Young Infant Mortality Associated with Preterm and Small-for-Gestational-Age Births in Rural Bangladesh: A Prospective Cohort Study.

OBJECTIVE: To assess the relative risk of mortality in infants born preterm and small for gestational age (SGA) during the first and second months of life in rural Bangladesh. STUDY DESIGN: We analyzed data from a cohort of pregnant women and their babies in Sylhet, Bangladesh, assembled between 2011 and 2014. Community health workers visited enrolled babies up to 10 times from birth to age 59 days. Survival status was recorded at each visit. Gestational age was estimated from mother's reported last menstrual period. Birth weights were measured within 72 hours of delivery. SGA was defined using the INTERGROWTH-21st standard. We estimated unadjusted and adjusted hazard ratios (HRs) and corresponding 95% CIs for babies born preterm and SGA separately for the first and second month of life using bivariate and multivariable weighted Cox regression models. RESULTS: The analysis included 17 643 singleton live birth babies. Compared with infants born at term-appropriate for gestational age, in both unadjusted and adjusted analyses, infants born preterm-SGA had the greatest risk of death in the first (HR 13.25, 95% CI 8.65-20.31; adjusted HR 12.05, 95% CI 7.82-18.57) and second month of life (HR 4.65, 95% CI 1.93-11.23; adjusted HR 4.1, 95% CI 1.66-10.15), followed by infants born preterm-appropriate for gestational age and term-SGA. CONCLUSIONS: The risk of mortality in infants born preterm and/or SGA is increased and extends through the second month of life. Appropriate interventions to prevent and manage complications caused by prematurity and SGA could improve survival during and beyond the neonatal period.

Neonatal mortality risk of vulnerable newborns by fine stratum of gestational age and birthweight for 230 679 live births in nine low- and middle-income countries, 2000-2017.

OBJECTIVE: To describe the mortality risks by fine strata of gestational age and birthweight among 230 679 live births in nine low- and middle-income countries (LMICs) from 2000 to 2017. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Liveborn infants from 15 population-based cohorts. METHODS: Subnational, population-based studies with high-quality birth outcome data were invited to join the Vulnerable Newborn Measurement Collaboration. All studies included birthweight, gestational age measured by ultrasound or last menstrual period, infant sex and neonatal survival. We defined adequate birthweight as 2500-3999 g (reference category), macrosomia as ≥4000 g, moderate low as 1500-2499 g and very low birthweight as <1500 g. We analysed fine strata classifications of preterm, term and post-term: ≥42+0 , 39+0 -41+6 (reference category), 37+0 -38+6 , 34+0 -36+6 ,34+0 -36+6 ,32+0 -33+6 , 30+0 -31+6 , 28+0 -29+6 and less than 28 weeks. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for neonatal mortality rates (NMR) and relative risks (RR). We also performed meta-analysis for the relative mortality risks with 95% confidence intervals (CIs) by the fine categories, stratified by regional study setting (sub-Saharan Africa and Southern Asia) and study-level NMR (≤25 versus >25 neonatal deaths per 1000 live births). RESULTS: We found a dose-response relationship between lower gestational ages and birthweights with increasing neonatal mortality risks. The highest NMR and RR were among preterm babies born at <28 weeks (median NMR 359.2 per 1000 live births; RR 18.0, 95% CI 8.6-37.6) and very low birthweight (462.8 per 1000 live births; RR 43.4, 95% CI 29.5-63.9). We found no statistically significant neonatal mortality risk for macrosomia (RR 1.1, 95% CI 0.6-3.0) but a statistically significant risk for all preterm babies, post-term babies (RR 1.3, 95% CI 1.1-1.5) and babies born at 370 -386 weeks (RR 1.2, 95% CI 1.0-1.4). There were no statistically significant differences by region or underlying neonatal mortality. CONCLUSIONS: In addition to tracking vulnerable newborn types, monitoring finer categories of birthweight and gestational age will allow for better understanding of the predictors, interventions and health outcomes for vulnerable newborns. It is imperative that all newborns from live births and stillbirths have an accurate recorded weight and gestational age to track maternal and neonatal health and optimise prevention and care of vulnerable newborns.

Neurodevelopmental outcomes following possible serious bacterial infection in early infancy in Karachi, Pakistan: a prospective cohort study.

