A descriptive analysis of antimicrobial resistance patterns of WHO priority pathogens isolated in children from a tertiary care hospital in India.

The World Health Organization (WHO) has articulated a priority pathogens list (PPL) to provide strategic direction to research and develop new antimicrobials. Antimicrobial resistance (AMR) patterns of WHO PPL in a tertiary health care facility in Southern India were explored to understand the local priority pathogens. Culture reports of laboratory specimens collected between 1st January 2014 and 31st October 2019 from paediatric patients were extracted. The antimicrobial susceptibility patterns for selected antimicrobials on the WHO PPL were analysed and reported. Of 12,256 culture specimens screened, 2335 (19%) showed culture positivity, of which 1556 (66.6%) were organisms from the WHO-PPL. E. coli was the most common organism isolated (37%), followed by Staphylococcus aureus (16%). Total of 72% of E. coli were extended-spectrum beta-lactamases (ESBL) producers, 55% of Enterobacteriaceae were resistant to 3rd generation cephalosporins due to ESBL, and 53% of Staph. aureus were Methicillin-resistant. The analysis showed AMR trends and prevalence patterns in the study setting and the WHO-PPL document are not fully comparable. This kind of local priority difference needs to be recognised in local policies and practices.

Model-based estimation of the economic burden of cholera in Africa.

OBJECTIVES: To estimate the economic burden of cholera in Africa. SETTINGS: Cholera affected 44 countries in Africa. PARTICIPANTS: The analysis used data from public sources in Africa published until September 2019. METHODS: Based on existing data from field-based cost-of-illness studies, estimated cholera incidence rates, and reported cholera cases to WHO, this research estimates the economic burden of cholera in Africa from a societal perspective with 2015 as the base year. The estimate included out-of-pocket costs, public health system costs, productivity loss related to illness and an optional productivity loss related to premature deaths valued by the human capital approach. As various input data such as cholera incidence, hospitalisation rates and the number of workdays lost were not well defined, a series of scenario analyses and uncertainty analyses, accounting for unknowns and data variability, was conducted. Similarly, the value of time lost due to illness and deaths using the human capital approach was explored through scenario analyses. RESULTS: In 2015, an estimated 1 008 642 cases in 44 African countries resulted in an economic burden of US$130 million from cholera-related illness and its treatment. When the estimated 38 104 cholera deaths were included in the analysis, the economic burden increased to US$1 billion or international $2.4 billion for the same year. At the same time, when only the 71 126 cases and 937 deaths reported to the WHO are considered, the economic burden was only US$68 million for the year 2015. The estimates of economic burden are thus heavily dependent on the cholera incidence rate, how time lost due to illness and deaths are calculated, hospitalisation rates and hospitalisation costs. CONCLUSION: The findings can be used as an economic justification for cholera control in Africa and for generating value-for-money evidence to underpin Ending Cholera-A Global Roadmap to 2030 with considerations to study limitations.

An overview of VaxchoraTM, a live attenuated oral cholera vaccine.

Cholera remains a public health threat among the least privileged populations and regions affected by conflicts and natural disasters. Together with Water, Sanitation and Hygiene practices, use of oral cholera vaccines (OCVs) is a key tool to prevent cholera. Bivalent whole-cell killed OCVs have been extensively used worldwide and found effective in protecting populations against cholera in endemic and outbreak settings. No cholera vaccine had been available for United States (US) travelers at risk for decades until 2016 when CVD 103-HgR (Vaxchora™), an oral live attenuated vaccine, was licensed by the US FDA. A single dose of Vaxchora™ protected US volunteers against experimental challenge 10 days and 3 months after vaccination. However, use of Vaxchora™ poses several challenges in resource poor settings as it requires reconstitution, is age-restricted to 18 to 64 years, has no data in populations endemic for cholera, and faces challenges related to cold chain and cost.

Economic burden of cholera in Asia.

