Burden of Typhoid and Paratyphoid Fever in India.

BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

Genomic analysis unveils genome degradation events and gene flux in the emergence and persistence of S. Paratyphi A lineages.

Paratyphoid fever caused by S. Paratyphi A is endemic in parts of South Asia and Southeast Asia. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study "Surveillance of Enteric Fever in India (SEFI)." In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis highlights that the genome degradation events and gene acquisitions or losses are key molecular events in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 hypothetically disrupted coding sequences (HDCS) or pseudogenes-forming mutations possibly associated with the emergence of lineages were identified. The pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We have identified six characteristic missense mutations associated with lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A, however, these mutations confer only a low structural impact and possibly have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human-restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and monitoring by means of genomic surveillance would be constantly needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today.

Environmental Surveillance for Salmonella Typhi and its Association With Typhoid Fever Incidence in India and Malawi.

BACKGROUND: Environmental surveillance (ES) for Salmonella Typhi potentially offers a low-cost tool to identify communities with a high burden of typhoid fever. METHODS: We developed standardized protocols for typhoid ES, including sampling site selection, validation, characterization; grab or trap sample collection, concentration; and quantitative PCR targeting Salmonella genes (ttr, staG, and tviB) and a marker of human fecal contamination (HF183). ES was implemented over 12 months in a historically high typhoid fever incidence setting (Vellore, India) and a lower incidence setting (Blantyre, Malawi) during 2021-2022. RESULTS: S. Typhi prevalence in ES samples was higher in Vellore compared with Blantyre; 39/520 (7.5%; 95% confidence interval [CI], 4.4%-12.4%) vs 11/533 (2.1%; 95% CI, 1.1%-4.0%) in grab and 79/517 (15.3%; 95% CI, 9.8%-23.0%) vs 23/594 (3.9%; 95% CI, 1.9%-7.9%) in trap samples. Detection was clustered by ES site and correlated with site catchment population in Vellore but not Blantyre. Incidence of culture-confirmed typhoid in local hospitals was low during the study and zero some months in Vellore despite S. Typhi detection in ES. CONCLUSIONS: ES describes the prevalence and distribution of S. Typhi even in the absence of typhoid cases and could inform vaccine introduction. Expanded implementation and comparison with clinical and serological surveillance will further establish its public health utility.

Sustainability in Dentistry: Assessing knowledge, attitude, and practices of dental practitioners about green dentistry.

Objective: Green dentistry is an emerging concept necessary to address the worsening climatic changes. It is essential to compile the existing literature on knowledge, attitude, and practice on green dentistry that can be accomplished by conducting a literature review. The objective of this literature review was to summarize and present the existing knowledge that dentists have regarding green dental practices, their attitude about this shift towards sustainability, and steps that they have taken in their personal practice to adhere towards an eco-friendlier dental approach. Methods: Three months of effective research and review development from March 2022 to June 2022. Design using keywords, a literature search was performed in PubMed, Google scholar and Web of Science databases. A total of 13 articles of 45, fulfilling the inclusion criteria were selected, of which two were excluded as these were not in English. Results: Dental practitioners have good knowledge about green dentistry and positive attitudes towards environment conservation, but implementation in their practice is not adequate. Most common themes of knowledge, attitude and practice assessment in green dentistry are amalgam management, radiographic management, infection control, waste management, water, and electricity management. Conclusion: The absence of adequate literature on eco-friendly practices in dentistry makes it difficult to validate the findings of most of these studies. Dental professionals are familiar with environmentally friendly dental practices and have a positive outlook on their role in environmental protection, but its application in practice is far from adequate.

Perceptions of professional social media interaction with patients and faculty members - a comparative survey among dental students from Malaysia and Finland.