BACKGROUND: Pakistan reports a significant burden of neonatal mortality, with infections as one of the major causes. We aim to assess the long-term impact of early infancy infections on neurodevelopmental outcomes during later childhood. METHODS: We conducted a prospective follow-up study of the cohort enrolled at the Karachi site of the Aetiology of Neonatal Infection in South Asia (ANISA) during 2019-2020. Children with a possible serious bacterial infection (based on the WHO IMCI algorithm) at early infancy were assessed for neurodevelopment at 6-9 years of age and compared with healthy controls. The Ten Questions (TQS) questionnaire, Strengths and Difficulties Questionnaire (SDQ), and Parent's Evaluation of Developmental Stage Assessment Level (PEDS: DM-AL) neurodevelopmental assessment tools, were administered and scored by the research staff who were blinded to the child's exposure status. Generalized Structural Equation Modelling (GSEM) was employed to verify relationships and associations among developmental milestones, anthropometry, and sociodemographic variables. RESULTS: A total of 398 children (241 cases and 157 controls) completed neurodevelopmental and growth assessments. Cases had a significantly higher rate of abnormal TQS scores (54.5% vs. 35.0%, p-value 0.001), greater delays in motor milestones (21.2% vs. 12.1%, p-value 0.02), lower fine motor skills (78.4 ± 1.4 vs. 83.2 ± 1.5, p-value 0.02). The receptive language skills were well-developed in both groups. According to the logistic regression model, exposure to infection during the first 59 days of life was associated with delayed TQS milestones (ß = -0.6, 95% CI -1.2,-0.04), TQS hearing domain (ß = -0.3, 95% CI: -1.2 to 0.7), PEDS: DM-AL fine motor domain (ß = -1.3, 95% CI: -4.4 to 1.7), PEDS: DM-AL receptive language development (ß = -1.1, 95% CI: -3.7 to 1.4) and child anthropometric measurements such as weight and height (ß = -0.2, 95% CI: -0.4 to 0.01 and ß = -0.2, 95% CI: -0.4 to -0.01, respectively). Early pSBI exposure was positively associated with PEDS: DM-AL self-help domain (ß = 0.6, 95% CI: -1.2 to 2.4) and SDQ-P overall score (ß = 0.02, 95% CI: -0.3 to 0.3). CONCLUSION: Children exposed to PSBI during early infancy have higher rates of abnormal development, motor delays, and lower fine motor skills during later childhood in Pakistan. Socioeconomic challenges and limited healthcare access contribute to these challenges, highlighting the need for long-term follow-ups with integrated neurodevelopment assessments.

Neonatal mortality risk of vulnerable newborns: A descriptive analysis of subnational, population-based birth cohorts for 238 203 live births in low- and middle-income settings from 2000 to 2017.

OBJECTIVE: We aimed to understand the mortality risks of vulnerable newborns (defined as preterm and/or born weighing smaller or larger compared to a standard population), in low- and middle-income countries (LMICs). DESIGN: Descriptive multi-country, secondary analysis of individual-level study data of babies born since 2000. SETTING: Sixteen subnational, population-based studies from nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Live birth neonates. METHODS: We categorically defined five vulnerable newborn types based on size (large- or appropriate- or small-for-gestational age [LGA, AGA, SGA]), and term (T) and preterm (PT): T + LGA, T + SGA, PT + LGA, PT + AGA, and PT + SGA, with T + AGA (reference). A 10-type definition included low birthweight (LBW) and non-LBW, and a four-type definition collapsed AGA/LGA into one category. We performed imputation for missing birthweights in 13 of the studies. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for the prevalence, mortality rates and relative mortality risks for the four, six and ten type classification. RESULTS: There were 238 203 live births with known neonatal status. Four of the six types had higher mortality risk: T + SGA (median relative risk [RR] 2.6, interquartile range [IQR] 2.0-2.9), PT + LGA (median RR 7.3, IQR 2.3-10.4), PT + AGA (median RR 6.0, IQR 4.4-13.2) and PT + SGA (median RR 10.4, IQR 8.6-13.9). T + SGA, PT + LGA and PT + AGA babies who were LBW, had higher risk compared with non-LBW babies. CONCLUSIONS: Small and/or preterm babies in LIMCs have a considerably increased mortality risk compared with babies born at term and larger. This classification system may advance the understanding of the social determinants and biomedical risk factors along with improved treatment that is critical for newborn health.

