Acute Complications and Sequelae from Foodborne Infections: Informing Priorities for Cost of Foodborne Illness Estimates

Abstract

Cost of foodborne illness (CoFI) estimates provide estimates of the overall impact of foodborne illnesses, including hospitalizations, long-term complications, and deaths. CoFI estimates are needed in countries that require cost–benefit analysis as part of the process of adopting new regulations, as is the case in the United States. Monetary estimates of the impact of disease also provide a meaningful way of communicating with the public about the impact of foodborne disease.

In 2014, researchers at the U.S. Department of Agriculture, Economic Research Service (ERS), published CoFI estimates for 15 pathogens that account for roughly 95% of illnesses and deaths from the 31 major foodborne pathogens included in the Centers for Disease Control and Prevention (CDC) foodborne disease incidence estimates. ERS is currently updating their estimates to include all 31 known pathogens and unspecific agents included in CDC incidence estimates. CoFI estimates are based on quantitative models of the health outcomes people experience as a result of these illnesses and an assessment of the costs associated with these health outcomes. Research on the incidence of foodborne disease provides a starting point for this disease modeling, but it usually must be supplemented by other additional synthesis of research on acute complications and long-term health outcomes of different foodborne diseases.

As part of its current work revising CoFI estimates, ERS convened a workshop attended by leading foodborne disease public health scientists to discuss how changes in scientific research on the incidence and outcomes of foodborne illnesses should inform the next revision of ERS's CoFI estimates. This article presents a summary, based on discussion at this workshop, of the state of scientific research available to inform updated economic modeling of the CoFI in the United States.

Introduction

There has been a surge in research over the past two decades aimed at improving measurement of the impacts of foodborne illness in high-income countries. This agenda has been driven, in part, by World Trade Organization 1995 Sanitary and Phytosanitary Agreement requirements for science-based food safety policy (Hoffmann and Harder 2010). Cost of foodborne illness (CoFI) estimates inform science-based policy development by providing a means of comparably measuring the impact of foodborne diseases that differ greatly in terms of severity and incidence (Hoffmann and Taylor 2005). They are also used in cost–benefit analyses that are required by many countries to adopt or repeal major regulations (U.S. Office of Management and Budget 1993, 2003; European Commission 2015; Government of Australia 2016; Treasury Board of Canada 2018; Her Majesty's Treasury 2019). In addition, CoFI estimates provide a meaningful way of communicating with the public about the impact of foodborne disease (Morrison and Hoffmann 2015).

In 2014, researchers at the U.S. Department of Agriculture (USDA) Economic Research Service (ERS), published CoFI estimates for 15 pathogens that account for roughly 95% of illnesses and deaths from the 31 major foodborne pathogens included in Centers for Disease Control and Prevention (CDC) foodborne disease incidence estimates (Scallan et al., 2011a; Hoffmann et al., 2012, 2015). ERS is currently updating their estimates to include all 31 known pathogens and unspecific agents included in CDC incidence estimates (Scallan et al., 2011a, b).

CoFI estimates are built on disease outcome models. Updating these models to reflect current scientific knowledge about the health outcomes of foodborne infections is a major part of the work of developing CoFI estimates. To ensure revised estimates are based on the most recent research, ERS invited leading foodborne disease public health scientists to a workshop in spring 2018. The workshop included 18 participants from federal agencies (Food and Drug Administration [FDA], USDA, Food Safety and Inspection Service, and CDC), universities (University of Florida, University of Minnesota, The Ohio State University, University of Arizona, U.S. Defense University, and Colorado School of Public Health), and a nongovernmental organization (Pew Charitable Trusts). The workshop focused on serious acute complications of foodborne illnesses that could increase the cost of hospitalization and on serious chronic outcomes that require on-going medical care and/or reduce the ability of those affected to work and go about normal activities. This article presents a summary, based on discussion at this workshop, of the state of scientific research available to inform disease modeling of these outcomes for use in CoFI estimates.

