Copyright by Rachael Michelle Singer 2020
The Dissertation Committee for Rachael Michelle Singer Certifies that this is the approved version of the following Dissertation:
Surveillance and Control of Neglected Intestinal Parasitic Infections of Poverty in the United States
Committee:
Abigail R. A. Aiken, Supervisor
Catherine Weaver
William Spelman
Sahotra Sarkar
Peter J. Hotez
Rojelio Mejia Surveillance and Control of Neglected Intestinal Parasitic Infections of Poverty in the United States
by
Rachael Michelle Singer
Dissertation
Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
The University of Texas at Austin August 2020 Dedication
To people everywhere suffering from these oppressive diseases and the conditions that promote them.
Acknowledgements
I thank my mother, Elyse Snyder, who would not allow me to take my education for granted. I thank my father, Ronald Singer, who always encouraged me to follow my ambitions. I am grateful for my sister Lexy, who gave the most sincere, constant support for my doctoral work; my brother Gideon, who offered camaraderie, inspiration, and technical support throughout my dissertation; and my sister Samantha, who champions honesty and passion for justice. My alma mater, Hampshire College, as both an institution and a community, imbued in me the value of limitless, experiential learning and the confidence and resourcefulness to make the research I want to happen. I am grateful for the people in Puerto Cabezas/Bilwi, Nicaragua, who participated in my early research and my enlightenment on the paradigm of parasites, conflict, poverty, and humanity. I thank my committee members, Catherine Weaver and William Spelman, who helped me to ask the right and real questions; and Sahotra Sarkar, one of the few at the University who shared an interest in neglected disease, has been a helpful mentor and collaborator, inspiring big picture perspectives. Committee members Rojelio Mejia and Peter Hotez served as mentors and collaborators, a welcoming bridge into the technical and clinical domain of neglected infectious disease, and partners in fighting to end NTDs. Peter’s gospel made room for and inspired me to carve out a career in fighting NTDs in my own way, not only via traditional medicine or molecular biology paths, and he models what true science communication and diplomacy look like. I especially thank my advisor, Abigail RA Aiken, for her all-encompassing mentorship and advising over the years, for modeling grace and how to walk the scholar-policy advocate divide, and for her advocacy of my scholarship and always finding ways to support me when I was an academic misfit. v And, finally, to Scott Niekum: in-home, all-hours statistical concept explainer and advisor of all things academia, scientific role model and thought sharer. Thank you for letting a schistosome grace the top of our wedding cake, wrapped around a PR2. For dinners and porch lights waiting for me after long fieldwork days. For listening, loving, and openly wondering about the work I do, the things I care about, and your enduring pride in me. I have endless gratitude for your guidance, support, and partnership in learning, life, and love.
vi Abstract
Surveillance and Control of Neglected Intestinal Parasitic Infections of Poverty in the United States
Rachael Michelle Singer, PhD The University of Texas at Austin, 2020
Supervisor: Abigail R. A. Aiken
My dissertation aims to inform strategies for the estimation of prevalence and burden of disease caused by neglected intestinal parasitic infections in the United States, with a view toward their control. The current burden of soil-transmitted helminth (STH) and intestinal protozoa (IP) infections in the US is unknown; consequentially, little existing surveillance and disease control framework exists to protect US residents. This group of infections is considered neglected due to lack of adequate surveillance. For example, despite documented historical and contemporary autochthonous transmission, the STH are not required by state law to be reported nor are they nationally notifiable, with the exception of mandated reporting for three species in Texas, as of September 2015. Without a tangible sense of the disease burden, little attention is paid to the prevention, diagnosis, and/or treatment of STH and IP in the US. I investigate the hypothesis that a significant burden of neglected intestinal parasitic infections persists in vulnerable communities throughout the US, and seek to identify and characterize the prevalence of intestinal parasites in a study at the local level. Our results from an epidemiological study in central Texas, as well as a species distribution modeling study of the STH Strongyloides stercoralis, suggest that STH represent a sufficient threat to US public health and therefore merit an organized public health response. Given that the US
vii has a rudimentary or non-existent framework for addressing STH, I conduct a systematic review of global examples of intestinal parasite prevalence estimation, surveillance, and control programs to model solutions that can be adapted for the US context. My dissertation contributes to the characterization of a neglected public health problem, quantifying the burden of intestinal parasites locally and offering evidence-based solutions at the local, state, national, and health systems levels. The epidemiological insights we have gained about intestinal parasitic infections in the US suggest several public health, clinical, and policy strategies that may help to address the burden of disease, and, combined with additional historic and contemporary evidence call for a shift in the way we think about health equity and the provision of human rights in the US.
viii Table of Contents
List of Tables ...... xiii
List of Figures ...... xiv
Introduction ...... 1
Neglected Infectious Diseases ...... 1
Soil-transmitted helminths ...... 2
Intestinal protozoa ...... 2
Intestinal Parasitism in the United States ...... 2
Soil-transmitted helminths in the United States ...... 2
Intestinal protozoa in the United States ...... 5
Theoretical Framework and Policy Context of Neglected Infections of Poverty ...... 7
Social Inequalities and Infectious Diseases ...... 7
Human Rights Frameworks for Health and Power ...... 9
Objectives and Overview ...... 12
Chapter 1: Prevalence of Intestinal Parasites in a Low-Income Texas Community ...... 13
Abstract...... 13
INTRODUCTION ...... 13
MATERIALS AND METHODS ...... 16
Sample population ...... 16
Sample collection ...... 17
Multi-parallel real-time quantitative PCR ...... 18
Strongyloides NIE-ELISA IgG ...... 19
Data analysis ...... 19 ix RESULTS ...... 20
Survey ...... 20
Strongyloides NIE-ELISA ...... 22
Multi-parallel real-time quantitative PCR ...... 26
DISCUSSION ...... 28
Strongyloides ...... 28
Blastocystis ...... 30
Clinical implications ...... 32
Policy implications ...... 33
Limitations ...... 34
Conclusion ...... 35
ACKNOWLEDGEMENTS ...... 36
Chapter 2: Modeling Strongyloidiasis Risk in the United States ...... 37
Abstract ...... 37
INTRODUCTION ...... 37
METHODS ...... 39
Species Distribution Model ...... 40
Multi-Criteria Analysis ...... 43
RESULTS ...... 44
Strongyloides stercoralis Biogeography ...... 44
Species Distribution Model ...... 45
Multi-Criteria Analysis ...... 47
DISCUSSION ...... 49
x
Limitations ...... 50
PUBLIC HEALTH IMPLICATIONS ...... 51
ACKNOWLEDGEMENTS ...... 52
Chapter 3: The Burden of Neglected Intestinal Parasitic Infections in the United States: a Systematic Review of Global Programs to Model Solutions for Prevalence Estimation and Disease Control ...... 53
Abstract ...... 53
INTRODUCTION ...... 53
METHODS ...... 55
RESULTS ...... 57
Availability of data ...... 57
I. Estimating Prevalence ...... 59
1. Epidemiology findings from around the world: risk factors & vulnerable populations ...... 59
Risk factors for intestinal parasitic infection ...... 59
Oceania, South and Southeast Asia ...... 59
Central Asia ...... 60
West Africa ...... 60
Vulnerable populations ...... 61
Indigenous communities ...... 61
Men who have sex with men and people living with HIV/AIDS ...... 61
Pregnant women ...... 62
Refugees and migrants ...... 62
Military at-risk ...... 63
Low-income and preschool-aged children ...... 63 xi High-risk patient populations/other vulnerable groups ...... 64
2. Mapping of neglected intestinal parasitic infections ...... 64
3. Modeling of neglected intestinal parasite transmission ...... 66
II. Disease Control and Surveillance ...... 66
1. Mass drug administration ...... 66
School-based versus community-based treatment ...... 67
2. Control strategies ...... 68
Integrated programming ...... 69
3. Monitoring & evaluation ...... 70
4. Partnerships ...... 71
5. Research & development ...... 72
III. US State and Federal Reporting and Surveillance of Intestinal Parasites ...... 73
DISCUSSION ...... 75
US policy priorities ...... 75
State and federal reporting and surveillance of intestinal parasites .....77
US health system awareness and capacity building ...... 79
Limitations ...... 80
Conclusions and future work ...... 82
Conclusions ...... 83
Theoretical and Epidemiological Contributions ...... 83
Implications for Policy ...... 84
Future Research Directions ...... 93
References ...... 96
xii List of Tables
Table 1. Age (years) and sex distribution of 92 surveyed households (N = 404) ...... 20 Table 2. Characteristics related to monthly household income (N = 391) ...... 22 Table 3. Risk factor analysis for participants without relevant missing data and
ELISA serum testing (N = 97) ...... 25 Table 4. Risk factor analysis for participants without relevant missing data and qPCR
stool testing (N = 43) ...... 27 Table 5. Environmental features for species distribution models ...... 42 Table 6. Non-dominated solutions from multi-criteria analysis ...... 48 Table 7: Intestinal parasites and their effects on human host ...... 54 Table 8: Reporting status of intestinal parasites in the United States ...... 75
xiii List of Figures
Figure 1. Study population characteristics ...... 21 Figure 2. Species distribution model for Strongyloides stercoralis ...... 46 Figure 3. Severe poverty and Strongyloides stercoralis suitability ...... 47 Figure 4: Flowchart demonstrating procedure for identifying relevant publications ...... 58
xiv
Introduction
NEGLECTED INFECTIOUS DISEASES
Parasitic infections in the group of diseases known as neglected tropical diseases (NTDs) such as intestinal worms are most often associated with developing countries and tropical climates. However, a combination of historical epidemiology and present-day risk factors has led parasitology experts to suspect that vulnerable populations within the US suffer from some of the same infections today. Globally, progress has been made to control and eliminate intestinal worms and other NTDs. Policymakers have established targets through two key documents, the 2012 London Declaration for NTDs for access to essential medicines and the 2013 World Health Assembly (WHA) resolution 66.12, which emphasizes the role of mass drug administration (MDA) in controlling several of the NTDs. In the US, a group of infections called neglected infections of poverty share much in common with their NTD counterparts in developing countries, in that they disproportionately affect under-represented minority populations, people of color, and people living in poverty.1 Indeed, some of the very same organisms that cause NTDs also cause neglected infections of poverty. Neglected infections of poverty occur outside of tropical regions and are not well recognized by the US public health and medical community. Such infections have a bidirectional relationship with poverty; they are both caused by conditions of poverty and they also promote poverty, through their impact on child physical and cognitive development, pregnancy outcomes, and adult economic productivity.1
1 This research focuses on the most common type of NTD, the intestinal parasites, which can be divided into two families of organisms: the soil-transmitted helminths (STH) and intestinal protozoa (IP).
Soil-transmitted helminths
Soil-transmitted helminths are intestinal worms spread through contaminated food, water, and soil; they are among the most prevalent organisms on the planet, estimated to infect almost one sixth of humanity.2 The three most common STH species are Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and hookworm, caused by both Necator americanus and Ancylostoma duodenale. A fourth STH species, Strongyloides stercoralis, causes the disease strongyloidiasis. Understanding STH biology, ecology, and transmission dynamics is essential for the prediction of their global distribution.
Intestinal protozoa
Intestinal protozoa are single-celled parasites transmitted by the fecal-oral route, involving the ingestion of contaminated food or water or through fomites and hand-to- mouth contact. Their transmission is driven by lack of basic sanitation and other environmental factors, and fluctuates with season, weather, nutrition, and other factors. Generally, IP infections are not chronic, limiting the usefulness of prevalence estimates.2
INTESTINAL PARASITISM IN THE UNITED STATES
Soil-transmitted helminths in the United States
S. stercoralis and A. lumbricoides have historically been found in the southern US. Ascariasis is thought to be prevalent in the Mississippi Delta and Appalachia, where
2 strongyloidiasis is also thought to occur. STH transmission occurs when stool from an infected individual contaminates the soil and another individual inadvertently steps on (in the cases of hookworm and strongyloidiasis) contaminated soil with bare feet or ingests contaminated soil through food, water, or poor hand hygiene. Mature intestinal worms reside in the intestine of infected individuals where they produce thousands of eggs every day. Helminth eggs, which are infective only after about three weeks in the soil under warm and moist conditions, are inadvertently ingested in contaminated food, such as unwashed fresh produce, or by contact with contaminated hands or utensils. STH infection is therefore preventable with adequate hygiene and sanitation, which is predicated on access to clean and safe water and waste disposal. Despite US economic advancement, access to basic sanitation in the US is not universal. It was estimated in 2000 that up to a quarter of Appalachian homes overall lacked complete plumbing, and 169,000 Central Appalachian homes lacked indoor plumbing altogether. On some Native American reservations up to one in five homes lack complete in-house plumbing, a rate twenty times the national average.3 According to the most recent American Community Survey, the number of US homes lacking complete plumbing facilities is estimated to be 508,997.4 Surveys for STH in Appalachia during the 1930s found high rates of ascariasis linked to severe poverty and inadequate sanitation; the prevalence in one Eastern
Kentucky county was higher than in many developing countries, at 75%.5 In the same area, nearly fifty years later, 14% of schoolchildren were infected with roundworm and almost 13% also with whipworm.6 Other surveys also confirmed that ascariasis was still very prevalent and endemic to Appalachia.7,8 Hotez estimates that approximately four million Americans, mostly in Appalachia and the American South, are infected with A. lumbricoides.1
Ascariasis cases have been historically detected outside of Appalachia, as well. In the 1930s, some of the highest prevalence rates of ascariasis were in Louisiana,5 and
3 some children had parasite intensities so high that they suffered intestinal obstruction, an emergency condition often requiring surgery.8,9 Ascariasis was not limited to rural Louisiana; it was also prevalent among New Orleans kindergarteners.10 To our knowledge, no surveys for ascariasis and other helminths in Louisiana have been published since. Largely due to the difficulty in detection by standard microscopic examination of the stool, strongyloidiasis is an underreported and underestimated disease.1,11–13 Relying on insensitive microscopy, and therefore producing underestimates, a study in the late 1970s examined 3,271 stool specimens and estimated that the overall prevalence in Kentucky was approximately 1%.6 The first recent study of soil-transmitted helminths in the US conducted since the early 1980s has revealed that strongyloidiasis and hookworm infections were present in 2013 in rural Alabama.14 The Rockefeller Sanitary Commission for the Eradication of Hookworm (RSC) invested upwards of $1 million in their campaign to eliminate hookworm from the US south. When the RSC first surveyed in 1914, 41.7% of southerners were infected; by 1930, hookworm prevalence decreased to 19.3%.15 Despite the successes of the RSC, hookworm and other STH were not eliminated from the American south and the current status of STH transmission in the US is unknown. Data show that sanitation improvements have not occurred universally.3,4
A 2010 systematic review of STH in the US identified fourteen high-quality studies published between 1942 and 1982 showing that infection with STH was prevalent throughout the American south and Appalachia as recently as 1982. The following are the ranges of prevalence rates reported: 0% to 19.6% hookworm, 0.5% to 55.2% trichuriasis, 1.3% to 49.4% ascariasis, and 0% to 3.8% strongyloidiasis.16 With the exception of strongyloidiasis, the highest prevalence rates of these infections approach or exceed the
World Health Organization (WHO) threshold of 20% for mass drug administration (MDA).17 Due to methodological limitations, all STH prevalence estimates derived from
4 these studies are considered by the authors and tropical medicine experts generally to be underestimates.