Invasive Bacterial Vaccine-Preventable Disease Surveillance: Successes and Lessons Learned in Bangladesh for a Sustainable Path Forward.

We have made considerable progress in setting and scaling up surveillance systems to drive evidence-based policy decisions, but the recent epidemics highlight that current systems are not optimally designed. Good surveillance systems should be coordinated, comprehensive, and adaptive. They should generate data in real time for immediate analysis and intervention, whether for endemic diseases or potential epidemics. Such systems are especially needed in low-resource settings where disease burden is the highest, but tracking systems are the weakest here due to competing priorities and constraints on available resources. In this article, using the examples of 3 large, and mostly successful, infectious disease surveillance studies in Bangladesh, we identify 2 core limitations-the pathogen bias and the vaccine bias-in the way current surveillance programs are designed for low-resource settings. We highlight the strengths of the current Global Invasive Bacterial Vaccine Preventable Disease Surveillance Network of the World Health Organization and present case studies from Bangladesh to illustrate how this surveillance platform can be leveraged to overcome its limitations. Finally, we propose a set of criteria for building a comprehensive infectious disease surveillance system with the hope of encouraging current systems to use the limited resources as optimally as possible to generate the maximum amount of knowledge.

Typhoid Conjugate Vaccine: An Urgent Tool to Combat Typhoid and Tackle Antimicrobial Resistance.

Typhoid is endemic in many countries in South Asia and sub-Saharan Africa. The high burden of this age-old, preventable disease exacerbates constraints on the health systems of these countries. Currently, most patients are treated effectively in the community or outpatient departments, but with rising antimicrobial resistance and the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against typhoid. Extensively drug-resistant Salmonella Typhi is spreading, and azithromycin is the last oral drug to continue treating typhoid in the community. With increasing azithromycin resistance, emergence of pan-oral drug resistant Salmonella Typhi is imminent. The high burden of typhoid is also an underlying cause of the unnecessary use of antimicrobials. In addition to implementing water sanitation and hygiene interventions to prevent typhoid, it is imperative to rapidly roll out typhoid conjugate vaccines in endemic countries. This will not only reduce the burden of typhoid but will also help interrupt the trend of increasing antimicrobial resistance.

Comparison of Culture, Antigen Test, and Polymerase Chain Reaction for Pneumococcal Detection in Cerebrospinal Fluid of Children.

BACKGROUND: Sensitivity of culture for the detection of Streptococcus pneumoniae is limited by prior antibiotic exposure. Immunochromatographic test (ICT) is highly sensitive and specific for pneumococcal antigen detection in the cerebrospinal fluid (CSF) of meningitis cases. We determined the specificity and sensitivity of culture, ICT, and polymerase chain reaction (PCR) and the effect of antibiotic exposure on their performance. METHODS: CSF specimens from suspected meningitis cases admitted to Dhaka Shishu Hospital, Bangladesh, were tested using culture, ICT and PCR. Additionally, 165 specimens collected from 69 pneumococcal cases after antibiotic treatment were tested. RESULTS: Of 1883 specimens tested, culture detected 9, quantitative PCR (qPCR) detected 184, and ICT detected 207 pneumococcal cases (including all culture and qPCR positives). In comparison to ICT, sensitivity of culture was 4.4% and of qPCR was 90.6%; both were 100% specific. After antibiotic exposure, culture sensitivity plummeted rapidly; conventional PCR and qPCR sensitivity disappeared after day 6 and 20, respectively. ICT detected pneumococcal antigen for >10 weeks. CONCLUSIONS: While culture provides the most information about bacterial characteristics, in high antibiotic exposure settings, ICT exhibits maximum sensitivity. We recommend culture and ICT as mainstay for pneumococcal diagnosis and surveillance; qPCR can generate additional molecular data where possible.

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.

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.

Utilization of Blood Culture in South Asia for the Diagnosis and Treatment of Febrile Illness.

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.

Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016-2019.

BACKGROUND: The Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan. METHODS: During September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases. RESULTS: Overall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin. CONCLUSION: Enteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever.

Antimicrobial Resistance in Typhoidal Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019.

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.

Diagnostic Value of Clinical Features to Distinguish Enteric Fever From Other Febrile Illnesses in Bangladesh, Nepal, and Pakistan.

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.

Antibiotic Use Prior to Hospital Presentation Among Individuals With Suspected Enteric Fever in Nepal, Bangladesh, and Pakistan.

