Economic evaluations of whole-genome sequencing for pathogen identification in public health surveillance and health-care-associated infections: a systematic review.

Whole-genome sequencing (WGS) has resulted in improvements to pathogen characterisation for the rapid investigation and management of disease outbreaks and surveillance. We conducted a systematic review to synthesise the economic evidence of WGS implementation for pathogen identification and surveillance. Of the 2285 unique publications identified through online database searches, 19 studies met the inclusion criteria. The economic evidence to support the broader application of WGS as a front-line pathogen characterisation and surveillance tool is insufficient and of low quality. WGS has been evaluated in various clinical settings, but these evaluations are predominantly investigations of a single pathogen. There are also considerable variations in the evaluation approach. Economic evaluations of costs, effectiveness, and cost-effectiveness are needed to support the implementation of WGS in public health settings.

The Cost of Foodborne Illness and Its Sequelae in Australia Circa 2019.

Foodborne illnesses cause a significant health burden, with Campylobacter and norovirus the most common causes of illness and Salmonella a common cause of hospitalization and occasional cause of death. Estimating the cost of illness can assist in quantifying this health burden, with pathogen-specific costs informing prioritization of interventions. We used a simulation-based approach to cost foodborne disease in Australia, capturing the cost of premature mortality, direct costs of nonfatal illness (including health care costs, medications, and tests), indirect costs of illness due to lost productivity, and costs associated with pain and suffering. In Australia circa 2019, the cost in Australian Dollars (AUD) of foodborne illness and its sequelae was 2.44 billion (90% uncertainty interval 1.65-3.68) each year, with the highest pathogen-specific costs for Campylobacter, non-typhoidal Salmonella, non-Shiga toxin-producing pathogenic Escherichia coli, and norovirus. The highest cost per case was for Listeria monocytogenes (AUD 776,000). Lost productivity was the largest component cost for foodborne illness due to all causes and for most individual pathogens; the exceptions were pathogens causing more severe illness such as Salmonella and L. monocytogenes, where premature mortality was the largest component cost. Foodborne illness results in a substantial cost to Australia; interventions to improve food safety across industry, retail, and consumers are needed to maintain public health safety.

Cost of whole genome sequencing for non-typhoidal Salmonella enterica.

BACKGROUND: While whole genome sequencing (WGS) may be more expensive than traditional testing and polymerase chain reaction (PCR), simple cost comparisons ignore the potential for WGS to reduce the societal costs of non-typhoidal Salmonella enterica through public health action to prevent illness. METHODS: We determined how many cases the use of WGS data would need to prevent to be cost-equal to serotyping and MLVA, or culture independent testing based on PCR in Australia. We then examined the costs and cost-savings of current typing methods compared with WGS in outbreak scenarios. RESULTS: A median of 275 (90% CrI -55-775) or 1.9% (90% CrI -0.4%-5.4%) of notified serotyped Salmonella cases would need to be prevented for WGS to be cost-equal to current typing methods and 1,550 (90% CrI 820-2,725) or 9.6% of all notified Salmonella cases would need to be prevented to be cost-equal to PCR. WGS is likely to result in cost savings in prolonged outbreaks, where data can support earlier public health action. CONCLUSIONS: Despite currently having a higher cost per isolate, routine WGS of Salmonella was no more expensive than existing typing methods or PCR where >2% of illness was averted.

Antibiotic Use Associated with Confirmed Influenza, Pertussis, and Nontyphoidal Salmonella Infections.

Purpose: Antibiotics are not the recommended treatment for uncomplicated influenza or nontyphoidal salmonella infections, whereas they are for current pertussis infection. We investigated adherence to these recommendations in a population of older community-dwelling adults. Methods: Population-based prospective cohort study of Australian adults 45 years of age and older followed by record-linkage to laboratory-confirmed influenza, pertussis, and nontyphoidal salmonella notifications, hospitalization records, and antibiotic dispensing data from January 1, 2009 to December 31, 2015. Proportions of those with infections who were prescribed antibiotics were estimated, and characteristics associated with antibiotic prescribing were examined. Results: There were 1,056 influenza, 151 pertussis, and 334 nontyphoidal salmonella cases in the cohort eligible for analysis. Antibiotics were dispensed in 56.2% (594/1,056) of influenza, 78.8% (119/151) of pertussis, and 39.5% (132/334) of nontyphoidal salmonella cases within the ±10-day window around the infection onset date. The likelihood of antibiotic dispensing did not differ according to most participant characteristics examined, including whether cases had an associated hospitalization, their age, and recorded comorbidities. Macrolides were the predominant class of antibiotics dispensed for pertussis (79%), whereas both beta-lactams (36.3%) and macrolides (35.4%) were used for cases of influenza. There was no dominant antibiotic class dispensed among those with nontyphoidal salmonella. Conclusions: Given concerns regarding increasing antibiotic resistance, the high proportion of adults with influenza and nontyphoidal salmonella cases dispensed antibiotics indicate the need for further strengthening of antimicrobial stewardship by raising education and awareness of guidelines for managing these infections.

