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.

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.

One-Year Decline of Poliovirus Antibodies Following Fractional-Dose Inactivated Poliovirus Vaccine.

BACKGROUND: Fractional dose (one-fifth of full intramuscular dose) of inactivated poliovirus vaccine (fIPV) administered intradermally is used as IPV dose-sparing strategy. We compared the rate of decline of poliovirus antibodies (PVA) in recipients of 2 doses of fIPV or IPV. METHODS: A community-based randomized controlled trial was conducted in Karachi, Pakistan. Children aged 14 weeks were randomized into fIPV or full IPV (study arms A, B) and received 1 vaccine dose at age 14 weeks and 1 at age 9 months. PVAs were measured at age 14, 18 weeks and 10, 21 months. RESULTS: Seroprevalence of poliovirus type 2 antibodies in 170/250 (68%) children after 2 IPV or fIPV doses at age 10 months in A and B reached 100% vs 99% (P = .339), and at 21 months, 86% vs 67% (P = .004). Between age 10 and 21 months antibody log2 titers dropped from ≥ 10.5 to 6.8 in A and from 9.2 to 3.7 in B. CONCLUSIONS: There was a significant decline in antibody titers 12 months following the second IPV dose. The slope of decline was similar for full IPV and fIPV recipients. The results provide further evidence that fIPV is a viable option for IPV dose-sparing. CLINICAL TRIALS REGISTRATION: NCT03286803.

Detection of typhoid carriers by duodenal fluid culture in a tertiary care hospital, Karachi: A cross-sectional study.

We aimed to detect typhoid carriers by performing duodenal fluid culture in patients in a tertiary care hospital in Pakistan. A cross-sectional study was conducted during 2017 at the Aga Khan University Hospital, Karachi. Patients who underwent upper gastrointestinal endoscopy were included. Participants were interviewed, and duodenal fluid samples were taken for culture to detect Salmonella typhi (S. typhi) and paratyphi. A polymerase chain reaction on 100 randomly selected sub-samples was also conducted. A total of 477 participants were enrolled. The mean age was 42.4±15.5 years. History of typhoid fever was present in 73 (15.3%) participants. Out of the 477 duodenal fluid cultures tested for various micro-organisms, 250 (52.4%) were positive. Neither S. typhi nor paratyphi were isolated. S. typhi was also not detected by PCR. To better detect S. typhi carriage in general population, future studies should target people with gall bladder diseases and screen them using culture and PCR based methods.

Infectious Etiologies of Intussusception Among Children <2 Years Old in 4 Asian Countries.

BACKGROUND: The etiology of intussusception, the leading cause of bowel obstruction in infants, is unknown in most cases. Adenovirus has been associated with intussusception and slightly increased risk of intussusception with rotavirus vaccination has been found. We conducted a case-control study among children <2 years old in Bangladesh, Nepal, Pakistan, and Vietnam to evaluate infectious etiologies of intussusception before rotavirus vaccine introduction. METHODS: From 2015 to 2017, we enrolled 1-to-1 matched intussusception cases and hospital controls; 249 pairs were included. Stool specimens were tested for 37 infectious agents using TaqMan Array technology. We used conditional logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of each pathogen associated with intussusception in a pooled analysis and quantitative subanalyses. RESULTS: Adenovirus (OR, 2.67; 95% CI, 1.75-4.36) and human herpes virus 6 (OR, 3.50; 95% CI, 1.15-10.63) were detected more frequently in cases than controls. Adenovirus C detection <20 quantification cycles was associated with intussusception (OR, 18.59; 95% CI, 2.45-140.89). Wild-type rotavirus was not associated with intussusception (OR, 1.07; 95% CI, 0.52-2.22). CONCLUSIONS: In this comprehensive evaluation, adenovirus and HHV-6 were associated with intussusception. Future research is needed to better understand mechanisms leading to intussusception, particularly after rotavirus vaccination.

Healthcare Utilization Patterns for Acute Febrile Illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project.

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.

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.

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.

Diabetes conversation map - a novel tool for diabetes management self-efficacy among type 2 diabetes patients in Pakistan: a randomized controlled trial.