BACKGROUND: Professional and personal boundaries are blurred with the wide application of social media (SM) in the health professions line of work. Little is known about practice of extending friend requests to patients and faculty members among dental students, which encompass a part of E-professionalism. The aim of this study is to assess the factors associated with the perceptions and practices of interactions with patients and faculty on SM among dental students from Malaysia and Finland. METHODS: Dental students from 4 institutions in Malaysia and Finland completed self-administered questionnaires on the practices and perceptions of SM use. The main variables assessed were the perceptions and practices of student-patient and student-faculty communication on SM, between the two countries. Students' country, age, gender, time spent on SM and perceived importance of communicating dental related aspects over SM were analysed as potential explanatory variables. Crosstabulation was used to estimate the distributions of the response variables by the background characteristics. Multivariate analyses were performed using a dichotomous logistic regression model to investigate relevant associations between the responses and the explanatory variables independent from other factors. RESULTS: A total of 643 students completed the survey in March-April 2021. More Malaysian students agreed with "guiding patients online is a new responsibility for dentists in the digital age" compared to Finnish students (86.4% vs. 73.4%). Similarly, significantly more Malaysian students befriended patients (14.1% vs. 1%) and invited faculty to be friends on SM (73.6% vs. 11.8%). Expectedly, clinical year students befriended patients more than pre-clinical (13.8% vs. 6.8%). Significantly more students who felt 'communication of dental related issues over SM' were likely to extend friend requests to faculty rather than accept patient friend requests. CONCLUSIONS: Social media regulations and socio-cultural practices contribute to dental students' attitudes and behaviour when befriending patients and faculty members on social media. Future dental curriculum should incorporate guidelines for professional communication on social media based on local and cultural needs. Students' should be encouraged to interact with their patients using professional identities on social media.

A feature-guided, focused 3D signal permutation method for subtomogram averaging.

Advances in electron microscope instrumentation, cryo-electron tomography data collection, and subtomogram averaging have allowed for the in-situ visualization of molecules and their complexes in their native environment. Current data processing pipelines commonly extract subtomograms as a cubic subvolume with the key assumption that the selected object of interest is discrete from its surroundings. However, in instances when the object is in its native environment, surrounding densities may negatively affect the subsequent alignment and refinement processes, leading to loss of information due to misalignment. For example, the strong densities from surrounding membranes may dominate the alignment process for membrane proteins. Here, we developed methods for feature-guided subtomogram alignment and 3D signal permutation for subtomogram averaging. Our 3D signal permutation method randomizes and filters voxels outside a mask of any shape and blurs the boundary of the mask that encapsulates the object of interest. The randomization preserves global statistical properties such as mean density and standard deviation of voxel density values, effectively producing a featureless background surrounding the object of interest. This signal permutation process can be repeatedly applied with intervening alignments of the 3D signal-permuted subvolumes, recentering of the mask, and optional adjustments of the shape of the mask. We have implemented these methods in a new processing pipeline which starts from tomograms, contains feature-guided subtomogram extraction and alignment, 3D signal-permutation, and subtomogram visualization tools. As an example, feature-guided alignment and 3D signal permutation leads to improved subtomogram average maps for a dataset of synaptic protein complexes in their native environment.

Reassessing Reported Deaths and Estimated Infection Attack Rate during the First 6 Months of the COVID-19 Epidemic, Delhi, India.

India reported >10 million coronavirus disease (COVID-19) cases and 149,000 deaths in 2020. To reassess reported deaths and estimate incidence rates during the first 6 months of the epidemic, we used a severe acute respiratory syndrome coronavirus 2 transmission model fit to data from 3 serosurveys in Delhi and time-series documentation of reported deaths. We estimated 48.7% (95% credible interval 22.1%-76.8%) cumulative infection in the population through the end of September 2020. Using an age-adjusted overall infection fatality ratio based on age-specific estimates from mostly high-income countries, we estimated that just 15.0% (95% credible interval 9.3%-34.0%) of COVID-19 deaths had been reported, indicating either substantial underreporting or lower age-specific infection-fatality ratios in India than in high-income countries. Despite the estimated high attack rate, additional epidemic waves occurred in late 2020 and April-May 2021. Future dynamics will depend on the duration of natural and vaccine-induced immunity and their effectiveness against new variants.

Pectin self-assembly and its disruption by water: insights into plant cell wall mechanics.

Plant cell walls undergo multiple cycles of dehydration and rehydration during their life. Calcium crosslinked low methoxy pectin is a major constituent of plant cell walls. Understanding the dehydration-rehydration behavior of pectin gels may shed light on the water transport and mechanics of plant cells. In this work, we report the contributions of the microstructure to the mechanics of pectin-Ca gels subjected to different extents of dehydration and subsequent rehydration. This is investigated using a pectin gel composition that forms 'egg-box bundles', a characteristic feature of the microstructure of low methoxy pectin-Ca gels. Large amplitude oscillatory shear (LAOS) rheology along with small angle neutron scattering and near infrared (NIR) spectroscopy on pectin gels is used to elucidate the mechanical and microstructural changes during dehydration-rehydration cycles. As the extent of dehydration increases, the reswelling ability, strain-stiffening behavior and yield strain decrease. These effects are more prominent at faster rates of dehydration and are not completely reversible upon rehydration to the initial undried state. Microstructural changes due to the aggregation of egg-box bundles and single chains and the associated changes in the water configurations lead to these irreversible changes.