Intestinal protozoa in the United States
Giardiasis, caused by Giardia lamblia (also known as G. duodenalis and G. intestinalis), is a protozoan parasite infecting the GI tract. The giardia parasite exists in two forms: the trophozoite, which infects the small intestine, and the infective cyst form. The giardia cyst is encountered in the environment; it is highly resistant and can survive in cold mountain streams, stomach acid, in chlorinated and even UV-treated water.2 In the US, there are an estimated 2.0-2.5 million annual cases of giardiasis, which is the most diagnosed parasitic infection in the US and a common cause of waterborne diarrhea outbreaks.1,18 The most frequent transmission pathways are through food and water, while person-to-person spread is important in day care settings and among men who have sex with men (MSM). G. lamblia is highly infectious, requiring ingestion of as few as 10-25 cysts to produce disease.18 In both 2011 and 2012, most giardia cases occurred among children aged 1-4, followed by those aged 5-9 years and adults aged 45- 49 years.19 In the US, an estimated 750,000 cases of cryptosporidiosis, caused by Cryptosporidium parvum and C. hominis, occur annually;20 due to the parasite’s extreme tolerance to chlorine, this infection has emerged as the leading cause of recreational water-associated outbreaks, particularly those associated with aquatic facilities, including swimming pools, water playgrounds and hot tubs or spas in the US.21 Cryptosporidiosis has been nationally notifiable in the US since 1995. Since 2004, the annual incidence has risen approximately threefold.21 Both cryptosporidiosis and giardiasis may be transmitted through contact with commercial livestock and domesticated animal feces.2
5 Giardiasis, cryptosporidiosis and cyclosporiasis are prevalent throughout all US regions. Perhaps because it is not nationally notifiable, there is not sufficient data to estimate the number of amebiasis cases caused by E. histolytica in the US, but it is thought to be most prevalent in the US-Mexico borderlands and to disproportionately affect poor communities.1 Both giardiasis and cryptosporidiosis are generally common; there is no evidence to suggest that these IP disproportionately affect low-income and minority populations.1 The US public health system itself has not undergone a comprehensive intestinal parasitic disease control program. While state health departments were involved to some degree in the Rockefeller campaign to eliminate hookworm disease from the American south, the US has not generally considered STH an endemic threat and has not prioritized these infections as a public health problem. As discussed, although several of the IP are reportable, there is limited US surveillance for these parasites; those with reportable status were likely selected due to their ability to cause significant and acute outbreaks of diarrheal disease, including in non-poor populations. According to Starr and Montgomery,
There is a common belief among clinicians and those people in the public health community that soil-transmitted helminths continue to be transmitted within areas of the US; however, this conclusion is based on unclear or historical evidence…. Summarizing the status of STH in the US is the first step to determining current knowledge and the need for future evaluations and interventions.16 Starr and Montgomery conclude that while the literature does not provide enough evidence to determine the current status of STH infection in the US, socioeconomic and environmental conditions may still be conducive to ongoing transmission. As previously discussed, substandard housing with inadequate sanitation is common, and these conditions encourage transmission of disease such as STH and IP. This research is designed to resume the epidemiological study of intestinal parasites in the US after decades of neglect, and to develop a framework for
6 systematically estimating prevalence and disease burden nationwide to enable the formulation of policy for their control.
THEORETICAL FRAMEWORK AND POLICY CONTEXT OF NEGLECTED INFECTIONS OF POVERTY
This research is rooted in the view that disparities in health are generally preventable and unjust; that they represent violations of basic human rights. For policymakers to generate a sustainable interruption to the vicious cycle of poverty and disease they will need to critically examine the institutions and power dynamics that enable the cycle to go unthwarted.
Social Inequalities and Infectious Diseases
Social inequalities have a pathogenic role in many of society’s ills, including health disparities. Public health researchers and policymakers alike often lack a critical perspective on big picture social forces, obscuring the pathways that lead from social inequality to disease and precluding effective policy change. Sometimes it is existing models and frameworks, such as “tropical medicine” and the concept of national, rather than intra-national health profiles, that mask trends that can be linked to the emergence of disease.22 Farmer argued that, “models and even assumptions about infectious diseases need to be dynamic, systemic, and critical”; explanatory power stems from the model’s capacity to account for ever-evolving clinical and biological phenomena and tie them to the large-scale social forces that sculpt the distribution and course of infectious diseases.22
7 A common distinction made about inequality is whether it is between or within nations. In his book, “The Great Escape: Health, Wealth, and the Origins of Inequality”, Deaton focuses on the former.23 He outlines the complex dynamic between economic and technological progress and inequality, and highlights the ways in which progress creates inequality, and how inequality may be helpful to those who manage to escape but especially unhelpful, “when those who have escaped protect their positions by destroying the escape routes behind them” (page xiii).23 This dissertation focuses on the latter, applying the same ideas about between-nation inequality to the landscape of social and economic inequality within the United States. The economists McGuire and Coelho interrogate the historical and evolving tension between disease and progress in the US in their book, “Parasites, Pathogens, and Progress: Diseases and Economic Development”, in which they argue that differential effects of infections on different racial groups and differential disease ecologies in the US north and south promoted racial slavery and racism, impacting long-term economic growth in ways that promote the vicious cycle of poverty and disease recognized across disciplines.24 They argue, as scholars in other fields do, that pathogens undeniably shaped human history and that historical interpretations and economic models that minimize or neglect to address disease ecology are incomplete or inaccurate.25–31 This research is largely motivated by the question of whether and to what extent infectious disease still affects socioeconomic stratification in the US, and, as suggested by McGuire and Coelho, is designed to assess the ecological (including anthropogenic) determinants of neglected parasite transmission in the US as a foundation for analyzing the socioeconomic effects such infections may have for Americans. Farmer tells us that a critical approach to routine social-production-of-disease theories requires us to ask more complex, less politesse-driven, and rarely raised questions, interrogating the roles that foreign (neocolonialism and trade) and domestic policies (structural racism) may play in the emergence of disease in certain groups.
8 To apply a critical lens, or what Farmer (1996) calls a critical epistemology, to the issue of intestinal parasites in the US, this research might ask, ‘Do institutional racism and xenophobia and the privatization of health care foster the persistence of intestinal parasitism and their socio-economic sequelae in poor US communities?’ In essence, are the soil-transmitted helminths and intestinal protozoa neglected because they are perceived to predominately afflict already neglected people, mostly immigrants and people of color? An affirmative answer to this question is suggested in the title to Peter Hotez’s book on NTDs, “Forgotten People, Forgotten Diseases”, in which he argues, as others do, that these infections represent a critical mechanism trapping neglected populations in a vicious cycle of poverty, stigma, and despair.28–33 Such complex questions require interdisciplinary investigation; it is for this reason that the community-level surveillance study (Chapter 1) was conceived in partnership with civil engineers and molecular biologists, and follow-up to that work entails collaboration with legal, housing, and environmental justice experts alongside community leaders. The overarching hypothesis of this body of work is that there is a largely hidden burden of parasitic disease within US society. The bodies of poor people is one place for what many would consider unfathomably grotesque diseases to hide, not just in the developing world, but in the wealthy, developed world. Such stark disparities in health occur especially, as Farmer states, “when the poor are socially and medically segregated from those whose deaths might be considered more important”.22
Human Rights Frameworks for Health and Power
As underscored by the current, acrid, debate about the US health care system, Americans’ position on the qualification of health as a human right is painfully unfixed.
This wavering is starkly in conflict with Article 25 of the United Nations’ (UN) Universal
9 Declaration of Human Rights,34 the Constitution of the World Health Organization,35 and the policy of most all developed countries, which recognize (though not always outright confer) this right in practice by adopting universal health care coverage for their residents. The right to health is varyingly described as a “fundamental, inalienable human right”, as “basic” or “essential”; the universal right to health was further codified by the UN’s International Convention on the Elimination of All Forms of Racial Discrimination36 and the International Covenant on Economic, Social and Cultural Rights (ICESCR).37 Article 12 of the ICESCR prescribes that states should take steps to realize “to the maximum available resources” the “highest attainable standard of health”, –– a reasonableness standard taken from the WHO constitution, acknowledging factors beyond a state’s control38 –– including the prevention, treatment, and control of infectious diseases. It is widely agreed that the right to health necessitates both negative freedoms and positive entitlements.38,39 While these international agreements are not enforceable and may be too vague in their assertion that member states should provide their citizens a right to health, diverse world leaders have supported the general framework for health as a human right –– the constitutions of greater than 70 nations recognize the right to health, with many more countries legislating aspects of the right.38 Treaties also fail to specify recommended implementation plans and funding sources, which is a severe limitation especially in regards to a positive right to health, for which states must provide pre-requisite entitlements. Pertinent to the issue of intestinal parasitic infection in the US, the UN General Assembly in 2010 also explicitly recognized access to safe water and sanitation as a basic human right, each a clear precondition for meeting the right to health.40 The most basic right, however, is the right to survive. The trampling of this right, argues Farmer, should be considered the most pressing issue of our times. It’s not much of a stretch,” he says, “to argue that anyone who wishes to be considered humane has
10 ample cause to consider what it means to be sick and poor in the era of globalization and scientific advancement (page 6).41 In “Power, Suffering, and the Struggle for Dignity: Human Rights Frameworks for Health and Why They Matter”, Yamin argues that the core of applying a so-called human rights-based approach to health and development “involves understanding that patterns of health and suffering reflect power relations as much as they do biological or behavioral factors” (page 5).42 She acknowledges that if human rights frameworks are to meaningfully help the people on whose behalf NGOs and international agencies purport to work, these approaches must strive to address what Farmer calls “pathologies of power” – the entrenched systems and institutions at the root of gross inequities both between and within world societies. Finally, both Yamin and Farmer stress the critical fact that assaults on human dignity, including those that preclude the attainment of the basic human rights to health and sanitation, are not random or haphazard. This remains as true across developing countries as it is within the United States. When people ascribe many of the societal structures that perpetuate poverty, inequality and human rights violations to “God”, “nature”, or “inevitability” they avoid a critical examination of the relationships between inequality, disease, and distributions of privilege and power and also what produces those inequities in society.
Human rights violations are not accidents; they are not random in distribution or effect. Rights violations are, rather, symptoms of deeper pathologies of power and are linked intimately to the social conditions that so often determine who will suffer abuse and who will be shielded from harm. If assaults on dignity are anything but random in distribution or course, whose interests are served by the suggestion that they are haphazard (page 7)?41
11
OBJECTIVES AND OVERVIEW
This dissertation explores in depth the contemporary landscape of neglected intestinal parasitic infections in the United States, at local and federal levels. The research questions addressed are motivated by an important gap in the literature and the corresponding need to better understand the prevalence and burden of disease associated with these infections, as well as the need for data to determine practical solutions that will control and prevent them. In Chapter 1, we assess the prevalence of intestinal parasites in a central Texas community and conduct a risk factor analysis related to the built environment. Guided by our findings, which suggest that one species in particular, S. stercoralis, may represent a substantial public health threat domestically, in Chapter 2 we model the risk of strongyloidiasis across the United States. We also conduct a multi-criteria analysis of ecological and anthropogenic composite risk for acquiring strongyloidiasis in the United States. We add to the weight of evidence that neglected intestinal parasitic infections represent a critical public health threat to large swaths of the United States, where conditions of poverty, including inadequate sanitation infrastructure, and climate permit the establishment of autochthonous transmission cycles. We also provide a tool for planning targeted surveillance initiatives to further characterize the threat. In light of the limited US experience and policy framework for these infections, Chapter 3 offers a thorough look at surveillance programming globally, and suggests how the US may come to adapt successful approaches for the US context. In so doing, the US would be closer to ending the neglect of intestinal parasitic infections, and to faithfully securing the human right to sanitation, and its end goal, health, for all Americans.
12 Chapter 1: Prevalence of Intestinal Parasites in a Low-Income Texas Community1
ABSTRACT. Strongyloidiasis affects an estimated hundreds of millions of people worldwide, with infection possibly persisting for life without appropriate therapy due to the helminth’s unique autoinfection cycle. Like other soil-transmitted helminths, because of the environmental conditions required for the life cycle of Strongyloides stercoralis, this parasite is endemic to tropical, subtropical, and temperate countries and areas with inadequate sanitation infrastructure. Given continued poverty and that nearly one in five American homes are lacking proper sanitation systems, many US regions are at risk for intestinal parasites. A central Texas community was chosen as the study site given previous reports of widespread sanitation failure, degree of poverty, and community willingness to participate. A total of 92 households were surveyed and residents tested for 9 intestinal parasites using a multi-parallel quantitative real-time PCR and ELISA serology. From 43 stool samples, 27 (62.8%) tested positive for Blastocystis spp., 1 (2.3%) for Giardia lamblia. From 97 serum samples, Strongyloides serology detected 16 (16.5%) positive individuals. These high rates of heterokont and helminthic lab findings in a peri-urban central Texas community suggest several key policy implications, including that strongyloidiasis should be added to the Texas notifiable conditions list, that clinical suspicion for this infection should be heightened in the region, and that residents without access to functioning and sustainable sanitation infrastructure should be provided that access as a basic human right and to promote public health.
INTRODUCTION
Intestinal parasitism is an important public health concern worldwide. Gastrointestinal (GI) parasites are known to disproportionately affect pre-school and school-aged children, while economically disadvantaged children are at greater risk for recurrent infections. These infections can cause significant disease in children leading to impaired physical and cognitive development, as well as poor school attendance and academic achievement.43–52 Consequently, untreated or recurrent infections can impact future economic potential, perpetuating the cycle of poverty.52
1Singer R, Xu TH, Herrera LNS, Villar MJ, Faust KM, Hotez PJ, Aiken ARA, Mejia R. Prevalence of Intestinal Parasites in a Low-Income Texas Community. Am J Trop Med Hyg. 2020;102(6):1386–95. [RS contributions: study design, fieldwork and data collection, data analysis and interpretation, manuscript preparation].
13 Despite these potential adverse outcomes, the prevalence of intestinal parasitism is not well defined in the United States (US). This lack of information is largely because the prevalence of GI parasites within at-risk populations is systematically underestimated due to the lack of national surveillance activities, low sensitivity of standard microscopic stool analysis methods, and lack of clinical suspicion for these infections generally.53–56 The present study employs molecular methods as a more sensitive and objective diagnostic technique and operates on the assumption that GI parasites may be present in a variety of population subgroups, especially where conditions of poverty persist. In addition to being underestimated in many resource-limited countries, GI parasites are often underreported in the US.55,57,58 At the clinical level, physicians and lab technicians do not often suspect and therefore do not test for intestinal parasitic infections, presumably due to a lack of awareness and deficits in traditional US medical education. At the policy level, the majority of the intestinal parasitic infections are not reportable by mandate at the state level nor are they voluntarily nationally notifiable at the federal level. Senate bill S. 2675, known as the Study, Treat, Observe, and Prevent (STOP) Neglected Diseases of Poverty Act, was introduced in 2019 in order to address some of these issues.59 As a consequence of widespread neglect and dearth of surveillance activities, the current prevalence of locally acquired GI parasite infection in the US is largely unknown.
