Spatial and Genomic Data to Characterize Endemic Typhoid Transmission.

BACKGROUND: Diverse environmental exposures and risk factors have been implicated in the transmission of Salmonella Typhi, but the dominant transmission pathways through the environment to susceptible humans remain unknown. Here, we use spatial, bacterial genomic, and hydrological data to refine our view of typhoid transmission in an endemic setting. METHODS: A total of 546 patients presenting to Queen Elizabeth Central Hospital in Blantyre, Malawi, with blood culture-confirmed typhoid fever between April 2015 and January 2017 were recruited to a cohort study. The households of a subset of these patients were geolocated, and 256 S. Typhi isolates were whole-genome sequenced. Pairwise single-nucleotide variant distances were incorporated into a geostatistical modeling framework using multidimensional scaling. RESULTS: Typhoid fever was not evenly distributed across Blantyre, with estimated minimum incidence ranging across the city from <15 to >100 cases per 100 000 population per year. Pairwise single-nucleotide variant distance and physical household distances were significantly correlated (P = .001). We evaluated the ability of river catchment to explain the spatial patterns of genomics observed, finding that it significantly improved the fit of the model (P = .003). We also found spatial correlation at a smaller spatial scale, of households living <192 m apart. CONCLUSIONS: These findings reinforce the emerging view that hydrological systems play a key role in the transmission of typhoid fever. By combining genomic and spatial data, we show how multifaceted data can be used to identify high incidence areas, explain the connections between them, and inform targeted environmental surveillance, all of which will be critical to shape local and regional typhoid control strategies.

Rainfall anomalies and typhoid fever in Blantyre, Malawi.

Typhoid fever is a major cause of illness and mortality in low- and middle-income settings. We investigated the association of typhoid fever and rainfall in Blantyre, Malawi, where multi-drug-resistant typhoid has been transmitting since 2011. Peak rainfall preceded the peak in typhoid fever by approximately 15 weeks [95% confidence interval (CI) 13.3, 17.7], indicating no direct biological link. A quasi-Poisson generalised linear modelling framework was used to explore the relationship between rainfall and typhoid incidence at biologically plausible lags of 1-4 weeks. We found a protective effect of rainfall anomalies on typhoid fever, at a two-week lag (P = 0.006), where a 10 mm lower-than-expected rainfall anomaly was associated with up to a 16% reduction in cases (95% CI 7.6, 26.5). Extreme flooding events may cleanse the environment of S. Typhi, while unusually low rainfall may reduce exposure from sewage overflow. These results add to evidence that rainfall anomalies may play a role in the transmission of enteric pathogens, and can help direct future water and sanitation intervention strategies for the control of typhoid fever.

Domestic River Water Use and Risk of Typhoid Fever: Results From a Case-control Study in Blantyre, Malawi.

BACKGROUND: Typhoid fever remains a major cause of morbidity and mortality in low- and middle-income settings. In the last 10 years, several reports have described the reemergence of typhoid fever in southern and eastern Africa, associated with multidrug-resistant H58 Salmonella Typhi. Here, we identify risk factors for pediatric typhoid fever in a large epidemic in Blantyre, Malawi. METHODS: A case-control study was conducted between April 2015 and November 2016. Cases were recruited at a large teaching hospital, and controls were recruited from the community, matched by residential ward. Stepwise variable selection and likelihood ratio testing were used to select candidate risk factors for a final logistic regression model. RESULTS: Use of river water for cooking and cleaning was highly associated with risk of typhoid fever (odds ratio [OR], 4.6 [95% confidence interval {CI}, 1.7-12.5]). Additional risk factors included protective effects of soap in the household (OR, 0.6 [95% CI, .4-.98]) and >1 water source used in the previous 3 weeks (OR, 3.2 [95% CI, 1.6-6.2]). Attendance at school or other daycare was also identified as a risk factor (OR, 2.7 [95% CI, 1.4-5.3]) and was associated with the highest attributable risk (51.3%). CONCLUSIONS: These results highlight diverse risk factors for typhoid fever in Malawi, with implications for control in addition to the provision of safe drinking water. There is an urgent need to improve our understanding of transmission pathways of typhoid fever, both to develop tools for detecting S. Typhi in the environment and to inform water, sanitation, and hygiene interventions.

Intestinal Perforations Associated With a High Mortality and Frequent Complications During an Epidemic of Multidrug-resistant Typhoid Fever in Blantyre, Malawi.