Salmonella Typhi acquires diverse plasmids from other Enterobacteriaceae to develop cephalosporin resistance.

BACKGROUND: Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S. Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S. Typhi isolates from India to predict their potential dissemination. METHODS: Five ceftriaxone resistant S. Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S. Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. RESULTS: Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with blaCTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (blaSHV-12) or IncN (blaTEM-1B + blaDHA-1). CONCLUSION: Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally.

Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India.

BACKGROUND: The case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs. METHODS: We aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017-2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital. RESULTS: A total of 1236 hospitalized patients with blood culture-confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%-1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%-.29%) for all enteric fevers. CONCLUSIONS: Our estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

Case-Control Study of Household and Environmental Transmission of Typhoid Fever in India.

BACKGROUND: Typhoid fever causes substantial morbidity and mortality in low- and middle-income countries. We conducted a case-control study in Vellore, southern India, to understand risk factors for transmission of typhoid. METHODS: From April 2018 to October 2019, households of blood culture-confirmed typhoid cases that occurred within a fever surveillance cohort aged 6 months-15 years, and controls matched for age, sex, geographic location, and socioeconomic status, were recruited. Information on risk factors was obtained using standard questionnaires. Household and environmental samples were collected for detection of Salmonella Typhi using real-time polymerase chain reaction. Multivariable analysis was used to evaluate associations between risk factors and typhoid. RESULTS: One hundred pairs of cases and controls were recruited. On multivariable regression analysis, mothers eating food from street vendors during the previous week (odds ratio [OR] = 2.04; 95% confidence interval [CI], 1.03-4.12; P = .04) was independently associated with typhoid, whereas treatment of household drinking water (OR = 0.45; 95% CI, 0.25-0.80; P = .007) was protective. There was no significant difference in S Typhi detection between the environmental samples from case and control households. CONCLUSIONS: Street-vended food is a risk factor for typhoid in densely populated urban communities of Vellore. Improved sanitation facilities and awareness about point-of-use water treatment are likely to contribute to typhoid control.

Comparison of Strategies for Typhoid Conjugate Vaccine Introduction in India: A Cost-Effectiveness Modeling Study.

BACKGROUND: Typhoid fever causes substantial global mortality, with almost half occurring in India. New typhoid vaccines are highly effective and recommended by the World Health Organization for high-burden settings. There is a need to determine whether and which typhoid vaccine strategies should be implemented in India. METHODS: We assessed typhoid vaccination using a dynamic compartmental model, parameterized by and calibrated to disease and costing data from a recent multisite surveillance study in India. We modeled routine and 1-time campaign strategies that target different ages and settings. The primary outcome was cost-effectiveness, measured by incremental cost-effectiveness ratios (ICERs) benchmarked against India's gross national income per capita (US$2130). RESULTS: Both routine and campaign vaccination strategies were cost-saving compared to the status quo, due to averted costs of illness. The preferred strategy was a nationwide community-based catchup campaign targeting children aged 1-15 years alongside routine vaccination, with an ICER of $929 per disability-adjusted life-year averted. Over the first 10 years of implementation, vaccination could avert 21-39 million cases and save $1.6-$2.2 billion. These findings were broadly consistent across willingness-to-pay thresholds, epidemiologic settings, and model input distributions. CONCLUSIONS: Despite high initial costs, routine and campaign typhoid vaccination in India could substantially reduce mortality and was highly cost-effective.

Healthcare Utilization Survey in the Hybrid Model of the Surveillance for Enteric Fever in India (SEFI) Study: Processes, Monitoring, Results, and Challenges.

BACKGROUND: Lack of reliable data in India drove the "Surveillance of Enteric Fever in India" (SEFI) concept. Hybrid surveillance, combining facility-based surveillance for the crude incidence, and a community-based healthcare utilization survey (HCUS) to calculate the factor needed to arrive at the adjusted incidence, was used in 6 sites. The HCUS aimed to determine the percentage of utilization of study facilities by the catchment population for hospitalizations due to febrile illness. METHODS: Population proportional to size sampling and systematic random sampling, in 2 stages, were used to survey 5000 households per site. Healthcare utilization was assessed. RESULTS: Febrile illness accounted for 20% of admissions among 137 990 individuals from 30 308 households. Only 9.6%-38.3% of those admitted with febrile illness sought care in the study hospitals. The rate of rural utilization of the private sector for hospitalization was 67.6%. The rate of hospitalization for febrile illness, per 1000 population, ranged from 2.6 in Manali to 9.6 in Anantapur; for 25.8% of the deaths associated with febrile illness, no facility was used before death. CONCLUSIONS: One in 5 hospitalizations were associated with fever. Rural utilization of the private sector for hospitalization due to febrile illness was more than that of the public sector. Healthcare utilization patterns for hospital admissions due to febrile illness varied across sites. A meticulously performed HCUS is pivotal for accurate incidence estimation in a hybrid surveillance. CLINICAL TRIALS REGISTRATION: ISRCTN72938224.