With few contemporary exceptions, the last domestic surveys for these infections were completed in the 1980s and decades prior, when roundworm, hookworm, whipworm, and strongyloidiasis were found throughout the southern US and Appalachia.16 S. stercoralis, for example, was recognized as endemic to the southeastern US after studies from the last century detected prevalence rates of approximately 0.1-3.8%.16 In 1914, The Rockefeller Sanitary Commission determined that more than half of the Alabama population was infected with hookworm; by the 1930s, 32.3% of specimens from Alabama counties sampled tested positive for hookworm.60,61 A follow-up study in the 1950s determined
14 that hookworm rates generally fell but persisted in rural Alabama schoolchildren, averaging 17.1% in the same counties surveyed in 1937.62 Current reports indicate that autochthonous S. stercoralis remains endemic in pockets of Appalachia, Los Angeles County, California, and rural Alabama.14,63,64 Extreme poverty, together with deficiencies in water, sanitation, and hygiene (WASH) have emerged as primary risk factors for parasite infection in the historical literature,16,65 such that helminthic and intestinal parasitic infections should be considered as health and economic disparities. A large rise in extreme poverty, defined as cash income of no more than $2 per person per day, for a month or calendar quarter, has been documented among US households since 1996.66,67 According to the most recent American Community Survey, an estimated 470,774 occupied households lack full indoor plumbing, which may include a toilet.68 Based on Census Bureau estimates of average household size of 2.6, more than 1.2 million Americans live without the plumbing required for basic sanitation, although scholars believe that the Census estimates significantly undercount the true number of US residents lacking access to complete water and sanitation services.68,69 According to the most recent American Housing Survey, 18.1% of US homes are not serviced by public sewer.70 Although other sanitation technologies provide adequate service when installed and maintained properly, such alternative wastewater management strategies –– e.g., septic system or cesspool –– have higher incidences of failure in low-income areas as the impracticable burden of installation and maintenance largely falls on the household.71 A previous study found that human hookworm infection remains endemic in a low-income rural area of Alabama meeting these criteria of absent plumbing and sanitation, or the presence of open sewage.14 Through a household survey combined with stool and blood samples, this study aims to characterize the threat of GI parasites to an unincorporated, peri-urban Texas community with a history of sanitation infrastructure challenges –– a common history and present reality shared by many other communities nationwide.
15 MATERIALS AND METHODS
Sample population
The study was carried out in Community A, an unincorporated, peri-urban community in Guadalupe County, central Texas, containing approximately 400 lots. Unincorporated communities in the US are areas within a county not serviced by any municipality. While the nature of unincorporated communities varies greatly across the US, Texas unincorporated areas are generally low-income and lack some combination of functioning wastewater system, potable drinking water, electricity, and paved roads with drainage.72–74 Community A and its neighboring community had previously approached the University of Texas at Austin for assistance collecting data to apply for sanitation grants. Surveys (unpublished data) from 2010 suggested that 98% of households in these two communities rely on (mostly professionally installed) septic tanks for wastewater removal. Notably, despite professional installation, 44% of surveyed households reported signs of septic system failure (clogs, sewage backups, capacity issues, and leaks), potentially due to improper soil type and poor maintenance. Between March and July 2018, a total of 92 households containing 404 individuals enrolled in the present study, after an exhaustive door-to-door community- wide sampling approach. All accessible and occupied households were eligible to participate. Households were deemed inaccessible if they were gated for privacy, if a no trespassing sign was posted, or if apparently aggressive dogs were present ––– 79 households were inaccessible for one or more of these reasons. Each of 244 accessible households was approached 3 times by a pair of researchers with English-Spanish language parity and one household member was invited to participate in the household survey on behalf of all household members. Of all accessible households, 92 (37.7%) participated in the survey, 82 (33.6%) declined to participate, and 70 (28.7%) were
16 unresponsive or gave no definitive response after 3 contact attempts by the research team. All participating households gave informed consent. The survey was co-developed by public health and policy scholars and civil engineers to capture built environment data pertinent to health. After a native Spanish speaker translated it to Spanish, the household survey instrument underwent content validation and was pre-deployed by several additional members of our research team to ensure accessibility of the questions and correctness of data collected. The survey instrument included questions regarding sociodemographic and health history for all household members, household socioeconomic status, diarrheal, respiratory, and dermatological disease history, household building and construction characteristics, wastewater and drinking water systems and problems, as well as other infection risk factors. The survey also asked about the travel history of each resident outside the US within the past 5 years, and for children whether their birthplace was within the US. Survey data were collected and managed using REDCap electronic data capture tool.75 Individual household residents were eligible to participate in stool and/or blood sample collection if they lived in one of the 92 surveyed households, were at least 2 years of age, and did not report taking an anti-parasitic medication in the past year. In total, 43 stool and 97 blood samples were obtained. Informed parental consent was obtained for children under 18 years of age and informed assent was additionally obtained for children at least 7 years old. This study was approved by the University of Texas at Austin Institutional Review Board (study number 2017-01-0025) with a Research Collaboration Agreement with Baylor College of Medicine.
Sample collection
Stool samples were self-collected by the individual participants after instructions and materials were provided bilingually, both verbally and in writing. Participants were
17 instructed to fill stool collection containers with approximately 5 grams of stool and store in provided opaque double-sealed biohazard bags in refrigerator overnight or until the next scheduled visit (up to several days). All samples were stored in ice coolers immediately after collection and transported to a BSL-2 laboratory at the University of Texas at Austin for storage in -20°C freezers before final transport in dry ice coolers to the Laboratory of Clinical Parasitology and Diagnostics, Baylor College of Medicine, where they were again stored in -20°C freezers. Whole blood samples were collected by venipuncture by a registered nurse under sterile conditions and were stored in ice coolers immediately after collection and transported to a BSL-2 laboratory at the University of Texas at Austin for storage in a 4°C refrigerator before final transport in ice coolers to the Laboratory of Clinical Parasitology and Diagnostics, Baylor College of Medicine, where they were again stored in a 4°C refrigerator.
Multi-parallel real-time quantitative PCR
DNA was extracted from the frozen stool samples using MP FastPrep spin kits for soil (MP Biomedicals, Santa Ana, CA) after a modified method was developed by the primary investigator, as previously described for Ancylostoma duodenale, Ascaris lumbricoides, Cryptosporidium species, Entamoeba histolytica, Giardia lamblia, Necator americanus, Strongyloides stercoralis, and Trichuris trichiura DNA.57 Samples were analyzed on an ABI ViiA 7 Real-Time PCR System (Applied Biosystems, Foster City, CA) as previously described.76 DNA concentrations were calculated using parasite plasmid standard curves. All controls (positive, negative, internal control) were performed on subject samples in duplicate.77 For Blastocystis, primers were previously designed for a segment of the SSU rRNA gene with the ability to amplify DNA from subtypes 1-10.78 Standards were prepared for Blastocystis according to the identical
18 protocol previously described for other species. Plasmids containing the target sequences were synthesized (Genscript, Piscataway, NJ) and transformed into TOP10 competent E. coli cells (Life Technologies, Grand Island, NY) with subsequent purification, quantitation by spectrophotometry, and serial dilution to make a standard curve (Genebank accession number: J02459). All qPCR positive samples were reported as parasite DNA concentrations measuring in femtograms per microliter (fg/µL).
Strongyloides NIE-ELISA IgG
For the detection of S. stercoralis, a previously described NIE-ELISA protocol79 was implemented using serum from the 97 participants who provided blood samples. The NIE-ELISA is a recombinant antigen that has shown no cross-reactivity to other helminths77. Any positive laboratory result (qPCR, ELISA) was communicated back to the participant and their primary care provider by a results letter. This letter explained in detail the findings and recommended steps of therapy. Participants were also notified of negative results.
Data analysis
Descriptive statistics were computed to describe community demographic and built environment variables. Molecular and serological data were analyzed using 2-sided Fisher’s exact test to identify associations between risk indicators for infection with detected parasite species. In an effort to assess participation bias, we additionally tested for differences in household income between participants that did or did not provide stool or blood samples. Findings were considered statistically significant at an alpha level of 0.05. All analyses were performed in Stata version 14 (StataCorp. 2015. Stata Statistical
Software: Release 14. College Station, TX: StataCorp LP).
19 RESULTS
Survey
Table 1 displays descriptive statistics for the study population. Among all residents in surveyed households, 49.75% are male and 50.25% are female, with an age distribution as reported in Table 1. Because age data were not provided for 6 adults, the total population reflected in Table 1 are 398 of the 404 individuals in surveyed households.
Table 1. Age (years) and sex distribution of 92 surveyed households (N = 404) Female Male Total Age Count (%) Count (%) Count (%) <2 7 (3.5) 11 (5.6) 18 (4.5)
Preschool 15 (7.5) 16 (8.1) 31 (7.8) 2-5 Prepuberty 24 (12.0) 28 (14.1) 52 (13.1) 6-11 Adolescent 25 (12.5) 22 (11.1) 47 (11.8) 12-18 Adult 129 (64.5) 121 (61.1) 250 (62.8) ≥19 Total *200 *198 *398 (50.25%) (49.75%) (N = 404)
*Age data are missing for 6 adults.
Diarrhea in the past year was reported by 32.9% of individuals in surveyed households, while 6.1% reported a dermatological ailment and 14.8% reported a respiratory ailment in the past year. Of all residents in surveyed households, 32.0% reported that their septic tank overflows or backs up and 34.2% reported that their toilet backs up. Several residents additionally noted that septic tanks overflow with rain or
20 flooding and that laundry washing machine water is affected, presumably owing to septic backup. Of 148 children ≤ 18 years old, 93.9% were born in the US. Of all residents surveyed, 17.2% reported a travel history outside of the US within the past 5 years (Figure 1).
Figure 1. Study population characteristics
92 households surveyed (404 individuals)
Age [years] Gender 5-year travel history Diarrhea in past year Respiratory problems Septic Backup (n=398) (n=404) (n=390) (n=398) in past year (n=381) (n=393)
<2: 18 (4.5%) Female: 203 (50.3%) No travel: 322 (82.6%) Positive: 131 (32.9%) Positive: 122 (32.0%) preschool: 31 (7.8%) Male: 201 (49.8%) Travel: 67 (17.2%) Negative: 267 (67.1%) Positive: 58 (14.8%) Negative: 259 (68.0%) Negative: 335 (85.2%) prepuberty: 52 (13.1%) Unsure: 1 (0.3%) adolescent: 47 (11.8%) adult: 250 (62.8%)
≤18 born in US (n=148)
Born in US: Born outside 139 US: (93.9%) 9 (6.1%)
As a way of assessing participation bias, we tested for differences in household income between participants that did or did not provide stool or blood samples. After excluding 13 cases with missing household income data, the total population reflected in Table 2 is 391. Among individuals living in a household with monthly income less than $2,000, 21.5% provided stool and 78.5% did not, whereas among those individuals living in a household with monthly income greater than $2,000, 5.5% provided a stool sample and 94.5% did not (p<0.001, Table 2). Overall, 67.4% of individuals that provided stool samples live in households reporting a monthly income less than $2,000, in the context of
21 a community where 34.5% of individuals live in households reporting a monthly income less than $2,000. Likewise, 79.3% of those in households earning more than $2,000 monthly did not provide blood samples compared to 20.7% who did (p = 0.035) (Table 2). Since pet ownership can be a marker for income,80,81 which appears to be associated with participation in our study, we also tested for an association between dog ownership and monthly household income, and found that among those with monthly household income less than $2,000, 40.7% owned at least one dog, compared to 63.3% owning at least one dog among individuals with monthly household income greater than $2,000 (p <0.001, Table 2).
Table 2. Characteristics related to monthly household income (N = 391) Characteristic Monthly household Monthly household income p-value income <$2,000 [N = >$2,000 [N = 256 (%)] 135 (%)] Dog ownership <0.001*** Yes (n = 217) 55 (40.7) 162 (63.3) No (n =174) 80 (59.3) 94 (36.7) Provision of stool <0.001*** sample Yes (n = 43) 29 (21.5) 14 (5.5) No (n = 348) 106 (78.5) 242 (94.5) Provision of blood 0.035* sample Yes (n = 94) 41 (30.4) 53 (20.7) No (n = 297) 94 (69.6) 203 (79.3) Percentages displayed in parentheses; adjusted to account for exclusion of cases with missing data. p-values derived from Fisher’s exact test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001
Strongyloides NIE-ELISA
Among the 92 households that participated in the survey, 43 (46.7%) consented to blood sample collection. Within these 43 households, a total of 97 blood samples were
22 collected from individuals aged between 2 and over 65 years (an additional 3 individuals consented to blood draws but the nurse was unable to obtain a sample). Of the 97 blood samples tested, 16 (16.5%) were seroreactive by ELISA for S. stercoralis at 100% sensitivity and 94.12% specificity (cutoff value 16.76 IgG units/ml via ROC). Of the 16 seroreactive cases, 4 (25%) were detected in children ages 2 through 15, none of whom had traveled in the past 5 years. Of note, one S. stercoralis seroreactive case was also detected in a pregnant woman. Of the 16 seroreactive cases, 4 (25%) reported a travel history to an endemic country outside of the US in the past 5 years, roughly the same as the 21.3% that reported a travel history and had negative serology (Table 3). The remaining 12 (75%) seroreactive cases were ostensibly acquired autochthonously. None of the children with positive serology were born outside of the US. Stool samples were obtained for 21/97 (21.6%) participants who provided blood samples, and comparative stool qPCR was performed for only 7/16 (43.8%) cases of positive S. stercoralis serology. None of these 7 S. stercoralis seroreactive cases had a positive qPCR result for S. stercoralis. Among individuals tested, the vast majority (92.5%) of those residing in a household with monthly income greater than $2,000 tested seronegative for S. stercoralis. In other words, there is a significant negative association between Strongyloides seropositivity and monthly household income over $2,000 (p = 0.011). Among those with negative serology, 62.8% have a monthly household income greater than $2,000, whereas among those with positive serology, only a quarter comes from households with monthly income over $2,000 (Table 3). Strongyloides transmission is believed to commonly occur through skin penetration, such as walking barefoot in contaminated soil. Data about this behavior were collected for children ages 2 through 15, and in this small sample (n = 20) we cannot detect a significant association with positive serology (Table 3). S. stercoralis larval
23 development and survival are affected by immersion in water; flooding may represent a significant factor in their survival and subsequent transmission to humans and animals.82,83 In this study, no significant difference in serology outcome was detected for flooding around the home, though among those with negative serology, 74.1% reported flooding around their home, whereas the presence or absence of flooding was evenly split among those with positive serology (Table 3).
