XI and Proteobacteria, including bacteria related to Serratia and Escherichia coli. Remarkably, abundance of these Proteobacteria was also significantly higher in Dutch infants when compared to RV1-non-responders in Pakistan. This small but carefully matched study showed the intestinal microbiota composition to correlate with RV1 seroconversion in Pakistan infants, identifying signatures shared with healthy Dutch infants.

Impact of maternal respiratory infections on low birth weight - a community based longitudinal study in an urban setting in Pakistan.

BACKGROUND: The health of mothers and their newborns is intricately related. The weight of the infant at birth is a powerful predictor of infant growth and survival, and is considered to be partly dependent on maternal health and nutrition during pregnancy. We conducted a longitudinal study in an urban community within Karachi to determine maternal predictors of newborn birth weight. METHODS: Four hundred pregnant women were enrolled in the study during the period 2011-2013. Data related to symptoms of acute respiratory illness (fever, cough, difficulty breathing, runny nose, sore throat, headache, chills, and myalgia/lethargy) in the pregnant women were collected weekly until delivery. Birth weight of the newborn was recorded within 14 days of delivery and the weight of <2.5 kg was classified as low birth weight (LBW). RESULTS: A total of 9,853 symptom episodes were recorded of fever, cough, difficulty breathing, runny nose, sore throat, headache, chills, myalgias/lethargy in the enrolled pregnant women during the study. Out of 243 pregnant women whose newborns were weighed within 14 days of birth, LBW proportion was 21% (n = 53). On multivariate analysis, independent significant risk factors noted for delivering LBW babies were early pregnancy weight of < 57.5 kg [odds ratio adjusted (ORadj) = 5.1, 95% CI: (1.3, 19.9)] and gestational age [ORadj = 0.3, 95% CI (0.2, 0.7) for every one week increase in gestational age]. Among mothers with high socioeconomic status (SES), every 50-unit increase in the number of episodes of respiratory illness/100 weeks of pregnancy had a trend of association with an increased risk of delivering LBW infants [ORadj = 1.7, 95% CI: (1.0, 3.1)]. However, among mothers belonging to low SES, there was no association of the number of episodes of maternal respiratory illness during pregnancy with infants having LBW [ORadj = 0.9, 95% CI: (0.5, 3.5)]. CONCLUSIONS: While overall respiratory illnesses during pregnancy did not impact newborn weight in our study, we found this trend in the sub-group of mothers belonging to the higher SES. Whether this is because in mothers belonging to lower SES, the effects of respiratory illnesses were overshadowed by other risk factors associated with poverty need to be further studied.

Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial.

BACKGROUND: Infection in young infants is a major cause of morbidity and mortality in low-middle income countries, with high neonatal mortality rates. Timely case management is lifesaving, but the current standard of hospitalization for parenteral antibiotic therapy is not always feasible. Alternative, simpler antibiotic regimens that could be used in outpatient settings have the potential to save thousands of lives. METHODS: This trial aims to determine whether 2 simplified antibiotic regimens are equivalent to the reference therapy with 7 days of once-daily (OD) intramuscular (IM) procaine penicillin and gentamicin for outpatient management of young infants with clinically presumed systemic bacterial infection treated in primary health-care clinics in 5 communities in Karachi, Pakistan. The reference regimen is close to the current recommendation of the hospital-based intravenous ampicillin and gentamicin therapy for neonatal sepsis. The 2 comparison arms are (1) IM gentamicin OD and oral amoxicillin twice daily for 7 days; and (2) IM penicillin and gentamicin OD for 2 days, followed by oral amoxicillin twice daily for 5 days; 2250 "evaluable" infants will be enrolled. The primary outcome of this trial is treatment failure (death, deterioration or lack of improvement) within 7 days of enrollment. Results are expected by early 2014. DISCUSSION: This trial will determine whether simplified antibiotic regimens with fewer injections in combination with high-dose amoxicillin are equivalent to 7 days of IM procaine penicillin and gentamicin in young infants with clinical severe infection. Results will have program and policy implications in countries with limited access to hospital care and high burden of neonatal deaths.