BACKGROUND: This study aimed to measure the effect of diabetes education using the novel method of "diabetes conversation map (DCM)" as compared to routine counselling (RC) on diabetes management self-efficacy (DMSE) among patients living with type 2 diabetes in Karachi, Pakistan. METHODS: A parallel arm randomized controlled trial among patients with type 2 diabetes aged 30-60 years, with HbA1c > 7%, diagnosed for at least 5 yrs., was conducted at the national institute of diabetes and endocrinology in Karachi, Pakistan. A total 123 type 2 diabetes patients were randomized into DCM (n = 62) or RC (n = 61). Four weekly diabetes control sessions of 40 min each using the DCM or RC was provided. DMSE was measured using a validated Urdu language DMSE tool at baseline and after three months of the randomization. Change in DMSE and HbA1c levels within groups (pre-post) and between the groups after 3 months of enrollment was compared. RESULTS: Baseline characteristics except HbA1c were similar between the two arms. After 3 months of enrollment, there was no change in the DMSE score in the RC arm however, significant increase in DMSE score was noted in the DCM arm (P = < 0.001). The average difference (95% confidence interval) in DMSE score between the DCM and RC arm was 33.7(27.3, 40.0; p = < 0.001) after 3 months of the enrollment. Difference in HbA1c within groups was not significant. CONCLUSIONS: DCM significantly improved DMSE among type 2 diabetes patients in a developing country setting like Pakistan. Healthcare workers caring for type 2 diabetes patients need to be trained on DCM to effectively utilize this novel tool for educating diabetes patients. TRIAL REGISTRATION: This trial was prospectively registered. ClinicalTrials.gov Identifier: NCT03747471. Date of registration: Nov 20. 2018.

The effectiveness of Janus kinase inhibitors in treating atopic dermatitis: A systematic review and meta-analysis.

Primary studies have presented conflicting results on the efficacy of Janus kinase (JAK) inhibitors in treating atopic dermatitis. Hence, it is important to determine the summary effect of JAK inhibitors in order to guide the clinical application of this potentially beneficial drug. To determine the efficacy of JAK inhibitors in treating atopic dermatitis in all age groups. A systematic review with meta-analyses of randomized controlled trials (RCTs) reporting on the effect of JAK inhibitors on the signs and symptoms of atopic dermatitis were conducted. Six electronic databases, registries, and search engines (PubMed, Cochrane Central Register of Controlled Trials [CENTRAL], Google Scholar, ScienceDirect, Clinical.gov, and WHO ICTRP) were searched from inception to September, 2019. The search terms include "atopic dermatitis," "eczema," and "Janus kinase inhibitor." The search was restricted to humans. A total of 413 studies were identified through the database search and hand-searching. After the selection process, five RCTs were included in this systematic review. A meta-analysis of three studies showed that JAK inhibitors were effective in reducing Eczema Area and Severity Index (P = .0001) and pruritus scores (P = .0001). JAK inhibitors appear to be effective in treating atopic dermatitis. Future studies should aim to evaluate its cost-effectiveness and availability to patients especially in developing countries.

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.

Effect of diabetic counseling based on conversation map as compared to routine counseling on diabetes management self-efficacy and diabetic distress among patients with diabetes in Pakistan: a randomized controlled trial (study protocol).

BACKGROUND: Novel interactive and pictorial health education tool named Diabetes Conversation Map (DCM) might be effective for the improvement of diabetes management self-efficacy (DMSE) and diabetes distress (DD) among diabetic patients in lower middle-income setting. This study protocol will assess the effectiveness of DCM as compared to routine care (RC) to improve DMSE, decrease DD and glycated hemoglobin (HbA1c) among patients with type 2 diabetes (T2DM). METHODS: This will be two arms randomized controlled trial, conducted at national institute of diabetes and endocrinology (NIDE) in Karachi, Pakistan. A sample of 120 T2DM patients of age 30-60 years with suboptimal diabetes control will be screened through eligibility criteria and DD screening tool. Patients who fulfill the eligibility criteria and have diabetes distress will be randomized into interventional and control arm. The intervention arm will receive four education sessions (40 min each) using DCM for 4 weeks duration of enrollment. Controlled arm will receive RC. DMSE and DD will be measured using the validated Likert tools at baseline and after 3 months of enrollment. Latest results of HbA1c will be retrieved from the respective medical record files at baseline and 3 months. Change in DMSE, DD scores and HbA1c levels within groups (pre-post) and between the groups after 3 months of enrollment will be compared. Multivariable linear regression will be conducted to adjust for any potential confounders. DISCUSSION: In a study in UK, 70% of the patients with diabetes reported DCM had helped them in controlling their diabetes and recommended this method to teach other patients with diabetes also. In China, a study found that patients with diabetes who received DCM based education had significantly lower DD and significantly higher diabetes empowerment score after six months of the intervention as compared to the traditional counselling. A cross sectional study conducted in Pakistan also demonstrated that teaching based on DCM was useful in improving the knowledge, attitude and practices of patients with T2DM. Besides, no other study has evaluated the effectiveness of these novel tools for DMSE and diabetes distress DD in well-designed, sufficiently powered clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03747471 . Date of registration: Nov 20. 2018. Version and Date of Protocol: Version 1, IRB Approval date 28 June 2018.

Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP): An Overview and Lessons Learned.

Objective: The objective of Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP), a multiphase surveillance study characterizing the burden of disease in South Asia, was to inform data collection for prospective surveillance and to capture clinical aspects of disease. Methods: Through a retrospective record review conducted at hospitals in Bangladesh, India, Nepal, and Pakistan, we examined laboratory and clinical records to assess the culture positivity rate for Salmonella Typhi and Salmonella Paratyphi, age and sex distribution, and antimicrobial susceptability in each country. Results: Of all blood cultures performed in Bangladesh, India, Nepal, and Pakistan, 1.5%, 0.43%, 2%, and 1.49%, respectively, were positive for S. Typhi and 0.24%, 0.1%, 0.5%, and 0.67%, respectively, were positive for S. Paratyphi. A higher proportion of laboratory-confirmed infections in Bangladesh and Pakistan were aged ≤5 years, while India and Nepal had a higher proportion of participants aged 15-25 years. In all countries, the sex of the majority of participants was male. The majority of isolates in all countries were resistant to fluoroquinolones, with a high proportion also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Discussion: Enteric fever remains endemic in South Asia. Data generated by this study can help inform strategies for implementation and evaluation of prevention and control measures.

A Retrospective Study of Laboratory-Based Enteric Fever Surveillance, Pakistan, 2012-2014.

Introduction: The Surveillance for Enteric Fever in Asia Project (SEAP) is a multisite surveillance study designed to capture morbidity and mortality burden of enteric fever (typhoid and paratyphoid) in Bangladesh, Nepal, and Pakistan. We aim to describe enteric fever disease burden, severity of illness, and antimicrobial resistance trends in Pakistan. Methods: In this retrospective, cross-sectional study, laboratory records of hospitalized patients who received a blood culture in any of 3 Aga Khan University hospitals in Karachi and Hyderabad, Pakistan, from 2012 to 2014 were reviewed. A case was defined as having a positive blood culture for Salmonella Typhi (S. Typhi) or Salmonella Paratyphi (S. Paratyphi). Antimicrobial sensitivity patterns were characterized for all S. Typhi and S. Paratyphi isolates. Medical records were available for abstraction (demographics, clinical features, complications) only among hospitalized cases. Results: Of the 133017 blood cultures completed during the study period, 2872 (2%) were positive-1979 (69%) for S. Typhi and 893 (31%) for S. Paratyphi. Fluoroquinolone resistance was present in >90% of both the S. Typhi and the S. Paratyphi isolates; almost none of the isolates were resistant to cephalosporins. Multidrug resistance (resistance to ampicillin, chloramphenicol, and cotrimoxazole) was observed in 1035 (52%) S. Typhi isolates and 14 (2%) S. Paratyphi isolates. Among S. Typhi and S. Paratyphi isolates, 666 (23%) were linked to hospitalized patients with medical records. Of the 537 hospitalized S. Typhi cases, 280 (52%) were aged 5-15 years, 133 (25%) were aged 2-4 years, 114 (21%) were aged >15 years, and 10 (2%) were aged 0-1 years. Among the 129 hospitalized S. Paratyphi cases, 73 (57%) were aged >15 years, 41 (32%) were aged 5-15 years, 13 (10%) were aged 2-4 years, and 2 (2%) were aged 0-1 years. Significant differences in symptomology between S. Typhi and S. Paratyphi cases were observed for nausea/vomiting, diarrhea, loss of appetite, and headache. Leukopenia, thrombocytopenia, and encephalopathy were the most commonly reported complications among enteric fever cases. No deaths were reported. Conclusion: Evidence of high antimicrobial resistance levels and disease severity support the need for continued surveillance and improved diagnostics for typhoid. Further prospective studies on vaccination as a tool for prevention of enteric fever in Pakistan are needed to inform disease intervention strategies.