Socio-demographic and health service factors associated with antibiotic dispensing in older Australian adults.

BACKGROUND: Widespread use of antibiotics has led to the development of antibiotic resistance. However, there are limited data describing antibiotic use in the community setting, and examining factors associated with greater use. Our study aimed to quantify antibiotic dispensing in older adults in the community according to socio-demographics and health services use. METHODS: Prospective analysis of a population-based cohort study of 239,981 adults aged ≥45 years in Australia (the Sax Institute's 45 and Up Study). Data on socio-demographics and health from a questionnaire, were linked to 2015 antibiotic dispensing data from the Pharmaceutical Benefits Scheme (PBS), as well as other administrative health databases. We estimated the Defined Daily Dose (DDD) of systemic antibiotics dispensed, defined by an Anatomic Therapeutic Classification code beginning with J01, in 2015. We also conducted Poisson regression with robust standard errors to identify factors associated with antibiotic dispensing. RESULTS: Overall, 49.3% of 45 and Up Study participants had at least one systemic antibiotic dispensed in 2015 with a total of 392,856 prescriptions dispensed and an average of 36.5 DDDs/1000-persons/day in the study population. The quantity of antibiotics dispensed increased with increasing age (25.6 DDDs/1000/day in <60 years old versus 50.4 DDDs/1000/day in 80+ year old) and was higher comparing women to men (39.9 versus 32.4 DDDs/1000/day). Of factors examined, the greatest dispensing of antibiotics was among those who had been resident in an aged care facility and those with >15 general practitioner consultations in the last year (80.5 and 88.3 DDDs/1000/day, respectively). These factors remained strongly associated with greater antibiotic dispensing after adjusting for age, sex, education, income, area of residence and co-morbidities. CONCLUSIONS: Residence in aged care facilities and high GP visits are associated with greater antibiotic dispensing. This study provides important evidence regarding high use groups for antimicrobial stewardship.

Cost of Salmonella Infections in Australia, 2015.

Gastroenteritis caused from infections with Salmonella enterica (salmonellosis) causes significant morbidity in Australia. In addition to acute gastroenteritis, approximately 8.8% of people develop irritable bowel syndrome (IBS) and 8.5% of people develop reactive arthritis (ReA). We estimated the economic cost of salmonellosis and associated sequel illnesses in Australia in a typical year circa 2015. We estimated incidence, hospitalizations, other health care usage, absenteeism, and premature mortality for four age groups using a variety of complementary data sets. We calculated direct costs (health care) and indirect costs (lost productivity and premature mortality) by using Monte Carlo simulation to estimate 90% credible intervals (CrI) around our point estimates. We estimated that 90,833 cases, 4,312 hospitalizations, and 19 deaths occurred from salmonellosis in Australia circa 2015 at a direct cost of AUD 23.8 million (90% CrI, 19.3 to 28.9 million) and a total cost of AUD 124.4 million (90% CrI, 107.4 to 143.1 million). When IBS and ReA were included, the estimated direct cost was 35.7 million (90% CrI, 29.9 to 42.7 million) and the total cost was AUD 146.8 million (90% CrI, 127.8 to 167.9 million). Foodborne infections were responsible for AUD 88.9 million (90% CrI, 63.9 to 112.4 million) from acute salmonellosis and AUD 104.8 million (90% CrI, 75.5 to 132.3 million) when IBS and ReA were included. Targeted interventions to prevent illness could considerably reduce costs and societal impact from Salmonella infections and sequel illnesses in Australia.

Global disease burden of pathogens in animal source foods, 2010.