BACKGROUND: The economic burden data can provide a basis to inform investments in cholera control and prevention activities. However, treatment costs and productivity loss due to cholera are not well studied. METHODS: We included Asian countries that either reported cholera cases to the World Health Organization (WHO) in 2015 or were considered cholera endemic in 2015 global burden of disease study. Public health service delivery costs for hospitalization and outpatient costs, out-of-pocket costs to patients and households, and lost productivity were extracted from literature. A probabilistic multivariate sensitivity analysis was conducted for key outputs using Monte Carlo simulation. Scenario analyses were conducted using data from the WHO cholera reports and conservative and liberal disease burden estimates. RESULTS: Our analysis included 14 Asian countries that were estimated to have a total of 850,000 cholera cases and 25,500 deaths in 2015 While, the WHO cholera report documented around 60,000 cholera cases and 28 deaths. We estimated around $20.2 million (I$74.4 million) in out-of-pocket expenditures, $8.5 million (I$30.1 million) in public sector costs, and $12.1 million (I$43.7 million) in lost productivity in 2015. Lost productivity due to premature deaths was estimated to be $985.7 million (I$3,638.6 million). Our scenario analyses excluding mortality costs showed that the economic burden ranged from 20.3% ($8.3 million) to 139.3% ($57.1 million) in high and low scenarios when compared to the base case scenario ($41 million) and was least at 10.1% ($4.1 million) when estimated based on cholera cases reported to WHO. CONCLUSION: The economic burden of cholera in Asia provides a better understanding of financial offsets that can be achieved, and the value of investments on cholera control measures. With a clear understanding of the limitations of the underlying assumptions, the information may be used in economic evaluations and policy decisions.

Estimating Typhoid Fever Risk Associated with Lack of Access to Safe Water: A Systematic Literature Review.

Background: Unsafe water is a well-known risk for typhoid fever, but a pooled estimate of the population-level risk of typhoid fever resulting from exposure to unsafe water has not been quantified. An accurate estimation of the risk from unsafe water will be useful in demarcating high-risk populations, modeling typhoid disease burden, and targeting prevention and control activities. Methods: We conducted a systematic literature review and meta-analysis of observational studies that measured the risk of typhoid fever associated with drinking unimproved water as per WHO-UNICEF's definition or drinking microbiologically unsafe water. The mean value for the pooled odds ratio from case-control studies was calculated using a random effects model. In addition to unimproved water and unsafe water, we also listed categories of other risk factors from the selected studies. Results: The search of published studies from January 1, 1990, to December 31, 2013 in PubMed, Embase, and World Health Organization databases provided 779 publications, of which 12 case-control studies presented the odds of having typhoid fever for those exposed to unimproved or unsafe versus improved drinking water sources. The odds of typhoid fever among those exposed to unimproved or unsafe water ranged from 1.06 to 9.26 with case weighted mean of 2.44 (95% CI: 1.65-3.59). Besides water-related risk, the studies also identified other risk factors related to socioeconomic aspects, type of food consumption, knowledge and awareness about typhoid fever, and hygiene practices. Conclusions: In this meta-analysis, we have quantified the pooled risk of typhoid fever among people exposed to unimproved or unsafe water which is almost two and a half times more than people who were not exposed to unimproved or unsafe water. However, caution should be exercised in applying the findings from this study in modeling typhoid fever disease burden at country, regional, and global levels as improved water does not always equate to safe water.

Hepatitis E infection in Odisha, India: A descriptive analysis.

Up to 25% of hepatitis E virus (HEV)-infected pregnant women in their third trimester die. Despite HEV being an important cause of viral hepatitis, no robust surveillance exists in India. We reviewed jaundice outbreaks records and hospital records from jaundiced individuals seeking treatment and linked those records to laboratory results (HEV immunoglobulin M enzyme-linked immunosorbent assay) for January 2012 to September 2013 in Odisha state. A total of 14 HEV confirmed outbreaks were identified, of which 33% of 139 jaundiced cases were HEV positive. There were two deaths. An additional 495 jaundiced cases were identified through hospital records, of which 18% were HEV positive. Among HEV-positive women (n = 35), 34% were of childbearing age. While one may not be able to generalize our results, this finding suggests HE is widespread in Odisha and may represent hidden disease burden in this region. The policymakers should monitor HEV infections in similar geographical areas, especially among population of childbearing age women to initiate evidence-based control measures.

