Rivers, rainfall, and risk factors:geostatistical and epidemiological approaches to disentangle potential transmission routes of typhoid fever

Typhoid fever, caused by the bacterium Salmonella Typhi, is a severe febrile illness, with over 20 million cases and 100 thousand deaths occurring annually. In 2011, Blantyre, Malawi experienced a sharp increase in the incidence of typhoid fever, and transmission continues today. Although the disease is generally known to spread through the fecal-oral route, the precise mechanisms of transmission in endemic locations are not well characterized. Therefore, a challenge exists in determining which water and sanitation interventions may be the most important for control of typhoid fever. This thesis attempts to identify risk factors for typhoid fever in this setting, and employs geostatistical, epidemiological, and genomic approaches to data collected as part of routine disease surveillance as well as typhoid-specific epidemiological studies. The findings from this thesis indicate that transmission of typhoid fever in Blantyre is complex, with both environmental and social factors important components. Evidence of environmental transmission as found, through the use of non-drinking water from local rivers identified as a risk factor. This finding was used to generate hypotheses: testing whether river catchments are predictors of genomic patterns, and exploring rainfall anomalies as time-dependent predictors of incidence. Both investigations yielded significant results: river catchments were predictors of genomic patterns, and rainfall anomalies were found to be protective, further bolstering the hypothesized environmental component of transmission. Typhoid fever can also lead to severe clinical complications, and a methodological contribution was included that enabled the attribution of intestinal perforations to typhoid fever, independent of microbiological testing. Although new vaccines for typhoid offer a promising tool for control, investment in non-vaccine interventions will likely be critical for elimination, and the work presented suggests possible opportunities for interventions focused around hydrological systems and water usage

Cost-effectiveness of using environmental surveillance to target the roll-out typhoid conjugate vaccine

Typhoid conjugate vaccine (TCV) has been shown to be costeffective in some settings, but to make the most of limited healthcare funds, the WHO recommends that decisions about when and where to introduce TCV should be based on local evidence of transmission. Further, Gavi, The Vaccine Alliance, recommends that countries request TCV funding based on epidemiological data from within-country. Since few countries have reliable case reporting, we considered environmental surveillance as a decision-support tool for vaccine introduction choices. Environmental surveillance methods are still in development and this analysis assesses its potential as a decision support tool. We combined a disease transmission simulation model with an economic model, to quantify the value of surveillance. The disease transmission model is fit to historical case reporting from Blantyre, Malawi. The economic model takes a social perspective and incorporates the cost of environmental surveillance, vaccination, and both direct and indirect cost of care for acute typhoid cases. We find that the use of time-limited environmental surveillance to differentiate low- from high-endemicity areas is low cost relative to potential savings, especially if it is paired with a locally targeted vaccination campaign. These findings are robust to the uncertainty of cost model parameters and underlying endemicity

Respiratory infection in the hospital setting : modeling transmission patterns and intervention strategies using multitype contact networks

Respiratory infections in the hospital setting are a burden to patients, healthcare workers and the surrounding community. The patterns of disease spread in hospital settings are difficult to capture, due to the heterogeneous rates of contact among healthcare workers (HCWs). Patterns of healthcare worker contact were analyzed for a large Canadian hospital. A novel tool was developed to capture the heterogeneous patterns in contact in hospital settings, and data from the Canadian hospital was used to inform a realistic contact network. The spread of respiratory infections with reproductive numbers approximating SARS, influenza, and measles were simulated on the network, and control strategies including vaccination, transmission reduction, and social distancing were tested. The efficacies of measures were compared between subsets of the population, which were divided by occupation and contact rate. The results of this study found that nurses are in the most contact with other healthcare workers, but the least mobile. Additionally, “other” healthcare workers such as respiratory therapists are at a high likelihood for superspreading events in the hospital setting. This study also identified locations that would reach a large subset of the hospital, which could be used for hand-washing stations or other interventions. Simulations suggest targeting the most highly connected HCW occupations for vaccination, transmission reduction measures, and social distancing may lead to more effective disease containment in outbreak scenarios, and a reduction in resources needed. The results of this study can be used to inform policy decisions, and direct future research towards targeted control strategies in hospital settings.Medicine, Faculty ofPopulation and Public Health (SPPH), School ofGraduat

Cost-effectiveness of using environmental surveillance to target the roll-out typhoid conjugate vaccine

Typhoid conjugate vaccine (TCV) has been shown to be costeffective in some settings, but to make the most of limited healthcare funds, the WHO recommends that decisions about when and where to introduce TCV should be based on local evidence of transmission. Further, Gavi, The Vaccine Alliance, recommends that countries request TCV funding based on epidemiological data from within-country. Since few countries have reliable case reporting, we considered environmental surveillance as a decision-support tool for vaccine introduction choices. Environmental surveillance methods are still in development and this analysis assesses its potential as a decision support tool. We combined a disease transmission simulation model with an economic model, to quantify the value of surveillance. The disease transmission model is fit to historical case reporting from Blantyre, Malawi. The economic model takes a social perspective and incorporates the cost of environmental surveillance, vaccination, and both direct and indirect cost of care for acute typhoid cases. We find that the use of time-limited environmental surveillance to differentiate low- from high-endemicity areas is low cost relative to potential savings, especially if it is paired with a locally targeted vaccination campaign. These findings are robust to the uncertainty of cost model parameters and underlying endemicity

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

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

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.Medicine, Faculty ofNon UBCPopulation and Public Health (SPPH), School ofReviewedFacult

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

Total and operational costs per sample.

Table A in S3 Text. Total and operational costs per sample (modeled). (DOCX)</p

Cost model components, categorized by type and color-coded by function.

Detailed descriptions and formulas can be found in Table A in S3 Text. Operational costs include labor, truck operations and maintenance, equipment maintenance, and consumables.</p