Animal source foods (ASF) such as dairy, eggs, fish and meat are an important source of high-quality nutrients. Lack of ASF in diets can result in developmental disorders including stunting, anemia, poor cognitive and motor development. ASF are more effective in preventing stunting than other foods and promoting ASF consumption in low- and middle-income countries could help improve health, particularly among pregnant women and young children. Production and consumption of ASF are, however, also associated with potential food safety risks. Strengthening of food control systems, informed by quantitative assessments of the disease burden associated with ASF is necessary to meet global nutrition goals. We present the human disease burden associated with 13 pathogens (bacteria and parasites) in ASF, based on an analysis of global burden of foodborne disease (FBD) estimates of the WHO Foodborne Disease Burden Epidemiology Reference Group (FERG). The FBD burden of these pathogens was combined with estimates of the proportion of disease transmitted by eight main groups of ASF. Uncertainty in all estimates was accounted for by Monte Carlo simulation. In 2010, the global burden of ASF was 168 (95% uncertainty interval (UI 137-219) Disability Adjusted Life Years (DALYs) per 100,000 population, which is approximately 35% of the estimated total burden of FBD. Main pathogens contributing to this burden included non-typhoidal Salmonella enterica, Taenia solium, and Campylobacter spp. The proportion of FBD burden associated with ASF varied considerably between subregions and between countries within subregions. Likewise, the contribution of different pathogens and ASF groups varied strongly between subregions. Pathogens with a localized distribution included T. solium and fishborne trematodes. Pathogens with a global distribution included non-typhoidal S. enterica, Campylobacter spp., Toxoplasma gondii, and Mycobacterium bovis. Control methods exist for many hazards associated with ASF, and their implementation is linked to economic development and effective food safety systems.

Evaluation of the early warning, alert and response system after Cyclone Winston, Fiji, 2016.

OBJECTIVE: To assess the performance of an early warning, alert and response system (EWARS) developed by the World Health Organization (WHO) - EWARS in a Box - that was used to detect and control disease outbreaks after Cyclone Winston caused destruction in Fiji on 20 February 2016. METHODS: Immediately after the cyclone, Fiji's Ministry of Health and Medical Services, supported by WHO, started to implement EWARS in a Box, which is a smartphone-based, automated, early warning surveillance system for rapid deployment during health emergencies. Both indicator-based and event-based surveillance were employed. The performance of the system between 7 March and 29 May 2016 was evaluated. Users' experience with the system was assessed in interviews using a semi-structured questionnaire and by a cross-sectional survey. The system's performance was assessed using data from the EWARS database. FINDINGS: Indicator-based surveillance recorded 34 113 cases of the nine syndromes under surveillance among 326 861 consultations. Three confirmed outbreaks were detected, and no large outbreak was missed. Users were satisfied with the performance of EWARS and judged it useful for timely monitoring of disease trends and outbreak detection. The system was simple, stable and flexible and could be rapidly deployed during a health emergency. The automated collation, analysis and dissemination of data reduced the burden on surveillance teams, saved human resources, minimized human error and ensured teams could focus on public health responses. CONCLUSION: In Fiji, EWARS in a Box was effective in strengthening disease surveillance during a national emergency and was well regarded by users.

Burden of Clostridium difficile infection: Associated hospitalization in a cohort of middle-aged and older adults.

BACKGROUND: Clostridium difficile is the principal cause of infectious diarrhea in hospitalized patients. The aim of this study was to describe and compare length of stay (LOS), costs, and in-hospital deaths for C difficile infection (CDI) and non-CDI hospitalizations, in a cohort of middle-aged and older Australians. METHODS: We used survey data from the 45 and Up Study, linked to hospitalization and death data. We calculated the average LOS and costs per hospitalization, and the proportion of in-hospital deaths for CDI and non-CDI hospitalizations. We then compared hospitalizations with CDI as a secondary diagnosis to non-CDI hospitalizations by stratifying hospitalizations based on principal diagnosis and then using generalized linear models to compare LOS and in-hospital costs, and logistic regression for in-hospital deaths, adjusting for age and sex. RESULTS: There were 641 CDI hospitalizations during 2006-2012. The average LOS was 17 days; the average cost per hospitalization was AUD 12,704; and in 7.3% of admissions (47 out of 641) the patient died. After adjusting for age and sex, hospitalizations with CDI were associated with longer LOS, higher costs, and a greater proportion of in-hospital deaths compared with hospitalizations with similar principal diagnosis but without CDI. CONCLUSIONS: CDI places additional burden on the Australian hospital system, with CDI patients having relatively lengthy hospital stays and high costs.