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.

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.

Hospitalization of Pediatric Enteric Fever Cases, Dhaka, Bangladesh, 2017-2019: Incidence and Risk Factors.

BACKGROUND: Enteric fever causes substantial morbidity and mortality in low- and middle-income countries. Here, we analyzed Surveillance for Enteric Fever in Asia Project (SEAP) data to estimate the burden of enteric fever hospitalization among children aged <15 years and identify risk factors for hospitalization in Bangladesh. METHODS: SEAP used hospital surveillance paired with a community-based health-care utilization assessment. In SEAP hospital surveillance, blood was obtained for culture from children aged <15 years with ≥3 days of fever. In the hospital catchment area, a health-care utilization survey (HCUS) was conducted to estimate the proportion of febrile children hospitalized at the study hospitals. We analyzed hospital surveillance and HCUS data to estimate the health care-adjusted incidence of enteric fever hospitalization, and conducted univariable and multivariable logistic regressions. RESULTS: From July 2017 through June 2019, 2243 laboratory-confirmed enteric fever cases were detected in 2 study hospitals; 673 (30%) were hospitalized. The health care-adjusted incidence of enteric fever hospitalization among children <15 years old was 303/100 000 children/year (95% confidence interval [CI], 293-313). Salmonella Typhi contributed most to the enteric fever hospitalization incidence (277/100 000 children/year; 95% CI, 267-287). The incidence was highest among children aged 2 to <5 years (552/100 000 children/year; 95% CI, 522-583), followed by those aged <2 years (316/100 000 children/year; 95% CI, 288-344). Factors independently associated with enteric fever hospitalization included fever duration, diarrhea, vomiting, abdominal pain, and leukocytopenia. CONCLUSIONS: We estimated a high burden of hospitalization due to enteric fever among children aged <5 years in Bangladesh. The introduction of a typhoid conjugate vaccine would protect children from typhoid and avert typhoid hospitalizations.

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.

A mosaic tetracycline resistance gene tet(S/M) detected in an MDR pneumococcal CC230 lineage that underwent capsular switching in South Africa.

OBJECTIVES: We reported tet(S/M) in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions. METHODS: We whole-genome sequenced 12 254 pneumococcal isolates from 29 countries on an Illumina HiSeq sequencer. Serotype, multilocus ST and antibiotic resistance were inferred from genomes. An SNP tree was built using Gubbins. Temporal spread was reconstructed using a birth-death model. RESULTS: We identified tet(S/M) in 131 pneumococcal isolates and none carried other known tet genes. Tetracycline susceptibility testing results were available for 121 tet(S/M)-positive isolates and all were resistant. A majority (74%) of tet(S/M)-positive isolates were from South Africa and caused invasive diseases among young children (59% HIV positive, where HIV status was available). All but two tet(S/M)-positive isolates belonged to clonal complex (CC) 230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sublineage predicted to exhibit resistance to penicillin, co-trimoxazole, erythromycin and tetracycline. The birth-death model detected an unrecognized outbreak of this sublineage in South Africa between 2000 and 2004 with expected secondary infections (effective reproductive number, R) of ∼2.5. R declined to ∼1.0 in 2005 and <1.0 in 2012. The declining epidemic could be related to improved access to ART in 2004 and introduction of pneumococcal conjugate vaccine (PCV) in 2009. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sublineage. CONCLUSIONS: The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognized outbreak of CC230 in South Africa. Capsular switching in this MDR sublineage highlighted its potential to continue to cause disease in the post-PCV13 era.

Echocardiography 2020: Toward deciphering the "Rosetta stone" of left ventricular diastolic function.