24 Table 3. Risk factor analysis for participants without relevant missing data and ELISA serum testing (N = 97) Characteristic S. stercoralis S. stercoralis p-value negative ELISA positive ELISA [n [n = 81 (83.5%)] = 16 (16.5%)] Sex Male (n = 39) 34 (42.0) 5 (31.3) 0.579 Female (n = 58) 47 (58.0) 11 (68.8)
Monthly household income > $2,000 (n = 53) 49 (62.8) 4 (25.0) 0.011* < $2,000 (n = 41) 29 (37.2) 12 (75.0) Travel history (n = 20) 16 (21.3) 4 (25.0) 0.746 No travel history (n = 71) 59 (78.7) 12 (75.0) Diarrhea history (n = 42) 33 (43.4) 9 (56.3) 0.414 No diarrhea (n = 50) 43 (56.6) 7 (43.8)
Respiratory history (n = 18) 15 (20.3) 3 (18.8) 1.000 No respiratory (n = 72) 59 (79.7) 13 (81.3) Dermatological history (n = 8) 6 (8.1) 2 (12.5) 0.629 No dermatological (n = 82) 68 (91.9) 14 (87.5)
Children barefoot outdoors (n = 14) 12 (70.6) 2 (66.7) 1.000 Not barefoot (n = 6) 5 (29.4) 1 (33.3) Dog(s) in household (n = 58) 51 (63.0) 7 (43.8) 0.172 No dogs (n = 39) 30 (37.0) 9 (56.3) Cat(s) (n = 15) 12 (14.8) 3 (18.8) 0.709 No cats (n = 82) 69 (85.2) 13 (81.3)
Goat(s) (n = 2) 2 (2.5) 0 1.000 No goats (n = 95) 79 (97.5) 16 (100.0)
Flooding around home (n = 68) 60 (74.1) 8 (50.0) 0.074 No flooding (n = 29) 21 (25.9) 8 (50.0)
Septic backup (n = 40) 35 (43.8) 5 (31.3) 0.415 No septic backup (n = 56) 45 (56.3) 11 (68.8) Toilet backup (n = 35) 27 (33.3) 8 (50.0) 0.257 No toilet backup (n = 62) 54 (66.7) 8 (50.0)
Percentages displayed in parentheses; adjusted to account for exclusion of cases with missing data where n < 97. p-values derived from Fisher’s exact test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001
25
Multi-parallel real-time quantitative PCR
Only 43 of 404 (10.6%) residents in the surveyed population submitted stool samples. Samples were tested by qPCR for 9 species: Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Trichuris trichiura, Blastocystis spp., Cryptosporidium spp., Entamoeba histolytica, and Giardia lamblia. All stool samples were negative for A. lumbricoides, A. duodenale, N. americanus, S. stercoralis, T. trichiura, Cryptosporidium spp., and E. histolytica. Out of 43 stool samples received 27 tested positive for Blastocystis (62.8%) and one of these cases also tested positive for G. lamblia (2.3%). None of the children with Blastocystis or G. lamblia were born outside of the US. The child with the G. lamblia infection has no reported travel history within the past 5 years. Blastocystis infection status is not significantly associated with monthly household income over $2,000 (p = 1.000) among the 43 individuals tested (Table 4). In our study population, males were significantly more likely than females to be infected with Blastocystis (66.7% male, 33.3% female, p = 0.032, Table 4 as were those reporting diarrhea in the past year (70.4% with diarrhea, 29.6% without diarrhea, p = 0.002, Table 4). Males aged 6 through 11 had the most Blastocystis infections of any age group, with 84.6% in that age group testing positive.
Among individuals without Blastocystis, the households are approximately evenly split between having a dog and not, whereas among those with Blastocystis, the vast majority of individuals come from households that do not have a dog (18.5% with dogs, 81.5% with no dogs, Table 4). Among the 21 participants that provided both stool and blood samples, 5 (23.8%) had positive lab findings suggestive of polyparasitism with S. stercoralis and Blastocystis
26 spp. Stool Blastocystis DNA concentrations in positive samples ranged from 0.0041 to
598,962.1 fg/µL, with a mean of 42,711.8 fg/µL.
Table 4. Risk factor analysis for participants without relevant missing data and qPCR stool testing (N = 43) Characteristic Blastocystis Blastocystis p-value negative [n = 16 positive [n = 27 (37.2%)] (62.8%)] Sex Male (n = 23) 5 (31.3) 18 (66.7) 0.032* Female (n = 20) 11 (68.8) 9 (33.3)
Monthly household income > $2,000 (n = 14) 5 (31.3) 9 (33.3) 1.000 < $2,000 (n = 29) 11 (68.8) 18 (66.7) Travel history (n = 9) 3 (18.8) 6 (23.1) 1.000 No travel history (n = 33) 13 (81.3) 20 (76.9)
Diarrhea history (n = 22) 3 (18.8) 19 (70.4) 0.002** No diarrhea (n = 21) 13 (81.3) 8 (29.6)
Dermatological history (n = 5) 2 (12.5) 3 (12.0) 1.000 No dermatological (n = 36) 14 (87.5) 22 (88.0)
Dog(s) in household (n = 14) 9 (56.3) 5 (18.5) 0.018* No dogs (n = 29) 7 (43.8) 22 (81.5)
Cat(s) (n = 11) 5 (31.3) 6 (22.2) 0.719 No cats (n = 32) 11 (68.8) 21 (77.8)
Caged bird(s) (n = 9) 2 (12.5) 7 (25.9) 0.446 No caged birds (n = 34) 14 (87.5) 20 (74.1)
Flooding around home (n = 27) 13 (81.3) 14 (51.9) 0.101 No flooding (n = 16) 3 (18.8) 13 (48.1)
Septic backup (n = 11) 4 (25.0) 7 (25.9) 1.000 No septic backup (n = 32) 12 (75.0) 20 (74.1)
Toilet backup (n = 18) 6 (37.5) 12 (44.4) 0.755 No toilet backup (n = 25) 10 (62.5) 15 (55.6)
Percentages displayed in parentheses; adjusted to account for exclusion of cases with missing data where n < 43. p-values derived from Fisher’s exact test. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001
27 DISCUSSION
Among members of this central Texas community that participated in our study, we found that 16.5% were seroreactive for S. stercoralis, 62.8% tested positive for Blastocystis spp., and 2.3% tested positive for G. lamblia.
Strongyloides
The prevalence of blood samples seroreactive for Strongyloides stercoralis in our sample is 16.5%. The highest prevalence of S. stercoralis recorded in high-quality historic studies of soil-transmitted helminths in the US approached 4%, though this is considered an underestimate due to methodological limitations of the time.16,84 More recently, S. stercoralis antibody prevalence approached 2% in a seroprevalence study in rural Kentucky63, and a 5% prevalence was detected via combined serology and qPCR in a study of immigrants from Latin America residing in Washington DC.77 In rural Alabama, stool qPCR detected S. stercoralis in 7.3% of residents tested.14 Among a cohort of AIDS patients from a US urban center, 25% were seropositive for S. stercoralis, the majority of whom had emigrated from known endemic areas79 –– S. stercoralis prevalence in the US is generally higher among immigrants and refugees as well as travelers and veterans returning from endemic areas.84–87 Strongyloidiasis has also historically been found to be more prevalent among institutionalized persons in the US.88– 90 Globally, S. stercoralis prevalence estimates and corresponding data are heterogeneous, using incomparable varying diagnostic techniques.84,91 Existing, mixed- quality data suggest rates between 10% and 40% of populations are infected with S. stercoralis in many tropical and subtropical countries.91 While stool samples were available for only 7/16 (43.8%) cases of positive S. stercoralis serology, none of the 7 stool samples from individuals with chronic strongyloidiasis had positive qPCR for S. stercoralis –– this discrepancy may reflect
28 cleared infection and a previous history of strongyloidiasis or may also be a product of parasite biology –– parasite load is often low and larval output is irregular.92 Other studies document a similar discrepancy between stool and serology testing for Strongyloides.86,93–95 Given the presence of stray dogs and other animals in this area, the possibility remains that human toxocariasis, a zoonotic helminthiasis, is also prevalent and the sera from some of our study participants may have cross-reacted to Toxocara spp. However, recent studies on the Strongyloides NIE-ELISA IgG find that it exhibits high specificity, ranging from 90.7-98.9% in one study96 to 100% in another study77, reducing the likelihood of this possibility. Owing to the nematode’s autoinfection cycle, which, without adequate treatment, results in decades-long or lifetime infections in human hosts, chronic and latent Strongyloides infection can become life-threatening through hyperinfection and/or dissemination syndromes.56,84,87,97–99 Strongyloidiasis hyperinfection has resulted in mortality in up to 87% of reported cases.84 A population-based case-control study using mortality data from 1991-2006 found that deaths from strongyloidiasis were reported from 36 of the 50 states, with most (62.3%) deaths among persons born in the US.56 As are the other soil-transmitted helminths, Strongyloides is a severely under- recognized public health threat in North America.97–99 Both public and clinical awareness of the risk of Strongyloides infection are lacking, in human and veterinary medicine.97
Jariwala et al. argue for a “One Health” approach to the public health threat posed by the parasite, given that zoonotic and environmental factors are critical in Strongyloides epidemiology.97 The role of canines in Strongyloides transmission in Community A is uncertain but merits further investigation. The seriousness of infection with Strongyloides cannot be overstated, especially in the US clinical context. Disseminated strongyloidiasis is unique in that mortality in the
US is nearly always iatrogenic; especially in the case of patients taking steroids with chronic Strongyloides infection, fatal hyperinfection can result, with mortality frequently
29 owing to gram-negative sepsis.99 In their survey of US resident-physicians, Boulware et al. found that US physicians-in-training had poor recognition (9%) of the need for parasite screening generally and frequently prescribed empiric corticosteroids (23%).99 In comparison, 56% of international trainees recognized the need for parasite screening (p<0.001). 41% of US physicians were unable to choose any parasite causing pulmonary symptoms.99
Blastocystis
The prevalence of Blastocystis, a heterokont parasite transmitted via the fecal-oral route, in our sample is 62.8%. The highest prevalence of Blastocystis ever observed worldwide was 100% in a population of Senegalese children.100 Blastocystis prevalence among the general population of industrialized countries often exceeds 5% and can approach 30-60% in developing countries.101 Several epidemiological surveys from different countries identify Blastocystis spp. as the most common eukaryotic parasite detected in human fecal samples102 and, as in our study, its prevalence is overall higher than the prevalence of other intestinal protozoan parasites including Giardia, Entamoeba and Cryptosporidium103,104 –– 2.3% of our samples contained Giardia and the latter two protozoa were not detected in any of our stool samples. In a study of intestinal infections in residents of the US Rocky Mountain region, Blastocystis sp. was the most frequently detected species, at about 4% prevalence year-round.105 Nationally, annual prevalence of Blastocystis in the US declined from 23% in 2000 to 11% in 2004, when the last large scale investigation was conducted.106 From 2002-2004, the estimated prevalence of Blastocystis infection in Texas was 7%.106 At 62.8%, the prevalence of this parasite among study participants living in Community A is uncharacteristically high for a
30 developed country and for the state of Texas, alike, and underscores a substantial degree of ongoing environmental contamination with sewage. The pathogenicity of Blastocystis is thought to be related to specific subtypes and parasite burden, although even individuals harboring a small number of cysts can be symptomatic.107 Some clinicians recommend that individuals with low parasite burden and no symptoms not be treated, though those with gastrointestinal or dermatologic signs and symptoms and high parasite burden may require treatment.107 While other studies have also identified an increased risk for males to harbor Blastocystis,108–110 there are many studies that did not find a significant association with sex.111–117 In accordance with societal gender biases, it has been suggested that males are at increased risk for Blastocystis due to their increased participation in outdoor activities, which heightens the likelihood of fecal-oral transmission in environments where the parasite is present. During fieldwork in Community A, male children were more frequently observed playing outside than were female children, but this was not objectively measured. Of note, Community A has a large population of stray dogs, which often respect no lot boundaries, meaning that households that do not own a dog may still have dog feces in their yard. This issue blurs the association between dog ownership, dog feces exposure, and Blastocystis infection rates. While our results suggest a negative association between dog ownership and Blastocystis infection, this finding may be related to our sampling strategy, which, for safety reasons, excluded households with apparently aggressive dogs, barring communication to gauge resident interest in participation. The association with income may also partly explain our finding that having a dog in Community A is negatively associated with Blastocystis infection. No other pets were identified as significantly associated with Blastocystis infection. Contrary to our findings, dog ownership and/or living in close proximity to other domestic animals or pets was identified as a risk factor for Blastocystis infection in other studies.115,118,119 Future
31 investigation of canine fecal studies and seroprevalence may be informative, as both stray and domesticated dogs are omnipresent throughout the community and have been implicated in zoonotic transmission pathways for both protozoal and helminthic parasites.97,120–125 Blastocystis is transmitted via fecal-oral infection route, by which humans become infected through environmental contamination. Given the extent of septic failure, it is likely that human sewage is responsible for the increased prevalence of intestinal parasites in this sample. Problems with septic systems are widespread in Community A, and an analysis of soil types may provide an explanation. A 2018 USDA soil map obtained for the area clearly identifies over two-thirds of the community rests on soil types that are not compatible with septic systems due to very slow permeability, rendering the septic systems susceptible to clogging.126
Clinical implications
Limited knowledge of helminths by US clinicians puts a large population of both immigrant and US-born Americans in iatrogenic danger. Clinical suspicion for and awareness of neglected intestinal parasites may be improved with an emphasis on these infections in US medical training and continuing medical education.99 Boulware et al. suggest that while it may be unrealistic to expect comprehensive helminth knowledge among US physicians, basic knowledge of iatrogenic danger posed by corticosteroids and Strongyloides infection should exist.99 Clinical suspicion in both practice and laboratory settings may additionally be enhanced by mandatory reporting of Strongyloides and other helminths. While in 2016 Texas became the first state to mandate reporting of ascariasis, trichuriasis, and hookworm with the passage of 2015 H.B. 2055, An Act relating to the establishment of a sentinel surveillance program for emerging and neglected tropical
32 diseases, strongyloidiasis was excluded from the list of notifiable conditions.127 None of the soil-transmitted helminths are nationally notifiable.128
Policy implications
Several policy implications arise from our findings of high rates of Blastocystis and Strongyloides positive lab findings in central Texas. First, as suggested above, strongyloidiasis should be added to the Texas notifiable conditions list at the next annual update. Likewise, strongyloidiasis and the other endemic soil-transmitted helminths should be added to the list of nationally notifiable diseases, which is reviewed and updated annually by the Council of State and Territorial Epidemiologists and CDC.128 Second, given the lack of familiarity and awareness for strongyloidiasis among US-trained clinicians, state and national medical associations should highlight neglected parasitic infections in their campaigns and activities in their provision of continuing medical education. An emphasis should be placed on updated regional findings as well as vulnerable populations, with health departments alerting clinicians and laboratories to the most recent epidemiological findings in an effort to heighten clinical suspicion and capacity to treat. The US medical community can benefit from the lessons learned by developing countries with more experience with strongyloidiasis prevention and control.
Third, health departments should collaborate with other local, state, and federal resources to address the underlying equity issues promoting these health disparities, with an aim towards prevention. Findings such as a prevalence rate for Blastocystis on par with developing countries underscore that at least one American community suffers substantially from lack of access to functioning sanitation infrastructure –– as such, its residents are denied that basic human right and public health is jeopardized. Based on widespread economic and infrastructure disparities, there are likely many more
Americans facing similar realities nationwide.
33 Community A shares commonalities with the better-characterized peri- urban unincorporated communities along the Texas-Mexico border, often referred to as colonias or urban slums. A growing body of research suggests that the annexation and incorporation of these communities can drive the evolution of improved infrastructure access across energy, water, and wastewater systems129 and that residents experience improved standards of living owing to municipal oversight.130 However, Durst demonstrates a systematic failure of cities to annex surrounding minority communities, with cities selectively underbounding census blocks that contain colonias, especially those containing colonias with poor infrastructure.130 Despite the introduction by the Texas legislature of Subchapter B of Chapter 232, Local Government Code, in 1995, which intended to promote the upgrading of critical infrastructure in southern Texas colonias, decades later there are heterogeneous impacts of this policy on built environment parameters regionally. As Guerra Uribe et al. argue, decision makers should focus on localized efforts within the broader existing policy context to increase services access, highlighting the need for tailoring solutions to the county and city level.129 Community A residents will need to determine the most amenable path forward in addressing their wastewater infrastructure, given their local cultural, financial, and jurisdictional constraints.