Workshop Findings

Recent advances in science show that the extent of long-term health impacts of acute foodborne infections are more extensive than previously understood (Porter et al., 2016). At the same time, improvements in medical treatment can, and do, reduce complications and the likelihood or severity of long-term outcomes (Spinale et al., 2013). We summarize hereunder discussion from the workshop on acute complications, autoimmune and inflammatory responses, chronic gastroenteric disease, and chronic sequelae to toxoplasmosis and listeriosis. Toxoplasmosis and listeriosis are both leading causes of death from foodborne illness in the United States and have been associated with severe chronic sequela.

Acute complications

Acute complications typically occur when infections fail to respond to initial treatment, spread beyond the gastrointestinal (GI) tract, or if the pathogen produces toxins that damage vital organs. The 2014 ERS CoFI estimates included bloody diarrhea (campylobacteriosis, Shiga toxin–producing Escherichia coli [STEC] infection, and shigellosis), extended hospitalizations (campylobacteriosis, cryptosporidiosis, cyclosporidiosis, STEC infection, listeriosis, salmonellosis, toxoplasmosis, noncholera Vibrio infections, and yersiniosis), sepsis (noncholera Vibrio infections and yersiniosis), hemolytic-uremic syndrome (HUS) (STEC infections), and meningitis (listeriosis).

Additional acute complications have been identified in the literature, including meningitis (brucellosis, campylobacteriosis, listeriosis, and salmonellosis) (Motarjemi 2002; Batz et al., 2013; Porter et al., 2016); inflammation of the heart (brucellosis, campylobacteriosis, salmonellosis, and trichinosis) (Motarjemi 2002); and inflammation of bones, the pancreas, and gall bladder (campylobacteriosis and salmonellosis) (Motarjemi 2002). The challenge to including these outcomes in a CoFI estimate is having a sound basis for estimating the proportion of cases that develop these complications. National hospital discharge data have been a major data source used to estimate the likelihood that illnesses caused by specific pathogens result in specific complications. Therefore, including any additional complications is largely dependent on the availability of specific diagnostic codes and the ability to associate complications with specific infections, which may not be possible in every case.

Several observations were made at the workshop regarding the next round of ERS CoFI estimates. First, sepsis should be included as an acute complication for additional pathogens, over and above those noted previously. National hospital discharge data and other CoFI and burden of illness studies may provide a basis for estimating the likelihood that cases of illness caused by specific pathogens develop sepsis. Second, although the increasing number of antimicrobial-resistant infections may not be identifiable as such in hospital discharge data, they will likely be reflected in longer, more costly hospitalizations. Third, hospital discharge data will likely show a reduction in the rate of HUS from STEC infections because of improved diagnosis and treatment (Spinale et al., 2013). Finally, foodborne infections are increasingly thought to be a cause of urinary tract infections, although at this time, attribution to specific foodborne pathogen exposures could be difficult (Nordstrom et al., 2013).

Autoimmune and inflammatory responses

Foodborne infections can set off inflammatory and autoimmune responses (Porter et al., 2012). Either may be relatively short-lived or chronic. The only autoimmune or inflammatory response included in the 2014 ERS estimates was Guillain–Barré syndrome (GBS) for Campylobacter, which accounted for 56% of the cost of campylobacteriosis. Consideration was given to including reactive arthritis (ReA), a short-term or chronic inflammation of joints, for shigellosis, and yersiniosis, but this was not included because of ambiguity over how ReA is diagnosed (Selmi and Gershwin 2014).

GBS remains an important sequela and often leads to complications that can have a lifelong impact on an individual's health and ability to perform daily activities (Willison et al., 2016). The focus on GBS, which is primarily an inpatient condition, may have led to underestimation of outpatient cases associated with milder forms of acute infective polyneuritis. For example, Miller–Fisher syndrome, a self-limiting, nonparalytic variant of GBS with ophthalmoplegia, ataxia, and areflexia is often an ambulatory condition (O'Brien 2017). A targeted study on lifetime costs of GBS would be useful, and should include outpatient and posthospitalization health outcomes.