Geographical distribution of typhoid risk factors in low and middle income countries.

BACKGROUND: While the global burden of typhoid fever has been often brought up for attention, the detailed surveillance information has only been available for the limited number of countries. As more efficacious vaccines will be available in the near future, it is essential to understand the geographically diverse patterns of typhoid risk levels and to prioritize the right populations for vaccination to effectively control the disease. METHODS: A composite index called the typhoid risk factor (TRF) index was created based on data with the Global Positioning System (GPS). Demographic and Health Surveys (DHS) and National Geographical Data Center (NGDC) satellite lights data were used for this analysis. A count model was adopted to validate the TRF index against the existing surveillance burden data. The TRF index was then re-estimated for 66 countries using the most recent data and mapped out for two geographical levels (sub-national boundary and grid-cell levels). RESULTS: The TRF index which consists of drinking water sources, toilet facility types, and population density appeared to be statistically significant to explain variation in the disease burden data. The mapping analysis showed that typhoid risk levels vary not only by country but also by sub-national region. The grid-cell level analysis highlighted that the distribution of typhoid risk factors is uneven within the sub-national boundary level. Typhoid risk levels are geographically heterogeneous. CONCLUSIONS: Given the insufficient number of surveillance studies, the TRF index serves as a useful tool by capturing multiple risk factors of the disease into a single indicator. This will help decision makers identify high risk areas for typhoid as well as other waterborne diseases. Further, the study outcome can guide researchers to find relevant places for future surveillance studies.

What proportion of Salmonella Typhi cases are detected by blood culture? A systematic literature review.

Blood culture is often used in definitive diagnosis of typhoid fever while, bone marrow culture has a greater sensitivity and considered reference standard. The sensitivity of blood culture measured against bone marrow culture results in measurement bias because both tests are not fully sensitive. Here we propose a combination of the two cultures as a reference to define true positive S. Typhi cases. Based on a systematic literature review, we identified ten papers that had performed blood and bone marrow culture for S. Typhi in same subjects. We estimated the weighted mean of proportion of cases detected by culture measured against true S. Typhi positive cases using a random effects model. Of 529 true positive S. Typhi cases, 61 % (95 % CI 52-70 %) and 96 % (95 % CI 93-99 %) were detected by blood and bone marrow cultures respectively. Blood culture sensitivity was 66 % (95 % CI 56-75 %) when compared with bone marrow culture results. The use of blood culture sensitivity as a proxy measure to estimate the proportion of typhoid fever cases detected by blood culture is likely to be an underestimate. As blood culture sensitivity is used as a correction factor in estimating typhoid disease burden, epidemiologists and policy makers should account for the underestimation.

Revisiting typhoid fever surveillance in low and middle income countries: lessons from systematic literature review of population-based longitudinal studies.

BACKGROUND: The control of typhoid fever being an important public health concern in low and middle income countries, improving typhoid surveillance will help in planning and implementing typhoid control activities such as deployment of new generation Vi conjugate typhoid vaccines. METHODS: We conducted a systematic literature review of longitudinal population-based blood culture-confirmed typhoid fever studies from low and middle income countries published from 1(st) January 1990 to 31(st) December 2013. We quantitatively summarized typhoid fever incidence rates and qualitatively reviewed study methodology that could have influenced rate estimates. We used meta-analysis approach based on random effects model in summarizing the hospitalization rates. RESULTS: Twenty-two papers presented longitudinal population-based and blood culture-confirmed typhoid fever incidence estimates from 20 distinct sites in low and middle income countries. The reported incidence and hospitalizations rates were heterogeneous as well as the study methodology across the sites. We elucidated how the incidence rates were underestimated in published studies. We summarized six categories of under-estimation biases observed in these studies and presented potential solutions. CONCLUSIONS: Published longitudinal typhoid fever studies in low and middle income countries are geographically clustered and the methodology employed has a potential for underestimation. Future studies should account for these limitations.