Aetiology-Specific Estimates of the Global and Regional Incidence and Mortality of Diarrhoeal Diseases Commonly Transmitted through Food.

BACKGROUND: Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children. However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available. The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods. METHODS AND FINDINGS: We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region. The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1-3.3 billion) cases and 599,000 (95% UI 472,000-802,000) deaths worldwide in 2010. The largest number of cases were caused by norovirus (677 million; 95% UI 468-1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154-380 million), Shigella spp. (188 million; 95% UI 94-379 million) and Giardia lamblia (179 million; 95% UI 125-263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783-266,561), enteropathogenic E. coli (121,455; 95% UI 103,657-143,348), ETEC (73,041; 95% UI 55,474-96,984) and Shigella (64,993; 95% UI 48,966-92,357). There were marked regional differences in incidence and mortality for these nine diseases. Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age. CONCLUSIONS: Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children. These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods.

World Health Organization Estimates of the Global and Regional Disease Burden of 11 Foodborne Parasitic Diseases, 2010: A Data Synthesis.

BACKGROUND: Foodborne diseases are globally important, resulting in considerable morbidity and mortality. Parasitic diseases often result in high burdens of disease in low and middle income countries and are frequently transmitted to humans via contaminated food. This study presents the first estimates of the global and regional human disease burden of 10 helminth diseases and toxoplasmosis that may be attributed to contaminated food. METHODS AND FINDINGS: Data were abstracted from 16 systematic reviews or similar studies published between 2010 and 2015; from 5 disease data bases accessed in 2015; and from 79 reports, 73 of which have been published since 2000, 4 published between 1995 and 2000 and 2 published in 1986 and 1981. These included reports from national surveillance systems, journal articles, and national estimates of foodborne diseases. These data were used to estimate the number of infections, sequelae, deaths, and Disability Adjusted Life Years (DALYs), by age and region for 2010. These parasitic diseases, resulted in 48.4 million cases (95% Uncertainty intervals [UI] of 43.4-79.0 million) and 59,724 (95% UI 48,017-83,616) deaths annually resulting in 8.78 million (95% UI 7.62-12.51 million) DALYs. We estimated that 48% (95% UI 38%-56%) of cases of these parasitic diseases were foodborne, resulting in 76% (95% UI 65%-81%) of the DALYs attributable to these diseases. Overall, foodborne parasitic disease, excluding enteric protozoa, caused an estimated 23.2 million (95% UI 18.2-38.1 million) cases and 45,927 (95% UI 34,763-59,933) deaths annually resulting in an estimated 6.64 million (95% UI 5.61-8.41 million) DALYs. Foodborne Ascaris infection (12.3 million cases, 95% UI 8.29-22.0 million) and foodborne toxoplasmosis (10.3 million cases, 95% UI 7.40-14.9 million) were the most common foodborne parasitic diseases. Human cysticercosis with 2.78 million DALYs (95% UI 2.14-3.61 million), foodborne trematodosis with 2.02 million DALYs (95% UI 1.65-2.48 million) and foodborne toxoplasmosis with 825,000 DALYs (95% UI 561,000-1.26 million) resulted in the highest burdens in terms of DALYs, mainly due to years lived with disability. Foodborne enteric protozoa, reported elsewhere, resulted in an additional 67.2 million illnesses or 492,000 DALYs. Major limitations of our study include often substantial data gaps that had to be filled by imputation and suffer from the uncertainties that surround such models. Due to resource limitations it was also not possible to consider all potentially foodborne parasites (for example Trypanosoma cruzi). CONCLUSIONS: Parasites are frequently transmitted to humans through contaminated food. These estimates represent an important step forward in understanding the impact of foodborne diseases globally and regionally. The disease burden due to most foodborne parasites is highly focal and results in significant morbidity and mortality among vulnerable populations.

World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases, 2010: A Data Synthesis.