European, New Zealand, and other U.S. studies included ReA for several foodborne infections, including campylobacteriosis, salmonellosis, shigellosis, and yersiniosis (Lake et al., 2010; Havelaar et al., 2012; Scharff 2012; Minor et al., 2015). Lack of established diagnostic criteria or tests for ReA represents a significant challenge (Townes 2010). Moreover, the terms ReA and Reiter's syndrome are often used interchangeably, although they are different diseases. This lack of clarity has led to wide-ranging incidence estimates for ReA: campylobacteriosis (0–16%), salmonellosis (0–29%), and shigellosis (0–12%) (Ajene et al., 2013). Although the use of a more general concept of joint outcomes might ease ambiguity, and shift focus away from diagnosis to impact on daily life, treatment cost data are tied to specific diagnostic codes. FDA is currently conducting a systematic review of scientific research of inflammatory response and joint problems resulting from foodborne infections that could help inform revisions.

Chronic gastroenteric disease

Three types of chronic GI conditions can follow acute foodborne infections: (i) persistent abdominal symptoms (e.g., recurring diarrhea); (ii) chronic changes in gut function (e.g., irritable bowel syndrome [IBS], dyspepsia, or chronic constipation); and (iii) organic changes in the structure of the gut (e.g., inflammatory bowel/Crohn's disease [IBD] or celiac disease). The 2014 ERS CoFI estimates only included recurring diarrhea for cryptosporidiosis. CoFI and burden studies in the Netherlands, Australia, New Zealand, and other U.S. studies have included IBS and/or IBD from campylobacteriosis and salmonellosis (Lake et al., 2010; Havelaar et al., 2012; Gibney et al., 2014; Scallan et al., 2015).

Workshop discussion focused on IBS and IBD. IBD is one of the more serious chronic GI conditions. However, there is active debate over whether IBD results from GI infections (O'Brien, 2017; Nielsen et al., 2019). In contrast, there is general agreement that the evidence that GI infections result in functional gut syndrome is strong (Deising et al., 2013). Although IBS cases tend to be less severe than IBD and rarely require hospitalization, the prevalence in the U.S. population is thought to be high and those affected can have a substantial chronic impact up to a year after onset of the illness (Canavan et al., 2014).

The fundamental challenge with including chronic GI sequelae in CoFI modeling is quantifying incidence of disease and attributing outcomes to specific pathogens. Most U.S. research on the incidence of chronic GI sequelae has been conducted within the armed forces (Porter et al., 2011, 2016; Verdu and Riddle 2012). More research on the general population has been conducted outside the United States, particularly in the Netherlands (Havelaar et al., 2012). Burden studies in Australia and the United States have relied on a Dutch meta-analysis of case–control studies to include IBS after campylobacteriosis and salmonellosis (Scallan et al., 2009; Lake et al., 2010; Havelaar et al., 2012; Gibney et al., 2014).

A challenge for estimating the rate of functional bowel syndrome (e.g., IBS) is unavailability of practical clinical diagnostic tests. Instead, studies have used one of several symptom-based criteria, such as Rome criteria to define IBS (Quigley et al., 2012). Differences in the definition of IBS and the type and duration of the follow-up has contributed to differences in incidence estimates of post-GI infection IBS range from 4% to 46% (Klem et al., 2017).

In addition, incidence of IBS and other functional gut syndromes are thought to vary by pathogen. There was agreement that the biological plausibility and epidemiological evidence for IBS being a chronic outcome of Campylobacter, Salmonella, and Shigella infections is strong, and strong and emerging for dyspepsia after Shigella and Salmonella infections. Evidence that GI infections cause constipation is also emerging (Deising et al., 2013). There is also evidence that the rate of IBS after bacterial infection is higher than after infection by protozoa or parasite, for example, Giardia (Klem et al., 2017). The challenge remains finding empirical evidence on which to base pathogen-specific estimates of the likelihood, severity, and duration of IBS cases.

Toxoplasmosis chronic sequelae

Foodborne toxoplasmosis is the leading cause of death from foodborne illness in the United States (Scallan et al., 2011a). Toxoplasmosis can also cause serious chronic health impacts (Moncada and Montoya 2012; Torgerson et al., 2013; Ngoungou et al., 2015). The 2014 ERS CoFI estimates included acute, but not chronic, outcomes for acquired toxoplasmosis. Chronic consequences of adult or congenital cases were not included because of the difficulty of developing cost of illness estimates.