An Estimation of Private Household Costs to Receive Free Oral Cholera Vaccine in Odisha, India.

BACKGROUND: Service provider costs for vaccine delivery have been well documented; however, vaccine recipients' costs have drawn less attention. This research explores the private household out-of-pocket and opportunity costs incurred to receive free oral cholera vaccine during a mass vaccination campaign in rural Odisha, India. METHODS: Following a government-driven oral cholera mass vaccination campaign targeting population over one year of age, a questionnaire-based cross-sectional survey was conducted to estimate private household costs among vaccine recipients. The questionnaire captured travel costs as well as time and wage loss for self and accompanying persons. The productivity loss was estimated using three methods: self-reported, government defined minimum daily wages and gross domestic product per capita in Odisha. FINDINGS: On average, families were located 282.7 (SD = 254.5) meters from the nearest vaccination booths. Most family members either walked or bicycled to the vaccination sites and spent on average 26.5 minutes on travel and 15.7 minutes on waiting. Depending upon the methodology, the estimated productivity loss due to potential foregone income ranged from $0.15 to $0.29 per dose of cholera vaccine received. The private household cost of receiving oral cholera vaccine constituted 24.6% to 38.0% of overall vaccine delivery costs. INTERPRETATION: The private household costs resulting from productivity loss for receiving a free oral cholera vaccine is a substantial proportion of overall vaccine delivery cost and may influence vaccine uptake. Policy makers and program managers need to recognize the importance of private costs and consider how to balance programmatic delivery costs with private household costs to receive vaccines.

Effectiveness of an oral cholera vaccine campaign to prevent clinically-significant cholera in Odisha State, India.

BACKGROUND: A clinical trial conducted in India suggests that the oral cholera vaccine, Shanchol, provides 65% protection over five years against clinically-significant cholera. Although the vaccine is efficacious when tested in an experimental setting, policymakers are more likely to use this vaccine after receiving evidence demonstrating protection when delivered to communities using local health department staff, cold chain equipment, and logistics. METHODS: We used a test-negative, case-control design to evaluate the effectiveness of a vaccination campaign using Shanchol and validated the results using a cohort approach that addressed disparities in healthcare seeking behavior. The campaign was conducted by the local health department using existing resources in a cholera-endemic area of Puri District, Odisha State, India. All non-pregnant residents one year of age and older were offered vaccine. Over the next two years, residents seeking care for diarrhea at one of five health facilities were asked to enroll following informed consent. Cases were patients seeking treatment for laboratory-confirmed V. cholera-associated diarrhea. Controls were patients seeking treatment for V. cholerae negative diarrhea. RESULTS: Of 51,488 eligible residents, 31,552 individuals received one dose and 23,751 residents received two vaccine doses. We identified 44 V. cholerae O1-associated cases and 366 non V. cholerae diarrhea controls. The adjusted protective effectiveness for persons receiving two doses was 69.0% (95% CI: 14.5% to 88.8%), which is similar to the adjusted estimates obtained from the cohort approach. A statistical trend test suggested a single dose provided a modicum of protection (33%, test for trend, p=0.0091). CONCLUSION: This vaccine was found to be as efficacious as the results reported from a clinical trial when administered to a rural population using local health personnel and resources. This study provides evidence that this vaccine should be widely deployed by public health departments in cholera endemic areas.

Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment.