Limitations
The sample is representative of those that provided stool and/or blood samples from the surveyed households in Community A. Although our sampling strategy made a systematic attempt to include all households, we do observe a degree of participation bias. The relationships between monthly household income and provision of stool and blood samples suggest a systematic oversampling of lower income residents, although income has not been standardized for household size. Possible reasons for this type of
34 sampling bias may be that higher income households were less accessible to research personnel during study recruitment due to gated properties, and that participants were offered $15 compensation for completing the survey and for later providing stool and/or blood samples. In the case of some analyses, the sample used to test for an association between a given risk factor and positive lab finding was quite small. The Fisher’s exact test is designed to accommodate small samples, and is considered a conservative statistical test. However, due to reduced statistical power, lack of statistical significance cannot be interpreted as the absence of an association. Additionally, clustering by household, (where cases come from the same household) may influence the risk of infection transmission. The small number of stool and blood samples obtained precludes a meaningful multiple regression analysis by household cluster. The significant association between low income and S. stercoralis seropositivity is supported by prior work documenting this parasite in conditions of poverty and poor sanitation and hygiene.84,90,91
Conclusion
This pilot active surveillance study demonstrates the presence of neglected intestinal parasites in a Texas community, and adds to the weight of evidence demonstrating the burden of neglected intestinal parasites in the United States. Effective and sustainable public health programming will depend on accurate prevalence estimation as well as public willingness and support for addressing health disparities. To aid research and public health communities in focusing surveillance efforts on the most at-risk US populations, we are developing species distribution models for strongyloidiasis and other soil-transmitted helminths so that resources may be efficiently directed. Moreover, the public health information these studies generate could be used for
35 community-driven decision support initiatives to help secure effective sanitation and protection from preventable diseases.
ACKNOWLEDGEMENTS Data collection in the field was carried out by RS and the following University of Texas at Austin students (alphabetical order): Felipe Araya Araya, Kelsea Auguillard, Emily Baysden, Sara Becker, Carlos Lopez Bray, Catherine Cruz, Jessica Ellis, Bibiana Toro Figueira, Laney Hempel, Eric Johnson, Shreya Mallena, Monica Navarro-Jimenez, Chelsea Nguyen, Ebubechukwu Okeke, Camila Peterson, Eleonore Saliba, Ressiel Nicole Villegas. We thank Drs. Kerry Kinney and Juan-Pedro Maestre for their advice and for generously providing sample storage space in BSL-2 laboratory. Stephanie Borjas, RN performed phlebotomy. Anthropometric equipment was generously loaned from the University of Texas Health Science Center at Houston School of Public Health in Austin.
Financial support: Funds for participant compensation were generously provided by the LBJ School of Public Affairs. Funds for the phlebotomy portion were generously provided via the Doctoral Dissertation Grant Program of the Fahs-Beck Fund for Research and Experimentation, A Fund Established with The New York Community Trust. Research funding support for RM was provided by the U.S. Department of Health and Human Services, Health Resources and Services Administration for Baylor College of Medicine Center of Excellence in Health Equity, Training and Research (Grant No: D34HP31024). Funding also provided by the Texas Children’s Hospital Center for Vaccine Development, and the National School of Tropical Medicine, Baylor College of Medicine.
36 Chapter 2: Modeling Strongyloidiasis Risk in the United States
ABSTRACT We provide a spatial risk assessment for strongyloidiasis in the United States by prioritizing areas with high probability of Strongyloides stercoralis presence and offer recommendations for targeted screening and surveillance. The risk assessment was based on a species distribution model with parasite occurrence data and ecologically important environmental variables as input and local habitat suitability for the species as output. The model used a maximum entropy algorithm and occurrence records and environmental data from public sources. This ecological risk assessment was coupled to socioeconomic factors using multi-criteria analysis. The model predicts suitable habitat for the parasite in 10 states beyond the southeastern United States where it has been recorded including states in the south, east and northeast, and west coasts. We recommend that strongyloidiasis be classified as a reportable infection in 16 states at high risk. Moreover, near universal solid organ transplant screening should be implemented alongside approaches to heighten clinical suspicion.
INTRODUCTION
The soil-transmitted helminth (STH), Strongyloides stercoralis causes the neglected disease strongyloidiasis. Infection resulting from S. stercoralis is the most chronic and deadly of the soil-transmitted helminthiases; complications are associated with high mortality. It is estimated that hundreds of millions of people globally are infected with S. stercoralis and, without adequate anthelmintic therapy, may be chronically infected for life owing to a unique auto-infective component of the parasite’s life cycle.99 Chronic and latent strongyloidiasis can become life-threatening through hyperinfection and/or dissemination syndromes,56,84,87,97,99 with hyperinfection resulting in mortality in up to 87% of reported cases.84 In the United States, deaths from strongyloidiasis have been reported in 36 of 50 states, with the majority (62.3%) of deaths occurring among persons born in the United States.56 The STH are a group of human parasites responsible for some of the most common neglected tropical diseases (NTDs). Though these NTDs predominantly occur in poor countries in the tropics, these infections are not exclusively restricted to the tropical developing world; in fact, many NTDs are endemic to the developed world including the
37 wealthiest countries, though accurate prevalence estimates are typically not available and the epidemiology of these infections are largely unknown.131 With a few exceptions from recent work, active surveillance to detect STH has not been conducted in the United States since the early 1980s. As summarized by Starr and Montgomery, studies published in the period 1942-1982 document that STH were endemic to large swaths of the American south and Appalachia,16 with prevalence rates for some species exceeding or approaching 20%, which is the World Health Organization threshold for mass drug administration.17 Since the last century, it has been established that S. stercoralis is present primarily in the southeastern United States, though this species was far less frequently surveyed through active surveillance studies than the more common STH: Ascaris lumbricoides, Trichuris trichiura, and hookworm species.16 Its exclusion from many United States surveys in the last century may be because, prior to the introduction of serology and molecular diagnostics, S. stercoralis was more difficult to detect in human stool samples owing to irregular larval output.92 While uncomplicated cases are more routinely missed, case reports of deaths, hyperinfection, and disseminated strongyloidiasis have been described in a majority of states, including reports out of Galveston, Texas in the 1980s and 1990s in Texas residents.56,132,133 A renewed attention to STH in the United States began in the 2010s, when hookworm was detected in 34.5% of the individuals and strongyloidiasis in 7.3% of them in a sample of residents in rural Alabama.14 State and federal public health officials assessed the prevalence of S. stercoralis antibodies in a rural Appalachian population, and found that 1.9% of the sample they screened in rural Kentucky tested seropositive.63 A recent study in Texas suggests ongoing autochthonous transmission of S. stercoralis in a central Texas community, where 16.5% of individuals tested seropositive.134 Yet, strongyloidiasis is not reportable in Alabama, Kentucky, Texas, or any other state, suggesting that even passive surveillance is not conducted for this infection. Organ donor
38 screening for S. stercoralis is not uniformly practiced among United States organ procurement organizations (OPOs); only 10% of all U.S. OPOs screen donors for this infection.135,136 Seroprevalence in human and canine or other animal populations with zoonotic potential remain unknown throughout the United States. Given the decades-long gap in STH surveillance in the United States, and contemporary results which suggest these infections persist in at least some regions, United States health officials and policymakers have reason to seek to initiate and expand strategic surveillance to identify whether and where STH pose a threat to public health. Active surveillance is a resource-demanding public health activity; as such, its optimal implementation requires a systematic and data-driven approach. The objective of this study is to provide a spatial risk assessment of strongyloidiasis in the United States to highlight regions with elevated risk and to provide recommendations for targeted screening and surveillance. It first uses species distribution modeling techniques developed by ecologists to predict suitable habitat for S. stercoralis based on occurrence records for the species and environmental layers pertinent for its ecological persistence. This ecological risk assessment is then modified to provide a composite risk assessment using poverty data for the United States in a multi-criteria analysis (MCA).
METHODS
Study Area. The study area for species distribution model (SDM) construction encapsulates all known occurrence points, and was delimited at the south by the 5.458°N line of latitude along the Panama-Colombia border, by the coasts of North and Central America to the east and west, continued by the lines -179.166°W and 52.727°W and the line 83.125°N at the north (see Figure 2). The study area was divided into 16,058,360 cells at a resolution of 2.5 arc-minutes, with each cell area 4 km2. For the MCA, the study
39 area was restricted to the continental United States for risk analysis based on poverty data.
Species Distribution Model
Data. S. stercoralis species occurrence data were obtained from biodiversity databases, museum collections, published literature, one county health department with a history of reporting strongyloidiasis, and an active surveillance field study in central Texas, the results of which were reported in chapter 1 134 (see Acknowledgements for more detailed information on databases and collections). A systematic search of PubMed (with no filter on dates of coverage; the database starts in 1950) and Google Scholar (no date filter) was carried out from October to December 2018 using the search terms “latitude” AND “longitude” AND “Strongyloides stercoralis”. All references were managed with Zotero Version 5.0. To be included in the model, occurrence records had to specifically reference laboratory confirmed cases of S. stercoralis in any country within the study area. All data were georeferenced using the MaNIS protocol (http://georeferencing.org/georefcalculator/gc.html, Accessed 2019 August 21), and error was estimated following established best practices.137,138 Due to the spatial resolution of the analysis, only records with an estimated error less than 2.5 arc-minutes were retained for modeling purposes. Records with known or assumed travel history, such as those reported from Veterans Affairs facilities or in immigrants, were excluded. Model Construction. The species distribution model was constructed from S. stercoralis occurrence points and environmental layers using the Maxent software package (Version 3.4.0),139 which employs a maximum entropy algorithm. Maxent is a general-purpose prediction method especially suited for problems presenting with incomplete information. Maxent locates the probability distribution of maximum entropy
(one that is most spread out, or closest to uniform) to estimate a target probability
40 distribution based on a set of constraints representing incomplete data about the target distribution.140 Maxent has been demonstrated as robust for modeling species distributions from presence-only records for a large variety of taxa.141 Maxent was run with duplicates permitted so that in select instances there was more than one sample per pixel; this was deemed appropriate in the context of reported occurrence cases from the same location in different years (corresponding to separate studies of unique individuals in the same institution) and in the context of unique residences with confirmed cases from the same community under study (with only one case per household represented). In accordance with published recommendations,140,142 Maxent was implemented with features of five classes: threshold, hinge, linear, quadratic, and product features.142 The convergence threshold was set to a conservative 1.0×10-5. Averages over 100 replicate models were computed for the area under the receiver operating characteristic (ROC) curve (AUC). The test:training ratio was set to 25:75 for each model, so that models were constructed using 75% of the data and tested with the remaining 25%. To reduce model overfitting, the regularization multiplier was kept at the default of 1. To assess model performance, a conservative threshold of 0.9 was used for the test AUC, where an optimal model is represented by an AUC approaching 1 and a model that predicts species occurrences at random would have an AUC of 0.5. The minimum threshold suggested in published recommendations is an AUC of 0.7.141
The 20 environmental layers used are listed in Table 5; 19 bioclimatic variables were sourced from the WorldClim database (www.worldclim.org; last accessed September 15, 2019) and one topographic variable, the compound topographic index, was sourced from the Hydrologic Derivatives for Modeling and Analysis database.143 Environmental layers were processed using the Spatial Analyst extension of ArcGIS Pro (version 2.4.0) to ensure identical geographic extent, projection, and cell size.
41
Table 5. Environmental features for species distribution models Features Annual mean temperature Mean diurnal range [mean of monthly (max temp – min temp)] Isothermality (mean diurnal range/temperature annual range) (x100) Temperature seasonality (standard deviation x100) Max temperature of warmest month Min temperature of coldest month Temperature annual range Mean temperature of wettest quarter Mean temperature of driest quarter Mean temperature of warmest quarter Mean temperature of coldest quarter Annual precipitation Precipitation of wettest month Precipitation of driest month Precipitation seasonality (coefficient of variation) Precipitation of wettest quarter Precipitation of driest quarter Precipitation of warmest quarter Precipitation of coldest quarter Compound topographic index
SDM Output and Its Interpretation. The output from Maxent consists of relative habitat suitability values between 0 and 1. When normalized by division with the highest value, these values can be interpreted as the relative probabilistic expectation of the species’ presence in a geospatial cell.
Ecological Risk. With the aim of assessing risk of strongyloidiasis in a given locale, ecological risk was quantified by relative probabilistic expectation of S. stercoralis presence in each cell. Species suitability greater than 0 represents the minimal ecological conditions required for an infection to spread and establish an autochthonous (i.e. local) transmission cycle in an area. Where ecological risk is present, anthropogenic factors become critical determinants of the likelihood that an endemic transmission cycle may be established.
42 Multi-Criteria Analysis
Economic Data. Poverty microdata were obtained from the Integrated Public Use Microdata Series, taken from the 2017 (5-Year Estimates) American Community Survey of the United States Census Bureau.144 The geographic level of data used is the Public Use Microdata Sample Area (PUMA); PUMAs are the smallest geographic units associated with household-level census data and roughly follow county boundaries, containing between 100,000 to 200,000 residents each. Poverty is expressed as a ratio of income to poverty level in the past 12 months, and contains data for the United States population for whom poverty status is determined. The data are categorized into 7 variables: under 0.50, 0.50 to 0.99, 1.00 to 1.24, 1.25 to 1.49, 1.50 to 1.84, 1.85 to 1.99, and 2.00 and over. Ratios below 100 percent of the federal poverty level are below the official poverty definition, with ratios below 50 percent of the poverty level representing the most severe poverty, having income below half the federal poverty threshold. Anthropogenic Risk. It is well-established that degree of poverty is associated with poor infrastructure and housing conditions, which in turn are strong predictors of infection with intestinal parasites.14,16,63,134 Economic insecurity increases the odds of inadequate household plumbing; households with incomes twice the PUMA median have been found 1.5 times more likely to have complete plumbing145, a primary protective factor against STH like S. stercoralis. Though it may assume a more direct relationship between income and infection risk than ideal, we use severe poverty as a proxy for anthropogenic risk for strongyloidiasis. In the absence of complete sanitation data at the household level, we assume this extreme measure of poverty is among the most relevant variables available that may help predict risk of strongyloidiasis. Non-Dominated Alternatives. Any attempt to integrate ecological and anthropogenic risk requires MCA for which a wide variety of techniques are available.146,147 However, methods that are consistent with standard economic theory require quantitative weights to be attached to the criteria.148 However, in the present case,
43 any attempt to assign quantitative weights to the ecological and anthropogenic risk factors for infection would not only be arbitrary but would be open to objections that they were not elicited from the preferences of a representative sample of stakeholders. Therefore, this analysis used a method that does not require weights on criteria, namely, dominance,146,149 or the identification of non-dominated alternatives. The alternatives were PUMA spatial units. One alternative (that is, PUMA) “dominates” another with respect to performance if it has either higher ecological or anthropogenic-based risk, and neither its ecological risk nor its anthropogenic risk is lower than that of the other alternative (or PUMA). An alternative (or PUMA) spatial unit is “non-dominated” if no alternative dominates it. (The non-dominated set of alternatives corresponds to the Pareto optimal set of standard economic theory). The collective risk of the set of non-dominated solutions is higher than that of the other alternatives, none of which is worse off than all of the non-dominated solutions according to both criteria. Multi-criteria analyses were performed using ArcGIS Pro.