Research on the chronic consequences of toxoplasmosis has been very active. Congenital cases have been associated with developmental delay, vision impairment, and damage to newborns' brains and central nervous systems (CNS) (including intracranial calcification, hydrocephalus, CNS hemiplegia, and mild retardation) (Havelaar et al., 2007; Moncada and Montoya 2012). Some sequelae of congenital toxoplasmosis are not apparent at birth and may not appear until the second or third decade of life (Berrébi et al., 2010). Acquired toxoplasmosis has also been associated with serious chronic conditions including chronic vision impairment, inflammation of the retina and covering of the eye, chronic hearing loss, epilepsy, inflammation of the heart (pancarditis), polymyositis (inflammation of muscles), and possibly schizophrenia and other neuropsychiatric effects (suicide, self-directed violence in women, and increased risk of traffic accidents) (Kravetz and Federman 2005; Fekadu et al., 2010; Jones and Holland 2010; Hurley and Taber 2012; Flegr 2013; Torgerson and Mastroiacovo 2013; Gale et al., 2014; Ngoungou et al., 2015; Wohlfert et al., 2017). People who are infected with Toxoplasma in childhood or adulthood can develop chronic outcomes even if they do not experience acute symptoms (Berrébi et al., 2010).

Much of the evidence used to quantify the chronic impacts of toxoplasmosis comes from research outside the United States. Other CoFI and burden of foodborne disease studies in the United States and the Netherlands, and Global Burden of Foodborne Disease estimates included chorioretinitis as a chronic outcome of acquired toxoplasmosis, and included miscarriages, neonatal deaths, chorioretinitis, intracranial calcifications, hydrocephalus, and other CNS abnormalities as consequences of congenital infections (Havelaar et al., 2012; Torgerson and Mastroiacovo 2013; Scallan et al., 2015). These estimates drew on Dutch modeling and a Canadian study (Bowie et al., 1997; Mylonakis et al., 2002; Havelaar et al., 2012). The U.S. CDC has also produced estimate ocular toxoplasmosis (Jones and Holland 2010). Workshop participants viewed the evidence for vision impairment from both acquired and congenital toxoplasmosis as strong, but did not think that evidence on other outcomes was adequate to support their inclusion in U.S. CoFI estimates.

U.S. Toxoplasma strains may be a mix of those prevalent in Europe and Latin America (Torgerson and Mastroiacovo 2013). The strain of Toxoplasma prevalent in Latin America causes more severe health outcomes than that found in Europe (Ajzenberg 2012; Jones et al., 2014, 2018). In addition, France and Austria have mandatory prenatal screening of women for Toxoplasma during pregnancy, which allows early treatment and reduction of the rate and severity of congenital outcomes (Mandelbrot 2012; Sagel et al., 2012). In the United States, only Massachusetts has such screening (Stillwaggon et al., 2011; Peyron et al., 2017). The rate of congenital outcomes for untreated toxoplasmosis is quite consistent across high-income countries (World Health Organization 2015).

Listeriosis chronic sequelae

Listeriosis is estimated to be the third leading cause of death from foodborne illnesses with known pathogen causes in the United States (Scallan et al., 2011a). The disease modeling for listeriosis included in the 2014 ERS CoFI estimates was taken from earlier ERS research (Buzby et al., 1996). This work included moderate and severe sepsis and meningitis as complications to acquired listeriosis, but no chronic sequelae. For congenital cases, ERS estimates included stillbirths, neonatal deaths, and mild to severe mental or physical disability. Newer disease modeling developed for ERS quality-adjusted life-year estimates included additional chronic congenital outcomes: seizure disorder, hearing impairment, and mental and physical disability with mild to severe impact on learning and daily life (Batz et al., 2014). Multiple listeriosis outcome models are available from other studies. For congenital (or perinatal) cases, Global Burden of Foodborne Disease modeling included deaths and stillbirths, leukemia, CNS disorders, and neurological sequelae to meningitis (Kemmeren et al., 2006; Maertens de Noordhout et al., 2014). Models of acquired listeriosis were generally simpler than the ERS model and included meningitis, death, and neurological sequelae from meningitis.