BACKGROUND: No access to safe water is an important risk factor for typhoid fever, yet risk-level heterogeneity is unaccounted for in previous global burden estimates. Since WHO has recommended risk-based use of typhoid polysaccharide vaccine, we revisited the burden of typhoid fever in low-income and middle-income countries (LMICs) after adjusting for water-related risk. METHODS: We estimated the typhoid disease burden from studies done in LMICs based on blood-culture-confirmed incidence rates applied to the 2010 population, after correcting for operational issues related to surveillance, limitations of diagnostic tests, and water-related risk. We derived incidence estimates, correction factors, and mortality estimates from systematic literature reviews. We did scenario analyses for risk factors, diagnostic sensitivity, and case fatality rates, accounting for the uncertainty in these estimates and we compared them with previous disease burden estimates. FINDINGS: The estimated number of typhoid fever cases in LMICs in 2010 after adjusting for water-related risk was 11·9 million (95% CI 9·9-14·7) cases with 129 000 (75 000-208 000) deaths. By comparison, the estimated risk-unadjusted burden was 20·6 million (17·5-24·2) cases and 223 000 (131 000-344 000) deaths. Scenario analyses indicated that the risk-factor adjustment and updated diagnostic test correction factor derived from systematic literature reviews were the drivers of differences between the current estimate and past estimates. INTERPRETATION: The risk-adjusted typhoid fever burden estimate was more conservative than previous estimates. However, by distinguishing the risk differences, it will allow assessment of the effect at the population level and will facilitate cost-effectiveness calculations for risk-based vaccination strategies for future typhoid conjugate vaccine.

Case fatality rate and length of hospital stay among patients with typhoid intestinal perforation in developing countries: a systematic literature review.

BACKGROUND: Typhoid fever remains a major health problem in the developing world. Intestinal perforation is a lethal complication and continues to occur in impoverished areas despite advances in preventive and therapeutic strategies. OBJECTIVES: To estimate the case fatality rate (CFR) and length of hospital stay among patients with typhoid intestinal perforation in developing countries. DATA SOURCES: Peer-reviewed publications listed in PubMed and Google Scholar. STUDY ELIGIBILITY: The publications containing data on CFR or length of hospitalization for typhoid fever from low, lower middle and upper middle income countries based on World Bank classification. Limits are English language, human research and publication date from 1st January 1991 to 31st December 2011. PARTICIPANTS: Subjects with reported typhoid intestinal perforation. INTERVENTIONS: None, standard practice as reported in the publication. STUDY APPRAISAL AND SYNTHESIS METHODS: Systematic literature review followed by meta-analysis after regional classification on primary data. Descriptive methods were applied on secondary data. RESULTS: From 42 published reports, a total of 4,626 hospitalized typhoid intestinal perforation cases and 706 deaths were recorded (CFR = 15·4%; 95% CI; 13·0%-17·8%) with a significant regional differences. The overall mean length of hospitalization for intestinal perforation from 23 studies was 18.4 days (N = 2,542; 95% CI; 15.6-21.1). LIMITATIONS: Most typhoid intestinal perforation studies featured in this review were from a limited number of countries. CONCLUSIONS: The CFR estimated in this review is a substantial reduction from the 39.6% reported from a literature review for years 1960 to 1990. Aggressive resuscitation, appropriate antimicrobial coverage, and prompt surgical intervention may have contributed to decrease mortality. IMPLICATIONS: The quantification of intestinal perforation outcomes and its regional disparities as presented here is valuable in prioritizing and targeting typhoid-preventive interventions to the most affected areas.

Prevalence of specific learning disabilities among primary school children in a South Indian city.

OBJECTIVE: To measure the prevalence of specific learning disabilities (SpLDs) such as dyslexia, dysgraphia and dyscalculia among primary school children in a South Indian city. METHODS: A cross-sectional multi-staged stratified randomized cluster sampling study was conducted among children aged 8-11 years from third and fourth standard. A six level screening approach that commenced with identification of scholastic backwardness followed by stepwise exclusion of impaired vision and hearing, chronic medical conditions and subnormal intelligence was carried out among these children. In the final step, the remaining children were subjected to specific tests for reading, comprehension, writing and mathematical calculation. RESULTS: The prevalence of specific learning disabilities was 15.17% in sampled children, whereas 12.5%, 11.2% and 10.5% had dysgraphia, dyslexia and dyscalculia respectively. CONCLUSIONS: This study suggests that the prevalence of SpLDs is at the higher side of previous estimations in India. The study is unique due to its large geographically representative design and identification of the problem using simplified screening approach and tools, which minimizes the number and time of specialist requirement and spares the expensive investigation. This approach and tools are suitable for field situations and resource scarce settings. Based on the authors' experience, they express the need for more prevalence studies, remedial education and policy interventions to manage SpLDs at main stream educational system to improve the school performance in Indian children.