RESULTS
Strongyloides stercoralis Biogeography
While it is known that Strongyloides species can occur in many tropical, subtropical, and temperate settings, autochthonous transmission in the United States has only generally been established for the southeastern states, especially rural Appalachia. Our data collection and analysis extended the known distribution of S. stercoralis in the United States into 10 states outside of the southeastern United States (as defined by the U.S. Geological Survey, excepting Kentucky, which is known to have cases): Arizona, California, Connecticut, Delaware, Maryland, New Jersey, Ohio, Texas, Virginia, and
West Virginia.
44 Species Distribution Model
Data: A search of the PubMed database yielded 39 articles, none of which contained coordinates for S. stercoralis within the study area. An initial search of the Google Scholar database yielded 360 articles; a filter was applied with the terms AND “Mexico” OR “United States” OR “Canada”, refining the yield to 191 articles, with duplications. A thorough search by hand of references resulted in additional articles that satisfied inclusion criteria. As appropriate, authors were contacted for further detail if insufficient geographic data were provided in the article; in two cases, contact with authors at county, state, and federal public health agencies permitted the extraction of data from pertinent studies. After accounting for duplicates, exclusion criteria, and spatial requirements, 28 occurrence records were retained from the literature. Museum collections and biodiversity databases yielded one occurrence data point, and a county health department collecting strongyloidiasis data yielded another nine. Field investigations yielded seven additional occurrence points, representing seven separate households, often containing more than one case, with no travel history. From a combination of literature search, museum collections, biodiversity databases, county health department data, and field investigations, 45 records satisfied inclusion criteria and spatial resolution requirements and were retained for species distribution modeling. No records originated from Canada, three records came from Belize, three records came from Mexico, and 39 records came from the United States. Model: Model performance was judged by the test AUC. The average test AUC for the 100 replicate models was 0.973, and thus above the threshold of 0.9, with a standard deviation of 0.032. In addition to the high AUC, model predictions are likely reliable given the 45 presence records used to construct the model; a past study suggests reliability of Maxent models using more than 10 presence records.150 Ecological Risk: Ecological risk quantifies probable exposure to S. stercoralis due to its ecological suitability in a given cell, and is represented by the map in Figure 2.
45 Figure 2. Species distribution model for Strongyloides stercoralis
Continuous grey scale; light to dark represents relative species suitability values 0-1.0.
Twelve out of 45 (27%) occurrence records fell in cells with habitat suitability ≤0.5, while the majority (73%) of occurrence records fell in cells with habitat suitability ≥0.5. There is a high probability (≥0.5) of S. stercoralis in specific areas of the following states: Arizona, Arkansas, California, Connecticut, Delaware, Kentucky, Louisiana, Maryland, New Jersey, North Carolina, Ohio (only Scioto and Lawrence counties), South Carolina, Tennessee, Texas, Virginia, and West Virginia (Figure 2). This list should not be viewed exhaustive; it may reflect the limited data available as input for the model.
46 Multi-Criteria Analysis
The non-dominated set of at-risk solutions is displayed in Figure 3 and Table 6.
Figure 3. Severe poverty and Strongyloides stercoralis suitability
Triangles represent non-dominated solutions, those which have no alternatives above or to the right. Income to Poverty Ratio: Estimates of individuals per PUMA with income less than half the poverty threshold.
When we consider ecological risk and anthropogenic risk in the multi-criteria dominance analysis, six unique PUMAs are in the non-dominated set, with Los Angeles County represented three times, for a total of eight non-dominated solutions with PUMAs in: Santa Barbara and Los Angeles Counties, California; Richmond City, Virginia; Brazos County, Texas; Philadelphia, Pennsylvania; and Chicago, Illinois.
47 Two of these cases (Philadelphia and Los Angeles) have occurrence incidences of S. stercoralis. Since we do not know the actual weights of the criteria, we would not expect all of the non-dominated solutions to be high-risk for strongyloidiasis, especially not outliers that feature very low and far to the right, such as Chicago (Figure 3). To differing degrees, the PUMAs in Santa Barbara, Los Angeles, and Brazos Counties as well as Richmond, have high suitability for the presence of the parasite, and, where anthropogenic risk factors coexist, are foci of elevated concern for strongyloidiasis.
Table 6. Non-dominated solutions from multi-criteria analysis Location Predicted S. stercoralis Estimated individuals per PUMA suitability with income less than half of poverty* South Coast Region PUMA, Santa 0.97183 17,370 Barbara County, California
Los Angeles City PUMA, Los 0.94658 20,664 Angeles County, California
Los Angeles City PUMA, Los 0.91255 23,793 Angeles County, California
Los Angeles City PUMA, Los 0.90667 25,134 Angeles County, California
Richmond City PUMA, Richmond 0.51472 29,175 City, Virginia
College Station and Bryan Cities 0.48932 31,376 PUMA, Brazos County, Texas
Philadelphia City PUMA, 0.2722 31,628 Philadelphia, Pennsylvania
North and South Lawndale, 0.02693 33,513 Humboldt Park, East and West Garfield Park PUMA, Chicago, Illinois
*Source: American Community Survey, 2013-2017 5-Year Estimates
48 DISCUSSION
Consistent with previous studies, our model predicts that the Cumberland Valley region of Kentucky is a potential hot zone for strongyloidiasis.63 In addition to a basis for further research and active surveillance, this result reinforces the suggestion that the state of Kentucky should make strongyloidiasis a reportable condition and should work to promote clinical suspicion for the infection regionally. This is particularly critical in the case of organ donation and transplantation amongst Kentucky residents; the screening process in these cases should be extremely sensitive to detecting active and latent strongyloidiasis in both donors and recipients. Other immunocompromised patients, including cancer patients or those on steroid therapy, should also be screened prior to the initiation of treatment. Despite a study that detected strongyloidiasis in residents of Lowndes County, Alabama,14 this area had a predicted suitability of <0.1. The lab-confirmed cases of strongyloidiasis in Lowndes County were found in local-born residents without travel history. While these cases fit our inclusion criteria, we were unable to obtain geographic data of sufficient resolution for them, and their absence as input data for our model likely resulted in an underestimation of S. stercoralis suitability in this region. In the absence of occurrence records, Lowndes County would not be predicted as suitable unless other occurrence records were similar enough in environmental profile. This discrepancy with the literature likely indicates that our risk analysis is conservative: whereas all areas predicted to have high risk are actually at high risk, not all high risk areas were so identified by our analysis. The case of Lowndes County, Alabama, also points to the critical importance of reliable surveillance –– a dearth of known occurrence data for a neglected parasite compromises the predictive power of modeling attempts. Four occurrence points reported from the literature represent institutional settings for children and adults with developmental disabilities in Staten Island, New York, and
Philadelphia, Pennsylvania; S. stercoralis suitability in Staten Island approached 0.5, at
49 0.476 and was less than 0.2 in Philadelphia. It is generally known that the risk of strongyloidiasis is greater for residents of institutional settings and our findings combined with the literature highlight that even in a moderately hospitable climate, where anthropogenic conditions permit, strongyloidiasis can thrive, meriting special care in those settings.90,151 Due to 10 occurrence points on the west coast, a heavy distribution in California is predicted, meriting further investigation to clarify whether or not autochthonous transmission is truly occurring in this region. While nine of the 10 California occurrence points represent human cases reported in non-foreign born residents, travel history was not obtained to rule out infection out-of-area. The tenth California occurrence point represents a soil or sludge sample reported in a 1976 study of the usage of wastewater sludge in agricultural soil enrichment.152
Limitations
In many cases, travel history for the individuals represented in the occurrence points could not be obtained or verified; that is, the specific locale where infection was acquired is unknown. Had we excluded occurrence points for which travel history was unavailable, the sample size would have been prohibitively small. Our exclusion criteria at least excluded the clearest cases of assumed travel history, i.e. veterans of overseas conflicts. Additionally, independent of where the infection was acquired, if climatic and sanitation factors are sufficiently suitable, the probability of an endemic transmission cycle in areas where the parasite is present is high. A second important limitation is the reliance on Census economic data, which often suffer from low response rates. In particular, some of the most vulnerable, lowest income PUMAs may contain households for which participation in Census surveys is known to be low, resulting in systematic undercounting for many communities.153 This
50 may mean that our multi-criteria analysis relying on poverty data may have missed some PUMAs that in reality would fall into our non-dominated alternatives set, representing high-risk areas.
PUBLIC HEALTH IMPLICATIONS
Given the resources required to conduct field investigations for infectious disease, the American research community and policymakers interested in characterizing the burden of strongyloidiasis will need to be strategic in choosing sites for active surveillance. This modeling study provides a method for identifying sites where active surveillance should be focused in the United States, enabling public health officials and policymakers to most efficiently direct limited resources to maximize prevalence estimates over our large national population. Beyond research, we recommend that disease reporting for strongyloidiasis be adopted in at least the states containing areas at high risk for parasite suitability: Arizona, Arkansas, California, Connecticut, Delaware, Kentucky, Louisiana, Maryland, New Jersey, North Carolina, Ohio, South Carolina, Tennessee, Texas, Virginia, and West Virginia. We also advocate heightened clinical suspicion and public awareness for this infection, through public health education programming and continuing medical education. Stricter solid organ transplant screening for both donors and recipients should be implemented in not just the aforementioned states, but in any case where either donor or recipient has ever traveled to any of these states. Again, this list is not exhaustive of the potential states where strongyloidiasis may be present. Given the gravity of hyperinfection and disseminated strongyloidiasis in the case of immunocompromised transplant recipients, it may be wise to implement universal screening of donors and
51 recipients; when adopted, this practice has been found to save lives, and its utility is not always dependent on known epidemiological risk factors.136,154
ACKNOWLEDGEMENTS
For discussions and sharing data, thanks are due to Peter J. Hotez, Curtis Croker, and Elizabeth Gray. The following institutions and collections were sources of S. stercoralis specimen data: Smithsonian, Natural History Museum London, Global Biodiversity Information Facility, and Integrated Digitized Biocollections. Thanks are due to all the researchers and curators who made these resources available.
52 Chapter 3: The Burden of Neglected Intestinal Parasitic Infections in the United States: a Systematic Review of Global Programs to Model Solutions for Prevalence Estimation and Disease Control
ABSTRACT The prevalence of soil-transmitted helminth and intestinal protozoan infections in the United States is largely unknown. Historical and current evidence suggests that southern and Appalachian communities are at risk where sanitation remains inadequate. The aim of this review is to assess the present need for reliable prevalence estimates for soil- transmitted helminths and intestinal protozoa in the United States and to suggest approaches to prevalence and burden estimation as well as disease control based on international successes. We prospectively registered a protocol in PROSPERO. We performed a systematic literature search in PUBMED and Web of Science. We included studies that describe or assess surveillance and control programs for these infections in human populations. We conducted an analysis of US intestinal parasitic infection reporting through a search of state health department websites. There is a critical gap in the literature on the burden that intestinal parasites present in the US. Mapping and mathematical modeling studies fill a gap where prevalence estimates are scarce. State and national disease reporting status in the US is incongruent with addressing historical and current prevalence estimates. Developing a strategy to estimate prevalence is a critical foundation for control and elimination. Estimates of soil-transmitted helminth prevalence in the US, particularly in the US south and Appalachia, should be updated using sensitive and consistent diagnostic technology. Surveillance for intestinal protozoa should be inclusive of all known pathogenic species including Entamoeba histolytica and should be expanded nationwide in an effort to update disease burden estimates. State- and national- level policymakers should revisit the reporting requirements for neglected intestinal parasitic infections.
INTRODUCTION
As discussed in the Introduction, historical and contemporary evidence suggests an uncharacterized burden of disease caused by neglected intestinal parasitic infections in the United States. Table 7 lists the most prevalent helminthic and protozoal organisms and the impact each infection can have on human hosts.
53 Table 7: Intestinal parasites and their effects on human host Organism and disease Health consequences Soil-transmitted helminths Ascaris lumbricoides Ascariasis GI: abdominal pain, nutritional deficiency, mechanical bowel obstruction (severe infection in children), obstruction of the bile or pancreatic duct due to aberrant parasite migration (rare), impaired child development;
Pulmonary: cough, chest pain, wheezing (Loeffler’s syndrome due to pulmonary migration of maturing parasite) Trichuris trichiura Trichuriasis GI: abdominal pain, bloody diarrhea (causing anemia), rectal prolapse (severe infection) Ancylostoma duodenale, Necator americanus Hookworm GI: abdominal pain, indigestion, nausea, vomiting, diarrhea, constipation, ascites due to protein deficiency (in severe cases);
Pulmonary: cough, chest pain, wheezing (Loeffler’s syndrome);
Cardiovascular: iron-deficiency anemia, cardiac failure due to severe anemia in heavy infection (rare) Strongyloides stercoralis Strongyloidiasis GI: diarrhea, chronic enteritis, bloating, tenderness, blood in stool, impaired child development, eosinophilia, disseminated disease and hyperinfection syndrome in immunocompromised hosts;
Pulmonary: cough, chest pain, wheezing (Loeffler’s syndrome);
Cutaneous: rash Intestinal protozoa Giardia lamblia Giardiasis Severe acute diarrhea, Chronic diarrhea, Nutritional disorders, Failure to thrive Entamoeba histolytica Amebiasis Amoebic dysentery, Disseminated disease Cryptosporidium parvum/hominis Cryptosporidiosis Prolonged diarrhea, life-threatening diarrhea in immunocompromised hosts
Chapter 1 characterizes the risk of intestinal parasites in a central Texas community, and chapter 2 estimates a wide spatial risk of strongyloidiasis across the US.
54 In light of this contemporary as well as the historical evidence of a substantial risk of infection with intestinal parasites in the US, the aim of this review is to develop a framework for the policy demands of quantifying and addressing soil-transmitted helminths and intestinal protozoa in the United States. To achieve this aim, we conducted a systematic review to identify successful international prevalence estimation strategies to inform US policy priorities in assessing the burden of STH and IP and their control in US communities.
METHODS
We developed this systematic review in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.155 We prospectively registered a protocol in PROSPERO (registration number PROSPERO: CRD42017068128) and performed a systematic literature search in PUBMED (1950- May 2017) and Web of Science (1900-May 2017) using a combination of disease and intervention terms. No language, publication year, or geographic restrictions were applied. The search was restricted to search terms found in title and/or abstract to ensure relevance when a search returned fifty or more results. During the three-month study time period, we monitored the US CDC Morbidity and Mortality Weekly Report (MMWR) weekly for any reports related to STH or IP. We included studies, reviews, and commentaries that describe or assess surveillance, mapping, monitoring, control or elimination programs for STH and/or IP in human populations. We included only articles published in peer-reviewed publications; status was determined using Ulrichsweb global serials directory. The sole exception to this criterion is the MMWR, which is not peer-reviewed, but provides timely updates on US disease surveillance. We initially selected studies based on their titles and abstracts, and then, if they appeared to satisfy inclusion criteria, we obtained full text. We hand-
55 searched reference lists of selected articles to identify other relevant sources that may have been missed in database searches. We excluded case reports or articles describing clinical outcomes, and those pertaining to non-infectious disease, or infectious disease other than STH and IP, as well as in-vitro or non-human subject research. We excluded non-US based cross-sectional prevalence surveys that do not also include details on surveillance and control strategies. Finally, because in many reporting countries STH and IP coincide with other NTDs, some articles report on STH and/or IP in addition to other diseases. When a study outcome is contingent on a control program for one of these other diseases, such as lymphatic filariasis or trachoma, we exclude the study because the effect on the relevant intestinal parasitic disease outcome cannot be disentangled from the effects of the other disease control program. The following data were extracted when applicable, based on article type: first author, publication year, title, journal peer-review status, study setting and geographic context, infections discussed, study population and participant demographics, details of the intervention and control conditions, study methodology including parasitological assessment, recruitment and attrition rates, outcomes and frequency of measurement, indicators of acceptability to users, suggested mechanisms of intervention action, main results, argument or position, and information for assessment of the risk of bias.