RSV associated hospitalizations in children in Karachi, Pakistan: Implications for vaccine prevention strategies.

Major progress is being made in vaccines against Respiratory Syncytial Virus (RSV), with multiple vaccine candidates currently in the clinical phase of development. Making an investment case for public sector financing of RSV vaccine will require estimation of burden, cost-effectiveness, and impact. The aim of this study is to determine the proportion, age distribution and clinical spectrum of RSV associated hospitalizations in children in Karachi, Pakistan. A three years prospective study was conducted at the Aga Khan University Hospital in Karachi, a city of 20 million in south Pakistan, from August 2009 to June 2012. Children less than five years old admitted with acute respiratory infections (ARI) were enrolled. Throat swabs were collected and tested for RSV using real-time PCR. Multivariable log binomial regression analysis was performed to identify the associated factors of RSV infection. Out of 1150 children enrolled, RSV was detected among 223 (19%). Highest rate of RSV detection was in young infants less than 3 months of age (48/168, 29%), which accounted for 22% of all RSV detected. Most common diagnosis in RSV positive infants (<12 months of age) was bronchiolitis followed by pneumonia, while in older children between the ages of one and 5 years of age, pneumonia and asthma were the most common diagnosis. Although identified year-round, RSV was most prevalent from August to October with peak in September, coinciding with the rainy season. This study identified RSV to be independently associated with younger age (P = 0.036), rainy season (P < 0.001), post-tussive emesis (P = 0.008), intubation (P = 0.003), and discharge diagnosis of bronchiolitis (P = 0.004). Vaccines against RSV that target this age group are likely to yield remarkable benefit.

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.

Longevity of serologic responses following a single dose of typhoid conjugate vaccine among children living with HIV in Pakistan: A prospective cohort study.

BACKGROUND: This study aimed to assess the longevity of serologic response and seroconversion rates at several time points following TCV vaccination among children living with HIV aged 6 months to 15 years in Pakistan. METHODS: From November 20, 2020, to January 2, 2021; 336 children were enrolled and followed up prospectively for 12 months. Blood samples were collected before the administration of TCV and at 4-6 weeks, 6 months, and 1 year after administration of a single dose (0.5 ml) of intramuscular Typbar TCV®. Samples were analyzed for anti-Vi-IgG antibodies using ELISA. Geometric mean titers (GMTs), seroconversion rates (fourfold rise in anti-Vi-IgG from baseline), and factors associated with sustained seroconversion at 1 year were evaluated using generalized linear mixed models. FINDINGS: The seroconversion rates were significantly lower in children aged 6 months to 5 years compared to children > 5 years; (127/216 (58·8%)) versus (81/111 (73·0%)) at 6 months and (110/217 (50·7%)) versus (78/109 (71·6%)) at 1 year, only two-third; 188/326 (57·7%) remained seroconverted at 1 year. The GMTs (95 % CI) were significantly lower in children aged 6 months to 5 years compared to children > 5 years, 9·6 (7·6, 12·0) versus 28·9 (20·2, 41·4) at 6 months, and 6·6 (5·4, 8·0) versus 23·1 (16·4, 32·5) at 1 year time point. The odds of sustained seroconversion significantly decreased with time (adjusted odds ratio (aOR): 0·232; 95 % CI: 0·136,0·396). The odds of sustained seroconversion following 1 year of TCV vaccination were significantly higher among children with non-severe HIV clinical disease (aOR: 10·6; 95 % CI: 1·5, 73·9) and children in elder age group (aOR: 7·45; 95 % CI: 11·2, 47·0). CONCLUSIONS: There was a decline in seroconversion after one year of TCV in children living with HIV. The decline was significant in children with severe or advanced HIV disease. A significant decrease in seroconversion rates was observed among children living with HIV following one year of TCV administration.

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.

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.

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.