Data on chronic sequelae for listeriosis are lacking in the United States. Research from other countries could inform U.S. estimates. For example, in the Netherlands, a retrospective study of 207 cases of listeriosis-related meningitis over a 20-year period, estimated that 14% of the adults with listeriosis-related meningitis developed neurological sequelae. Long-term sequelae accounted for 6% in the disease burden from listeriosis in the Netherlands (Kemmeren et al., 2006).

Conclusions

Both short-term and long-term priorities emerged from the workshop's discussions. The short-term focuses on what can and needs to be done for the next set of ERS CoFI revisions. The long-term focuses on both scientific and economic research needed to solidify knowledge about major outcomes, particularly about chronic outcomes.

There was general agreement that additional complications and chronic outcomes need to be included in the next revision of ERS estimates. In particular, workshop participants agreed that IBS needs to be included for Campylobacter, Salmonella, and Shigella. There was also agreement that effort should be made to find a way to quantitatively estimate the rate of ReA following infections by Campylobacter, Salmonella, Shigella, and Yersinia. Participants agreed that hospitalization data should show that the rate of HUS per case of E. coli O157:H7 infection has fallen because of improvements in diagnosis and treatment.

Other CoFI and disease burden studies conducted in the United States and elsewhere make wide use of research from around the world and there was agreement that this is an appropriate practice. In the next round of estimates, ERS should be leveraging epidemiological research conducted outside the United States, while being aware of biological and socioeconomic differences that could affect the applicability of this information for U.S. modeling. Difference in medical care systems is particularly important. In particular, non-U.S. research needs to be used to support modeling of the chronic impacts of toxoplasmosis on vision and on newborns, and chronic consequences of meningitis from listeriosis. In response to the workshop, ERS is conducting systematic reviews and meta-analyses of chronic outcomes associated with both acquired and congenital/perinatal listeriosis and toxoplasmosis and from noncholera Vibrio infections.

In the long run, there was recognition that there are areas where further research is needed but may not be possible to complete in time to support the next set of ERS cost of illness estimates. These include valuation studies for biotoxins, heavy metals, and allergens in foods, all of which are of continuing or increased concern for both FDA and USDA (Philpott 2010; U.S. Centers for Disease Control and Prevention 2018; Food Safety News 2018; Neltner 2018). Because of the ambiguity in diagnosis of ReA and other infection-related joint inflammation, it would be useful to have a study targeted at estimating the rate of joint-related disease resulting from foodborne infections. A targeted study on the lifetime costs of GBS in also needed, including GBS that is not preceded by a hospitalization.

The USDA ERS has a long history of leadership on estimation of the CoFI in the United States (Buzby et al., 1996; Frenzen 2007; U.S. Economic Research Service 2014; Hoffmann et al., 2015). Cost of illness estimates are needed to assess whether proposed policy actions will increase or decrease public welfare. They can also inform prioritization and provide a measure of the total impact of foodborne cases, hospitalizations, and deaths in terms that policy makers and the public understand, that is, monetary terms. The workshop discussed here is part of an ongoing effort to update and improve ERS cost of illness estimates in response to changes in research and disease patterns.

Footnotes

Acknowledgments

The authors greatly appreciate the intellectual contributions of workshop participants: Michael Batz (U.S. Food and Drug Administration [FDA]), Nate Bauer (U.S. Department of Agriculture [USDA], Food Safety and Inspection Service [FSIS]), Michael Bazaco (U.S. FDA), Beau Bruce (U.S. Centers for Disease Control and Prevention [CDC]), Eric Ebel (USDA FSIS), Arie Havelaar (University of Florida), Craig Hedberg (University of Minnesota), Mike Hoekstra, Karin Hoelzer (Pew Charitable Trusts), Barbara Kowalcyck (The Ohio State University), Clark Nardinelli (United States FDA), Kristen Pogreba-Brown (University of Arizona), Regonlinski, April (USDA FSIS), Mark Riddle (U.S. Defense University), Anne Straily (U.S. CDC), and Hilary Whitham (U.S. CDC). This work was made possible by a cooperative agreement between the USDA ERS and the Colorado School of Public Health. This article is dedicated to Prof. Peter Berck, University of California, Berkeley, who suffered from Crohn's disease for over 40 years and died too young of intestinal cancer, August 2018. He had much left to give the world. His family, students, and colleagues needed him to live longer.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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