BACKGROUND: Typhoid fever remains a major source of morbidity and mortality in low-income settings. Its most feared complication is intestinal perforation. However, due to the paucity of diagnostic facilities in typhoid-endemic settings, including microbiology, histopathology, and radiology, the etiology of intestinal perforation is frequently assumed but rarely confirmed. This poses a challenge for accurately estimating burden of disease. METHODS: We recruited a prospective cohort of patients with confirmed intestinal perforation in 2016 and performed enhanced microbiological investigations (blood and tissue culture, plus tissue polymerase chain reaction [PCR] for Salmonella Typhi). In addition, we used a Poisson generalized linear model to estimate excess perforations attributed to the typhoid epidemic, using temporal trends in S. Typhi bloodstream infection and perforated abdominal viscus at Queen Elizabeth Central Hospital from 2008-2017. RESULTS: We recruited 23 patients with intraoperative findings consistent with intestinal perforation. 50% (11/22) of patients recruited were culture or PCR positive for S. Typhi. Case fatality rate from typhoid-associated intestinal perforation was substantial at 18% (2/11). Our statistical model estimates that culture-confirmed cases of typhoid fever lead to an excess of 0.046 perforations per clinical typhoid fever case (95% CI, .03-.06). We therefore estimate that typhoid fever accounts for 43% of all bowel perforation during the period of enhanced surveillance. CONCLUSIONS: The morbidity and mortality associated with typhoid abdominal perforations are high. By placing clinical outcome data from a cohort in the context of longitudinal surgical registers and bacteremia data, we describe a valuable approach to adjusting estimates of the burden of typhoid fever.

Tenacious Endemic Typhoid Fever in Samoa.

BACKGROUND: Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation. METHODS: Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person. RESULTS: In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases. CONCLUSIONS: Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned.

A proposed case-control framework to probabilistically classify individual deaths as expected or excess during extreme hot weather events.

BACKGROUND: Most excess deaths that occur during extreme hot weather events do not have natural heat recorded as an underlying or contributing cause. This study aims to identify the specific individuals who died because of hot weather using only secondary data. A novel approach was developed in which the expected number of deaths was repeatedly sampled from all deaths that occurred during a hot weather event, and compared with deaths during a control period. The deaths were compared with respect to five factors known to be associated with hot weather mortality. Individuals were ranked by their presence in significant models over 100 trials of 10,000 repetitions. Those with the highest rankings were identified as probable excess deaths. Sensitivity analyses were performed on a range of model combinations. These methods were applied to a 2009 hot weather event in greater Vancouver, Canada. RESULTS: The excess deaths identified were sensitive to differences in model combinations, particularly between univariate and multivariate approaches. One multivariate and one univariate combination were chosen as the best models for further analyses. The individuals identified by multiple combinations suggest that marginalized populations in greater Vancouver are at higher risk of death during hot weather. CONCLUSIONS: This study proposes novel methods for classifying specific deaths as expected or excess during a hot weather event. Further work is needed to evaluate performance of the methods in simulation studies and against clinically identified cases. If confirmed, these methods could be applied to a wide range of populations and events of interest.

Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness.

Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9 months of age, and routine vaccination at 9 months with a one-time catch-up campaign (ages 9 months to 15 years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10 years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46 % over a 10-year time horizon under an optimistic scenario (95 % initial vaccine efficacy and 19-year mean duration of protection), and by 2-16 % under a pessimistic scenario (82 % initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90 % and 6-35 % in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.

Typhoid fever in Santiago, Chile: Insights from a mathematical model utilizing venerable archived data from a successful disease control program.

Typhoid fever is endemic in many developing countries. In the early 20th century, newly industrializing countries including the United States successfully controlled typhoid as water treatment (chlorination/sand filtration) and improved sanitation became widespread. Enigmatically, typhoid remained endemic through the 1980s in Santiago, Chile, despite potable municipal water and widespread household sanitation. Data were collected across multiple stages of endemicity and control in Santiago, offering a unique resource for gaining insight into drivers of transmission in modern settings. We developed an individual-based mathematical model of typhoid transmission, with model components including distinctions between long-cycle and short-cycle transmission routes. Data used to fit the model included the prevalence of chronic carriers, seasonality, longitudinal incidence, and age-specific distributions of typhoid infection and disease. Our model captured the dynamics seen in Santiago across endemicity, vaccination, and environmental control. Both vaccination and diminished exposure to seasonal amplified long-cycle transmission contributed to the observed declines in typhoid incidence, with the vaccine estimated to elicit herd effects. Vaccines are important tools for controlling endemic typhoid, with even limited coverage eliciting herd effects in this setting. Removing the vehicles responsible for amplified long-cycle transmission and assessing the role of chronic carriers in endemic settings are additional key elements in designing programs to achieve accelerated control of endemic typhoid.

Implementation and applications of EMOD, an individual-based multi-disease modeling platform.

Individual-based models provide modularity and structural flexibility necessary for modeling of infectious diseases at the within-host and population levels, but are challenging to implement. Levels of complexity can exceed the capacity and timescales for students and trainees in most academic institutions. Here we describe the process and advantages of a multi-disease framework approach developed with formal software support. The epidemiological modeling software, EMOD, has undergone a decade of software development. It is structured so that a majority of code is shared across disease modeling including malaria, HIV, tuberculosis, dengue, polio and typhoid. In additional to implementation efficiency, the sharing increases code usage and testing. The freely available codebase also includes hundreds of regression tests, scientific feature tests and component tests to help verify functionality and avoid inadvertent changes to functionality during future development. Here we describe the levels of detail, flexible configurability and modularity enabled by EMOD and the role of software development principles and processes in its development.