Bibliographic data of all search results were imported into a Zotero 4.0 database where each citation was coded based on inclusion and exclusion criteria. An additional descriptive analysis was undertaken for state-based neglected parasitic disease reporting. A search was made of fifty US state health department websites and that of the District of Columbia and New York City, as well as the Nationally Notifiable Infectious Diseases (NNDSS) reporting list from CDC.
56
RESULTS
Availability of data
Initial searches identified 584 articles; their titles and abstracts were reviewed for relevance, with exception of six articles for which no abstract or full text was available (six of seven total dead links). Hand searching of selected article references led to the inclusion of an additional 34 sources; only one study was found by monitoring MMWR.21 Articles were excluded for irrelevance (392), unavailable full text (5), not published in English for which no reliable translation could be obtained (5), not published in peer- reviewed publication (9), and dead link (7). Therefore, 167 articles identified through the initial search met inclusion criteria and were included in this review plus an additional 34 sources (Figure 4), for a total of 201 articles. Of these studies, 37 were reviews, 53 were epidemiological surveys or other types of observational studies, 25 were mapping or modeling studies, 27 were commentaries, 3 were systematic reviews and/or meta- analyses, 5 were experimental or interventional studies, 3 were study protocols, 2 were feasibility studies, 10 were qualitative studies, and 2 were evaluation studies. Upon request a full list of articles included in this review, but not cited, is available.
57
Figure 4: Flowchart demonstrating procedure for identifying relevant publications
1,042 articles identified 34 additional sources through initial search identified
6 dead links 618 articles after duplicates (458) without abstracts removed
385 records excluded on 612 abstracts initial screen: dead links (7), irrelevant (324), case screened studies (3), in-vitro or non- human (51)*
227 full-text articles 26 full-text articles assessed for eligibility excluded on full review: no mention of STH or IP, too broad, purely clinical (7); no reliable translation 201 studies included in available (5); no full qualitative synthesis text available (5); not peer-reviewed (9)
*Some articles excluded for more than one reason; only one reason is represented in breakdown.
We will first review the evidence for strategies to estimate prevalence of STH and IP, including identifying common risk factors and species-specific transmission dynamics through epidemiological, mapping and modeling studies. We will then review best practices for control of STH and IP, program monitoring and evaluation, surveillance, and technological innovations. We will then present an analysis of US state and federal intestinal parasite reporting policy.
58
I. ESTIMATING PREVALENCE
1. Epidemiology findings from around the world: risk factors & vulnerable populations
The following epidemiological highlights are from mostly observational studies that collectively reveal what is known about STH and IP risk factors worldwide. Often, the countries studied have used these data to design and inform control programs over time. The risk factors identified for intestinal parasites in other countries may help identify US populations at risk, although important differences exist between populations worldwide. In turn, the identification of vulnerable communities will be essential to inform a US strategy to control STH and IP.
Risk factors for intestinal parasitic infection
Observational studies aiming to estimate prevalence and identify risk factors for STH and IP indicate that the prevalence of hookworm infection in general is strongly correlated with adult age, low socioeconomic status (SES), and poor sanitation, while ascariasis is linked to younger age and limited access to water, sanitation, and hygiene (WASH). Likewise, observational studies show that giardiasis and amebiasis are associated with source of drinking water.
Oceania, South and Southeast Asia
Low socioeconomic status, male sex, and both pre-school and adult age were risk factors identified for hookworm infection in Timor-Leste, while older pre-school aged-
59 children (PSAC) and younger school-aged children (SAC) and adults lacking access to piped water were at elevated risk for ascariasis.156 Lack of sanitation was similarly associated with hookworm infection in villages of Solomon Islands, where the authors identified heterogeneity in health behaviors by village, leading them to recommend a community-tailored approach to STH elimination.157 Farming, adult age, having a pet cat, and poor hygiene were associated with hookworm in southern India, although there sex did not significantly increase risk.158 Lack of latrine usage emerged as a major risk factor for strongyloidiasis in rural Cambodia.13 Malaysian playgrounds were contaminated with helminth eggs and protozoan cysts from both human and stray animal sources, representing a potential source of infection to young children playing in them.159
Central Asia
Public tap water emerged as a protective factor against giardiasis for schoolchildren in Tajikistan, where protected spring water reduced the risk of amebiasis as well as infection with the tapeworm Hymenolepis nana, which was the most common helminth species detected in the study of 602 children.160
West Africa
Risk of hookworm was also tied to an agricultural setting in western Côte d’Ivoire, where urban farmers’ risk of hookworm also increased with unsafe water source and low SES and schoolchildren’s risk also increased with poverty.161,162 In southeast Côte d’Ivoire, a high prevalence of giardiasis was also positively associated with inadequate drinking water, while tap water was negatively associated with E. histolytica/E. dispar infection in schoolchildren.163 Among children in Burkina Faso, those living in households with freely roaming domestic animals, particularly dogs, showed higher odds of giardiasis.164
60
Vulnerable populations
Indigenous communities
Indigenous groups worldwide face health disparities, often including a higher prevalence of STH and IP.165,166 High rates of STH were detected in southern Belize especially in indigenous populations living in conditions of rural poverty and communities of Mayan and African descent.165 Recognizing and understanding the variation in epidemiology of these parasites among different indigenous groups, including sub-tribes with overlapping geographical range, is critical to customizing effective and sustainable control programming for each community.167 A survey of intestinal parasitism among the Suruí Indians in the Brazilian Amazon found a low overall prevalence of STH infections (36%), compared to what is often reported for other indigenous populations in the Brazilian Amazon. The authors argue that the low prevalence of STH among the Suruí is a result of MDA programs undertaken by the Indian Health Service. However, infections with IP were prevalent (70.7% with at least one protozoan species), suggesting that bottom-up rather than top- down intestinal parasite control programs should be implemented in indigenous communities, designed in collaboration with target populations, with an emphasis on improved housing, sanitation and water supply.168
Men who have sex with men and people living with HIV/AIDS
High rates of IP have been documented in men who have sex with men (MSM), with MSM being significantly more at risk for infection with IP and for polyparasitism when compared to a control group of non-MSM.169 HIV-positive MSM were more likely
61 to be infected with C. parvum than HIV-negative MSM.169 Diarrhea, low CD4+ counts, and lack of antiretroviral therapy (ART) were common factors among HIV-positive Congolese patients infected with C. parvum and C. hominis.170 The use of ART in the US has led to a 90% decrease in the incidence of cryptosporidiosis, which can be persistent in individuals with AIDS and diminished CD4+ counts.18
Pregnant women
The Uganda National NTD Control Programme found that community medicine distributors may be generally unaware of which medications are safe for pregnant and breastfeeding women, leading to this population of women being excluded from treatment programs, even in cases when their inclusion may be safe and beneficial.171 Giardiasis and ascariasis were among the most prevalent parasites detected in pregnant women in the Caribbean and were detected in all ten Caribbean countries included in the study.172
Refugees and migrants
Immigrants may be at increased risk for STH and IP due to the prevalence of these infections in their country of origin, exposure during migration or in refugee camps, or through conditions of resettlement. A high prevalence of these and other infectious diseases in the migrant population could lead to severe health problems if undetected and untreated, potentially representing a high cost to the health system in the country of resettlement, including possible transmission.173 In one study in northern Italy utilizing a case-control approach, immigration was associated with a higher risk of infection with S. stercoralis (though cases were still detected in native Italians) and overall, strongyloidiasis was nine times more frequent in individuals with eosinophilia than those within normal eosinophil range.174 A
62 retrospective review of infectious diseases in sub-Saharan African immigrants to Spain also found a significant association between eosinophilia and infection with STH; the authors recommend accurate screening and tailored protocols for infectious diseases in sub-Saharan immigrants.173 Notably, 66% of cases included in the review were asymptomatic; no association was found between having symptoms and the presence of imported infectious disease, suggesting that screening protocols should be performed regardless of clinical status.173 A lack of correlation between symptoms and detected STH and IP infections was also noted in a study of migrants in Germany, leading the authors to recommend a standardized routine screening program for all migrants.175
Military at-risk
In a study assessing intestinal protozoa infection in returning troops of the German Armed Forces, it was determined that risk was only increased for personnel deployed to areas where standard military food and drinking water hygiene precautions for field camps cannot be maintained; of the five deployment countries studied, only giardia infection in Sudan represented an increased risk.176
Low-income and preschool-aged children
Regular MDA campaigns typically target SAC preferentially over PSAC, and large areas are assumed to have heterogeneous prevalence. A study in two slum villages in Nairobi found that PSAC have similar prevalence of STH to SAC, suggesting that the younger children should also receive deworming.177 The study also demonstrated that prevalence rates might be dramatically heterogeneous on small geographic scales, leading to the suggestion that slums should be assessed individually in STH mapping, separately from their parent cities and in subsequent control program design.
63 High-risk patient populations/other vulnerable groups
We did not identify many studies in this review that assess elevated risk for intestinal parasites in specific patient populations, indicating that this is an area that merits more investigation. However, one study found that more cases of IP were detected in Saudi patients with chronic renal failure (CRF) and diarrhea in a study comparing cases of CRF against those of controls without CRF and with diarrhea, though parasites were common in all diarrheal feces in the study’s population.178 Globally, intestinal parasites are considered relegated to the developing world. The realization that NTDs and infections of poverty are not restricted to developing countries is shifting the health policy landscape. Hotez suggests that these infections are present, albeit hidden from neglect, in the poor among the wealthy G20 countries, and terms this blurring between health in developed and developing countries “blue marble health”. “Even very wealthy nations,” he writes, “such as the United States, have a hidden burden of NTDs, especially in the American south”, where it is the poor living among the wealthy who disproportionately suffer infections of poverty.179 In both developed and developing countries, prevalence estimates of STH and IP at community, regional, or national levels are scant or nonexistent. Mapping and modeling studies play a clear role in filling this gap.
2. Mapping of neglected intestinal parasitic infections
Increasingly, health policymakers rely on predictive risk mapping for both emerging and established diseases. Understanding the spatial distribution of STH and IP enables the planning, implementation, monitoring and evaluation of disease control programming, particularly MDA, surveillance, and elimination initiatives. Globally, STH are the most widespread NTDs, though until recently, broad geographical analyses were scarce.180 Karagiannis-Voules and colleagues predicted the spatial and temporal
64 distribution of hookworm, A. lumbricoides, and T. trichiura across sub-Saharan Africa, estimating the number of people infected and treatment needs.180 Chammartin and colleagues in South America and Lai and colleagues in China provide similar analyses.181–183 Detailed maps are typically generated for each disease-endemic area prior to implementation of MDA activities. Despite efforts to obtain updated, accurate data, depleted health systems infrastructures, remoteness, and conflict may present barriers to achieving the most up-to- date information.184 The limited sensitivity and specificity of diagnostic methods, as well as their lack of uniform use across studies also presents a challenge. Indeed, a new generation of rapid, point-of-care diagnostics will be the solid foundation for constructing reliable and up-to-date maps of the distribution of various NTDs.185 Common mapping technologies include geographical information systems (GIS) and remote sensing (RS). While GIS enables comparison between disease patterns and environmental data, RS uses high-resolution satellite data to estimate temperature, humidity, vegetation and other variables that contribute to more accurate mapping and prediction of disease patterns.185 GIS has been used in conjunction with environmental data, RS, and Bayesian geostatistical modeling to produce predictive risk maps of STH in Malaysia, Kenya and Brazil.183,186,187 Bayesian geostatistical modeling provides a robust method of measuring uncertainty in predicting at-risk populations, particularly for when prevalence data are scarce.185 Mapping can enable public health officials to prioritize control interventions and perform surveillance and response activities as efficiently as possible, informed by up-to-date and robust predictive data. Mapping of various diseases can be integrated on a national scale, either empirically or geostatistically.182,183,186–192 Because several of the STH and IP are known to infect other species, the integration of veterinary and human parasitological infection mapping and modeling is another area of focus. The “One Health” concept supports the merging of diagnosis and surveillance activities for neglected parasitic infections of both
65 veterinary and human importance; this area will especially benefit from innovative diagnostic and geospatial technologies.193
3. Modeling of neglected intestinal parasite transmission
Modeling studies of STH may be the most efficient approach to assessing impact of potential diagnostics at a population level.194 Mathematical models also play an important role in predictive infectious disease epidemiology and in helping to identify the variables that need to be measured to interpret an observed pattern, for example, the effect of MDA on STH parasite transmission dynamics.195,196 The time horizon afforded by empirical approaches, which rely on primary field data and are limited by time and resource constraints, is often limited to a few years, whereas modeling approaches can capture long-term intervention effects.197 Modeling studies have been used to characterize the spatial distribution and burden of STH and inform preventive chemotherapy strategies, in Bolivia and Brazil.190,191 Modeling studies demonstrate that each STH species has unique epidemiological characteristics, and can lead to distinct outcomes with any given MDA approach. Linking modeling studies with models of intervention cost-effectiveness can represent a powerful tool for informing policy.197
II. DISEASE CONTROL AND SURVEILLANCE
1. Mass drug administration
Regular deworming has been shown to enhance childhood growth and development, improve general nutritional status, improve cognitive, motor and language development in PSAC, and increase school attendance in SAC.198,199 WHO recommends
66 annual drug treatment of all school-aged children in areas where between 20% and 50% of people are infected, and twice a year if it is over 50% and targeted treatment of individuals in areas with prevalence under 20%.17 The majority of drugs used in MDA have exclusion criteria; for all of them pregnancy is a contraindication. Children under two years are excluded from treatment with albendazole. These gaps in treatment represent a potential untreated human reservoir for STH species.200 Additionally, the drugs typically used in MDA do not address the control of IP. There are concerns about potential resistance developing to both anthelmintics and antiprotozoals due to a limited arsenal and potential overuse.201–206 MDA using either donated mebendazole or albendazole has begun to reduce the global prevalence of ascariasis by approximately 20% over the last decade.207 Similar reductions in prevalence have not yet, however, occurred for trichuriasis or hookworm, for which drug efficacy is respectively low and variable.60, 66-67,76,82-83
School-based versus community-based treatment
In all but low-transmission settings, the expansion of MDA to PSAC and adults is warranted by empirical evidence as well as mathematical modeling studies demonstrating that younger children and adults also carry a significant burden of STH177,180,209 and that the exclusive treatment of SAC is unlikely to suppress transmission to a level sufficient for elimination.195,208,210–215 Combining school- and community-based treatment approaches would provide more comprehensive coverage by targeting children who do not attend school as well as adults, and addresses the fact that SAC are not always the primary output source for infective stages, especially where hookworm predominates.198,214,216–218 Sustainable control and elimination solutions for all STH require concomitant improvements in water quality, sanitation and hygiene; these
67 interventions can facilitate the capacity of MDA to interrupt transmission generally211 and are considered a requirement before elimination of STH can be considered a possibility.216
2. Control strategies
The implementation and sustainability of control interventions is both complex and variable between local contexts.2 The most effective control strategies take into account epidemiological, geographical, cultural, socio-economic, and political factors unique to countries and regions within countries.220 The three main methods of control are WASH, MDA, and a combination of the two; the different approaches to control have varying impacts on each STH species, and improvements in WASH are only effective when people use them properly.221 Program impact may vary substantially within a country or region, both geographically and by STH species. Large-scale epidemiological surveys with concomitant cartographic modeling using data derived from morbidity questionnaires are increasingly used to guide targeted, spatially explicit and cost-effective sanitation and mass or targeted drug administration.2 The intestinal protozoa are generally neglected in the preventive chemotherapy landscape; as Ferreira and colleagues note, we do not think “Giardia” when addressing parasite control. In many populations, infection with G. lamblia is as common as STH infections, but the protozoan is not considered for large-scale MDA intervention because of its short incubation period and frequent reinfections. Rather, its control is linked to improving WASH.199 Certainly, the availability and use of sanitation facilities and water treatment are associated with significantly lower odds of IP infections.222 However, high rates of post-treatment reinfection with STH species, particularly hookworm, is also
68 common,18 and STH control is perhaps equally linked to improvements in sanitation and the water supply.223 Many STH prevalence studies rely on the Kato-Katz method to identify helminth species in stool specimens, though this technique does not allow for the identification of IP, and therefore many studies do not report prevalence for these organisms. Studies that do employ techniques for the detection of IP point to the need to address and include IP in control interventions.199 Barriers to reaching some of the most at-risk and affected population groups present an obstacle to control interventions.200 Compliance, particularly when interventions must be repeated once or twice annually for an unknown period of time, is also an issue. As MDA does not address the socioeconomic, behavioral, and ecological root causes of transmission, reinfection occurs often and rapidly.224
Integrated programming
Integration involves creating linkages among existing programs with common elements with the aim of improving the efficiency and efficacy of delivery of health interventions in the context of existing commitments and resources.225 Embedding and integrating STH control programs within existing health systems can increase efficacy and reduce costs.226,227 Evidence for the success of multicomponent integration to control STHs in Seychelles demonstrates that integrating preventive chemotherapy and WASH not only reduces intensity and prevalence, but can also be effectively incorporated into the existing primary health care system.228 Notably, a US example of the success of integrated programming is the RSC, which combined MDA with latrines and health education and was credited with resultant economic development.229,230 In 2014, the
Tanzanian Ministry of Health and Social Welfare successfully coordinated the integration
69 of immunization and MDA programs, leveraging temporal and geographic congruencies and the strengths of compatible programs to reach 97% of targeted individuals with the measles and rubella vaccination campaign and 93% with the multiple NTD MDA campaign.231
3. Monitoring & evaluation
Monitoring and evaluation (M&E) is critical to ensure post-intervention surveillance. The disparate methods currently used to diagnose, measure, and report prevalence and infection intensity estimates precludes useful comparison and evaluation of programs. Given that the determination of prevalence and intensity of helminth infection is essential to all stages of the STH control framework, including mapping and M&E, quality assurance in helminth egg monitoring in fecal samples is strongly needed.232 Improved diagnostic and surveillance techniques are also required to maintain therapeutic efficacy against potential resistance as well as maintain program investor confidence.232 Evaluation of IP control also depends on accurate diagnostic technology because it is constrained by the need to distinguish between pathogenic and non-pathogenic species or strains. Morphologically similar and harmless commensal protozoans are ubiquitous and they are not the targets of control. Cost-effective IP control depends on the ability to isolate and target the pathogenic species and strains. MDA program administrators often use population surveys to validate coverage results as part of the monitoring of treatment coverage after MDA, a critical step in ensuring program success.233 Appropriate survey designs that can balance complexity and accuracy are needed as STH control programs expand and become integrated with other health systems components.