Geographic Pattern of Typhoid Fever in India: A Model-Based Estimate of Cohort and Surveillance Data.

BACKGROUND: Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India. METHODS: We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence. RESULTS: We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north. CONCLUSIONS: There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.

Hospitalization Rates and Direct Medical Costs for Fever in a Pediatric Cohort in South India.

BACKGROUND: Primary data on causes and costs of hospitalization are necessary for costing and cost-effectiveness analysis. Data on incidence and causes of hospitalization and consequent expenses among Indian children are limited. METHODS: A cohort of 6000 children aged 0.5-15 years residing in urban Vellore was followed for 3 years, under the Vellore Typhoid Study, 2016-2017, and later under the Surveillance for Enteric Fever project, 2017-2019. Data on hospitalization events and associated antibiotic use, and direct medical costs for fever-related hospitalization of study children were obtained from caregivers through weekly follow-up by study field workers. RESULTS: The incidence of hospitalization was 33 per 1000 child-years of observation. Children aged 0.5-5 years had the highest incidence of hospitalization. The top 5 infectious causes for hospitalization were acute undifferentiated fevers, respiratory tract infections, acute gastroenteritis, enteric fever, and dengue. The overall median cost of hospitalization for fever was 4243 (interquartile range, 2502-7215) Indian rupees (INR). An episode of dengue had a median cost of 5627 INR, followed by acute undifferentiated fevers and enteric fever with median costs of 3860 and 3507 INR, respectively. CONCLUSIONS: Hospitalization for fever is common in young children and impacts household finances in low-income Indian households.

Ileal Perforation and Enteric Fever: Implications for Burden of Disease Estimation.

BACKGROUND: Ileal perforation occurs in about 1% of enteric fevers as a complication, with a case fatality risk (CFR) of 20%-30% in the early 1990s that decreased to 15.4% in 2011 in South East Asia. We report nontraumatic ileal perforations and its associated CFR from a 2-year prospective enteric fever surveillance across India. METHODS: The Surveillance for Enteric Fever in India (SEFI) project established a multitiered surveillance system for enteric fever between December 2017 and March 2020. Nontraumatic ileal perforations were surveilled at 8 tertiary care and 6 secondary care hospitals and classified according to etiology. RESULTS: Of the 158 nontraumatic ileal perforation cases identified,126 were consented and enrolled. Enteric fever (34.7%), tuberculosis (19.0%), malignancy (5.8%), and perforation of Meckel diverticulum (4.9%) were the common etiology. In those with enteric fever ileal perforation, the CFR was 7.1%. CONCLUSIONS: Enteric fever remains the most common cause of nontraumatic ileal perforation in India, followed by tuberculosis. Better modalities of establishing etiology are required to classify the illness, and frame management guidelines and preventive measures. CFR data are critical for comprehensive disease burden estimation and policymaking.

Geographically Weighted Regression Modeling of Spatial Clustering and Determinants of Focal Typhoid Fever Incidence.

BACKGROUND: Typhoid is known to be heterogenous in time and space, with documented spatiotemporal clustering and hotspots associated with environmental factors. This analysis evaluated spatial clustering of typhoid and modeled incidence rates of typhoid from active surveillance at 4 sites with child cohorts in India. METHODS: Among approximately 24 000 children aged 0.5-15 years followed for 2 years, typhoid was confirmed by blood culture in all children with fever >3 days. Local hotspots for incident typhoid cases were assessed using SaTScan spatial cluster detection. Incidence of typhoid was modeled with sociodemographic and water, sanitation, and hygiene-related factors in smaller grids using nonspatial and spatial regression analyses. RESULTS: Hotspot households for typhoid were identified at Vellore and Kolkata. There were 4 significant SaTScan clusters (P < .05) for typhoid in Vellore. Mean incidence of typhoid was 0.004 per child-year with the highest incidence (0.526 per child-year) in Kolkata. Unsafe water and poor sanitation were positively associated with typhoid in Kolkata and Delhi, whereas drinking untreated water was significantly associated in Vellore (P = .0342) and Delhi (P = .0188). CONCLUSIONS: Despite decades of efforts to improve water and sanitation by the Indian government, environmental factors continue to influence the incidence of typhoid. Hence, administration of the conjugate vaccine may be essential even as efforts to improve water and sanitation continue.