BACKGROUND: Foodborne diseases are important worldwide, resulting in considerable morbidity and mortality. To our knowledge, we present the first global and regional estimates of the disease burden of the most important foodborne bacterial, protozoal, and viral diseases. METHODS AND FINDINGS: We synthesized data on the number of foodborne illnesses, sequelae, deaths, and Disability Adjusted Life Years (DALYs), for all diseases with sufficient data to support global and regional estimates, by age and region. The data sources included varied by pathogen and included systematic reviews, cohort studies, surveillance studies and other burden of disease assessments. We sought relevant data circa 2010, and included sources from 1990-2012. The number of studies per pathogen ranged from as few as 5 studies for bacterial intoxications through to 494 studies for diarrheal pathogens. To estimate mortality for Mycobacterium bovis infections and morbidity and mortality for invasive non-typhoidal Salmonella enterica infections, we excluded cases attributed to HIV infection. We excluded stillbirths in our estimates. We estimate that the 22 diseases included in our study resulted in two billion (95% uncertainty interval [UI] 1.5-2.9 billion) cases, over one million (95% UI 0.89-1.4 million) deaths, and 78.7 million (95% UI 65.0-97.7 million) DALYs in 2010. To estimate the burden due to contaminated food, we then applied proportions of infections that were estimated to be foodborne from a global expert elicitation. Waterborne transmission of disease was not included. We estimate that 29% (95% UI 23-36%) of cases caused by diseases in our study, or 582 million (95% UI 401-922 million), were transmitted by contaminated food, resulting in 25.2 million (95% UI 17.5-37.0 million) DALYs. Norovirus was the leading cause of foodborne illness causing 125 million (95% UI 70-251 million) cases, while Campylobacter spp. caused 96 million (95% UI 52-177 million) foodborne illnesses. Of all foodborne diseases, diarrheal and invasive infections due to non-typhoidal S. enterica infections resulted in the highest burden, causing 4.07 million (95% UI 2.49-6.27 million) DALYs. Regionally, DALYs per 100,000 population were highest in the African region followed by the South East Asian region. Considerable burden of foodborne disease is borne by children less than five years of age. Major limitations of our study include data gaps, particularly in middle- and high-mortality countries, and uncertainty around the proportion of diseases that were foodborne. CONCLUSIONS: Foodborne diseases result in a large disease burden, particularly in children. Although it is known that diarrheal diseases are a major burden in children, we have demonstrated for the first time the importance of contaminated food as a cause. There is a need to focus food safety interventions on preventing foodborne diseases, particularly in low- and middle-income settings.

Methodological Framework for World Health Organization Estimates of the Global Burden of Foodborne Disease.

BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization to estimate the global burden of foodborne diseases (FBDs). This paper describes the methodological framework developed by FERG's Computational Task Force to transform epidemiological information into FBD burden estimates. METHODS AND FINDINGS: The global and regional burden of 31 FBDs was quantified, along with limited estimates for 5 other FBDs, using Disability-Adjusted Life Years in a hazard- and incidence-based approach. To accomplish this task, the following workflow was defined: outline of disease models and collection of epidemiological data; design and completion of a database template; development of an imputation model; identification of disability weights; probabilistic burden assessment; and estimating the proportion of the disease burden by each hazard that is attributable to exposure by food (i.e., source attribution). All computations were performed in R and the different functions were compiled in the R package 'FERG'. Traceability and transparency were ensured by sharing results and methods in an interactive way with all FERG members throughout the process. CONCLUSIONS: We developed a comprehensive framework for estimating the global burden of FBDs, in which methodological simplicity and transparency were key elements. All the tools developed have been made available and can be translated into a user-friendly national toolkit for studying and monitoring food safety at the local level.

World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010.

Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old-although they represent only 9% of the global population-and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels.

Economic costs of Shiga toxin-producing Escherichia coli infection in Australia.

Shiga toxin-producing Escherichia coli (STEC) infections are an important cause of foodborne disease in Australia. Three percent to 7% of sporadic patients develop hemolytic uremic syndrome (HUS) and 40% of patients with HUS develop chronic complications. To examine costs associated with illness, we interviewed patients notified to the South Australian Department of Health with a structured questionnaire regarding severity of illness, medical treatment, time lost from work, hospitalization, and other costs. In 2003-2006, we interviewed 46 patients of STEC infection, 2 of whom developed HUS. The median duration of illness was 7 days (range 3-31 days) and 41% (19/46) of patients were admitted to hospital. The estimated total cost for the 46 STEC cases in South Australia was AUD$144,087, equating to a mean cost of AUD$3132 per case. We estimate that the annual total costs of STEC infection in South Australia and Australia are AUD$200,283 and AUD$2,633,181, respectively. We used linear regression to identify that STEC infection costs increase by AUD$608 per day regardless of severity, and that more severe illness is strong predictor of cost. This is the first Australian study to examine costs of STEC infection and highlights the significant impact of this illness.