In the year 1997, nearly a quarter-century ago, Nishimura and Tajik (J Am Coll Cardiol. 1997;30:8) suggested that Doppler echocardiography was the "Rosetta stone" (a metaphor for decrypting secrets of diastole) of left ventricular diastole, based solely on transmitral E/A ratio and its progression from grade I through IV, supported by cardiac catheterization, as the filling pressure started to increase to over 15 mm Hg. Ten years later, in 2007, the same Mayo group (Nagueh et al, J Am Coll Cardiology. 2008;51:679) was searching to decipher the secrets of diastole using multiple measures such as left atrial (LA) volume, E/E' ratio, pulmonary venous flow, and mitral inflow propagation velocity. This substantial leap from E/A ratio led to the more formal recommendation proposed by the American Society of Echocardiography in 2009 (Nagueh et al, J Am Soc Echocardiogr. 2009;22:107) and, as an update, in the year 2016 (Nagueh et al, J Am Soc Echocardiogr. 2016;29:277): the later version gained popularity for the simplified approach to identify diastolic dysfunction in healthy subjects as well as in those with poorly contracting left ventricle. Despite 30 years of continuous search, we are not sure if we have been able to decipher the hidden secrets of diastolic function. With this background, the Echocardiography Journal under the leadership of Dr Navin Nanda as the Editor-in-Chief has taken this initiative to publish a theme issue on left ventricular diastolic function and when this becomes dysfunctional to diminish life.

Epidemiology of Typhoid and Paratyphoid: Implications for Vaccine Policy.

BACKGROUND: Typhoid and paratyphoid remain the most common bloodstream infections in many resource-poor settings. The World Health Organization recommends typhoid conjugate vaccines for country-specific introduction, but questions regarding typhoid and paratyphoid epidemiology persist, especially regarding their severity in young children. METHODS: We conducted enteric fever surveillance in Bangladesh from 2004 through 2016 in the inpatient departments of 2 pediatric hospitals and the outpatient departments of 1 pediatric hospital and 1 private consultation clinic. Blood cultures were conducted at the discretion of the treating physicians; cases of culture-confirmed typhoid/paratyphoid were included. Hospitalizations and durations of hospitalizations were used as proxies for severity in children <12 years old. RESULTS: We identified 7072 typhoid and 1810 paratyphoid culture-confirmed cases. There was no increasing trend in the proportion of paratyphoid over the 13 years. The median age in the typhoid cases was 60 months, and 15% of the cases occurred in children <24 months old. The median age of the paratyphoid cases was significantly higher, at 90 months (P < .001); 9.4% were in children <24 months old. The proportion of children (<12 years old) hospitalized with typhoid and paratyphoid (32% and 21%, respectively) decreased with age; there was no significant difference in durations of hospitalizations between age groups. However, children with typhoid were hospitalized for longer than those with paratyphoid. CONCLUSIONS: Typhoid and paratyphoid fever are common in Dhaka, including among children under 2 years old, who have equivalent disease severity as older children. Early immunization with typhoid conjugate vaccines could avert substantial morbidity, but broader efforts are required to reduce the paratyphoid burden.

Analysis of isolates from Bangladesh highlights multiple ways to carry resistance genes in Salmonella Typhi.

BACKGROUND: Typhoid fever, caused by Salmonella Typhi, follows a fecal-oral transmission route and is a major global public health concern, especially in developing countries like Bangladesh. Increasing emergence of antimicrobial resistance (AMR) is a serious issue; the list of treatments for typhoid fever is ever-decreasing. In addition to IncHI1-type plasmids, Salmonella genomic island (SGI) 11 has been reported to carry AMR genes. Although reports suggest a recent reduction in multidrug resistance (MDR) in the Indian subcontinent, the corresponding genomic changes in the background are unknown. RESULTS: Here, we assembled and annotated complete closed chromosomes and plasmids for 73 S. Typhi isolates using short-length Illumina reads. S. Typhi had an open pan-genome, and the core genome was smaller than previously reported. Considering AMR genes, we identified five variants of SGI11, including the previously reported reference sequence. Five plasmids were identified, including the new plasmids pK91 and pK43; pK43and pHCM2 were not related to AMR. The pHCM1, pPRJEB21992 and pK91 plasmids carried AMR genes and, along with the SGI11 variants, were responsible for resistance phenotypes. pK91 also contained qnr genes, conferred high ciprofloxacin resistance and was related to the H58-sublineage Bdq, which shows the same phenotype. The presence of plasmids (pHCM1 and pK91) and SGI11 were linked to two H58-lineages, Ia and Bd. Loss of plasmids and integration of resistance genes in genomic islands could contribute to the fitness advantage of lineage Ia isolates. CONCLUSIONS: Such events may explain why lineage Ia is globally widespread, while the Bd lineage is locally restricted. Further studies are required to understand how these S. Typhi AMR elements spread and generate new variants. Preventive measures such as vaccination programs should also be considered in endemic countries; such initiatives could potentially reduce the spread of AMR.