Factors Predicting Blood Culture Positivity in Children With Enteric Fever.

BACKGROUND: Blood culture, despite low sensitivity, is the gold standard for enteric fever diagnosis. Understanding predictors of blood culture positivity may help design strategies to optimize enteric fever diagnosis. METHODS: A cohort of 6760 children aged 0.5-15 years was followed for 3 years for enteric fever with blood cultures in an automated system, for fevers >3 days. Factors affecting test positivity in fevers and participant-level predictors for culture refusals were analyzed using regression models. RESULTS: Overall, 6097 suspected typhoid/paratyphoid fever (STF) episodes were reported, of which 5703 (93.5%) STFs had sampling for blood cultures, with 394 (6.5%) refusals. Salmonella enterica serovar Typhi/Paratyphi positivity was culture-confirmed in 3.8% (218/5703) of STF episodes. Older children (odds ratio [OR], 1.96 [95% CI, 1.39-2.77]), larger blood volume inoculated (OR, 2.82 [95% CI, 1.71-4.66]), higher temperatures during fever (OR, 3.77 [95% CI, 2.89-4.91]), and fevers diagnosed as suspected typhoid or acute undifferentiated fever (OR, 6.06 [95% CI, 3.11-11.78]) had a higher probability of culture positivity. Antibiotics before culture did not decrease culture positivity. Blood culture refusals were higher for children from wealthier households or with milder illness. CONCLUSIONS: Performing blood cultures in older children with fever, especially those fevers with toxic presentation and increasing blood volume for inoculation are strategies to improve enteric fever detection in surveillance settings.

Antibiotics for Fever Among Children: Findings From the Surveillance for Enteric Fever in India Cohorts.

BACKGROUND: Acute febrile illness in children is frequently treated with antibiotics. However, the inappropriate use of antibiotics has led to the emergence of multidrug-resistant pathogens. METHODS: We measured use of antibiotics for fever in 4 pediatric cohorts that were part of the Surveillance for Enteric Fever in India (SEFI) network. In this network, 24 062 children were followed up weekly, capturing information on fever and other morbidity between October 2017 and December 2019. RESULTS: An antibiotic was given in 27 183 of the 76 027 (35.8%) episodes of fever. The incidence of fever-related antibiotic use was 58.0 (95% confidence interval [CI], 57.2-58.6) per 100 child-years. The median time to initiation of antibiotics was 4 days, and in 65% of those who received an antibiotic it was initiated by the second day. Antibiotics were continued for <3 days in 24% of the episodes. Higher temperature, younger age, male sex, joint family, higher education, internet access, and availability of personal conveyance were associated with antibiotic treatment for fever. CONCLUSIONS: In developing countries where antibiotic use is not regulated, broad-spectrum antibiotics are initiated early, and often inappropriately, in febrile illness. Frequent and inappropriate use of antibiotics may increase risk of antimicrobial resistance.

Cost of Illness Due to Severe Enteric Fever in India.

BACKGROUND: Lack of robust data on economic burden due to enteric fever in India has made decision making on typhoid vaccination a challenge. Surveillance for Enteric Fever network was established to address gaps in typhoid disease and economic burden. METHODS: Patients hospitalized with blood culture-confirmed enteric fever and nontraumatic ileal perforation were identified at 14 hospitals. These sites represent urban referral hospitals (tier 3) and smaller hospitals in urban slums, remote rural, and tribal settings (tier 2). Cost of illness and productivity loss data from onset to 28 days after discharge from hospital were collected using a structured questionnaire. The direct and indirect costs of an illness episode were analyzed by type of setting. RESULTS: In total, 274 patients from tier 2 surveillance, 891 patients from tier 3 surveillance, and 110 ileal perforation patients provided the cost of illness data. The mean direct cost of severe enteric fever was US$119.1 (95% confidence interval [CI], US$85.8-152.4) in tier 2 and US$405.7 (95% CI, 366.9-444.4) in tier 3; 16.9% of patients in tier 3 experienced catastrophic expenditure. CONCLUSIONS: The cost of treating enteric fever is considerable and likely to increase with emerging antimicrobial resistance. Equitable preventive strategies are urgently needed.