70 Biases in disease monitoring can arise when parts of the population are excluded from monitoring activities, for example, when there are movements of the host population for seasonal work.197 Mathematical modeling insights should inform the design of M&E programs. For example, follow-up monitoring after MDA is typically confined to the age groups that received treatment – most often school-aged children.234 While this approach can assess the direct impact of treatment, these data cannot describe the infection status of the entire community.197 Results from modeling studies have elucidated the species-specific age profiles and trends that must be considered in M&E activities. Additionally, because reinfection is very common, any outcomes assessed outside the worm-free window would detract from demonstrating the benefits of periodic MDA.198 One argument against community-wide MDA is that it leaves no reservoir of STH parasites unexposed to the drug, unlike school-based deworming, thereby posing a risk for the development of parasite resistance and its spread. To date, there is no evidence of STH resistance but the need remains for careful and increased monitoring of drug efficacy with expanding treatment coverage.197
4. Partnerships
Public-private partnerships (PPPs) are a logical and common formation for NTD control work, combining the resources of the private sector, including nonprofit NGOs and pharmaceutical companies, with the authority and access of governments. Indeed, global health partnerships rely heavily on collective action from both public and private sectors.235 Nongovernmental development organizations (NGDOs) have historically had a key role in these partnerships, and have been instrumental in the delivery of advocacy and programming to control and eliminate NTDs in developing countries.
71 The London Declaration in 2012 involved 22 partners, including WHO, World Bank, Bill & Melinda Gates Foundation and 13 major pharmaceutical companies all committed to expanding and sustaining NTD elimination programs for 11 NTDs by 2020, a goal that would satisfy the targets set out in the WHO road map.200,236 PPPs for the development of novel drugs and vaccines to combat NTDs have also emerged as a solution to the lack of financial incentive pharmaceutical companies face for any innovation to combat NTDs, which afflict the world’s poorest populations. In this type of collaborative partnership, public, private and philanthropic groups consider new drugs to be global public goods, with their multilateral collective action promoting an artificial market presenting fewer risks for innovators.235 Product development-public private partnerships (PDPs) lead the way for the development and production of a new generation of vaccines to combat NTDs, known as anti-poverty vaccines. The PDPs are non-profit organizations that partner with industry or adopt industry practices with the goal of developing, manufacturing, and clinically testing vaccines. Of the STH, a vaccine for hookworm has been in development since 2000. Vaccines for the IP G. lamblia, E. histolytica, and Cryptosporidium parvum are in development but progress has been slow owing to numerous technical challenges.18 Partnerships are complex and presented with many challenges, not limited to the coordination of drug application procedures, complying with regulatory responsibilities and import taxes and administrative feats to deliver drugs where they are needed.200 Examples of success in country-level STH control emphasize the importance of strong national government leadership and partnership with international stakeholders and communities alike.237,238
5. Research & development
Funding for NTD research and development has been highly concentrated, favoring product development for HIV/AIDS, malaria and TB (“the big three”) with few
72 end products for other diseases, and has little correlation with burden of disease, as measured by DALYs.239–241 Infusing more money into the R&D stream is itself not sufficient to address the uneven progress in neglected disease product development, rather better targeting of funds is warranted, as well as attention to access through public health infrastructure and capacity-building.240,241 Beyond the fact that little R&D overall is dedicated to products that benefit the poor, lack of access to new and existing drugs and technologies to combat NTDs is a primary reason why the world’s poor suffer and become trapped in the cycle of poverty and disease.242 Specific R&D investment data became available with the Gates Foundation commissioning of the Global Funding of Innovation for Neglected Diseases project (G- FINDER), a survey to provide consistent, comparable, comprehensive data on neglected disease R&D.239 In addition to the observation that funding has been highly concentrated, the first report also observed that efforts to support new NTD products are not evenly distributed between organizations and countries; several major OECD governments are absent from the top 10, top 20, or even top 50 funders of NTD R&D. The trend that HIV/AIDS, TB and malaria collectively received the vast majority of global NTD R&D funding has persisted through the most recent, 2016 G-FINDER report.243 The same can be said for the highly concentrated nature of NTD R&D funding: in 2015, nearly half of all PDPs received more than half of their funding from the Gates
Foundation and researchers and developers generally continue to rely on a small number of large funders, particularly the US Government and NIH and the Gates Foundation.240
III. US STATE AND FEDERAL REPORTING AND SURVEILLANCE OF INTESTINAL PARASITES
Surveillance activities and reporting mandates vary substantially across US states, leaving gaps in the national surveillance network. US infectious disease surveillance is
73 generally passive rather than active, meaning that state health authorities rely on hospitals and providers to detect and report potential risks and do not actively screen for or require surveillance information.241,242 The current status of mandated reporting for STH and IP in the United States is shown in Table 8. Strongyloidiasis is not nationally notifiable and in no US states is it a reportable infection. As with other non-nationally notifiable diseases, this means that there exists no federal level ongoing surveillance collecting reports of strongyloidiasis from states and territories. Ascariasis, trichuriasis, and hookworm are reportable only in the state of Texas, as of 2015. When an infection or disease is reportable, it is mandatory that cases be reported to state and territorial jurisdictions when identified by a health provider, hospital, or laboratory. Each state has its own laws and regulations defining what diseases are reportable and how quickly they must be reported. Giardiasis is the most common parasite detected in stool of US individuals, being present in about 4% of stool specimens submitted to clinical laboratories when the ordering clinician requests ova and parasite (O&P) testing18 and is the most common cause of diarrhea in returning travelers.49 Giardia is nationally notifiable and reported in 43 states as well as the District of Columbia (DC) and New York City (NYC) (Table 8). Most states include "any other unusual condition" or "potential for outbreak" or "emerging infectious disease" as a catchall for any unlisted disease or condition that could present within the state. However, one of the functions of mandating reporting of a specific disease is to heighten awareness at clinics and laboratories, increasing the likelihood that cases will be suspected and in turn detected.
74 Table 8: Reporting status of intestinal parasites in the United States Infection States reporting Nationally notifiable Soil-transmitted helminths Ascariasis TX No Trichuriasis TX No Hookworm TX No Strongyloidiasis None No Intestinal protozoa Giardiasis 43 states, DC and NYC Yes Amebiasis 16 states, NYC No Cryptosporidiosis All states, DC and NYC Yes Cyclosporiasis 45 states, DC and NYC Yes Isosporiasis MD No DC= District of Columbia. NYC= New York City. Last updated May 2020.
DISCUSSION
US policy priorities
Policy recommendations to address neglected intestinal parasitic infections in the United States begin with more precisely and accurately defining the problem. To estimate parasite distributions in low-income regions of the US, investigators can employ mapping and modeling techniques, such as those used in chapter 2 of this thesis, followed by epidemiological surveys and active surveillance to obtain prevalence estimates of STH and IP burden. Mandated state, and recommended national reporting of these infections can facilitate this task. Reliable population-based estimates and disease burden data for STH and IP is a prerequisite for their control and elimination. Once affected populations are identified, mass or targeted treatments should be appropriately carried out, with careful monitoring and evaluation of intervention impact and ongoing, intensive surveillance if elimination is to be achieved. The sustainable control of STH and IP will require investments in environmental sanitation, piped clean water, and housing improvements in some of the poorest endemic areas.
75 Access to safe water and sanitation is a basic human right, explicitly recognized by the United Nations General Assembly in 201038 and should be the cornerstone of addressing intestinal parasitic infections especially in a capable and resource-rich nation such as the US. Yet, in America’s most vulnerable communities, both urban and rural, these basic needs remain unmet.3,244,245 STH and IP infection is linked to low socioeconomic status globally, and the same is likely to apply in the US. Although at-risk Americans may have knowledge about disease transmission, they may still be economically and structurally hindered from avoiding it.246 The prioritization by US policymakers and public health experts of STH and IP control is simultaneously a cost-effective way to lift Americans out of poverty and in line with American values of equity and equality.1 While generally conceived to apply in the context of developing countries, the WHO’s recognition that neglected disease control represents a fundamental human right can and should also be applied to the US and developed nations that demonstrate blue marble health.176 In 2011 Representative Henry Johnson of Georgia re-introduced the bipartisan H.R. 528 Neglected Infections of Impoverished Americans Act of 2011 for consideration in the 112th US Congress after the bill passed the House of Representatives in 2010 but stalled in the Senate. The bill would require the Secretary of Health and Human Services to report to Congress “on the epidemiology of, impact of, and appropriate funding required to address neglected diseases of poverty, including neglected parasitic diseases such as… the soil-transmitted helminths….” It would require the report to include information necessary to formulate future health policy to “(1) accurately evaluate the current state of knowledge concerning such diseases and define gaps in such knowledge, and (2) address the threat of such diseases”.247 The bill was referred to the Committee on Energy and Commerce and in the latest action was placed on the Union Calendar in 2011.
The Congressional Budget Office estimated the cost of H.R. 528 implementation to be less than $500,000; enacting the bill would not affect direct spending or revenues and
76 H.R. 528 contains no intergovernmental or private-sector mandates and would impose no costs on state, local, or tribal governments.248
State and federal reporting and surveillance of intestinal parasites
State and jurisdiction reporting of nationally notifiable infections to the CDC is voluntary. The trend of decreasing jurisdictions opting to report giardiasis cases could negatively impact the ability to interpret national surveillance data; determining the barriers to and facilitators of case reporting should be prioritized.19 Only the state of Texas mandates reporting of ascariasis, trichuriasis and hookworm, and zero states mandate reporting of strongyloidiasis (Table 8). States should conduct surveillance and mandate reporting for the conditions which have already been documented or for which evidence suggests could be present or emerge in their state – for the STH, this includes states in the southern US and Appalachia for which historical precedent exists for endemic transmission. While US reporting for intestinal protozoan infections is more common than it is for STH, important gaps remain. Amebiasis, for example, is not nationally notifiable and is reportable in only 22 states (and only infection of the central nervous system is reportable in three of those states), DC and NYC, yet this infection is the second most common cause of diarrhea in returning travelers243 and it is also a Category B biodefense agent. E. histolytica possesses several unfortunate properties that could be exploited for misuse in an act of bioterror or war, including a low infectious dose of less than 10 cysts and resistance to chlorination.18 Giardiasis and cryptosporidiosis, on the other hand, are nationally notifiable. These diseases are acquired the same way as amebiasis but due to insufficient data it is not known how the burden of amebiasis compares to the other intestinal protozoa. The standard criterion for listing a disease as notifiable is whether timely information about
77 individual cases of the disease is considered necessary for its prevention and control. In the case of intestinal protozoa with similar routes of infection and course of disease, it is unclear why the public health response for one food or waterborne parasite would not be the same as for another. The discrepancy appears to come down to epidemiological disparities alone: giardiasis and cryptosporidiosis are known to cause outbreaks in Americans of all social and economic classes, whereas amebiasis is thought to be most prevalent in low-income Americans along the US-Mexico border. We argue that there is a characteristic pattern to the notifiable infectious diseases list; that, despite clinical and transmission similarities with notifiable diseases (and the potentially worse status for some indicators/higher disease burdens for certain STH and IP), one striking difference is that infections of poverty are absent, and these diseases disproportionately affect a variety of vulnerable populations. Attention should be paid to the known risk factors associated with each infection and carefully identified at-risk communities should be actively screened for the infections. Active surveillance, while costly, is required to obtain accurate prevalence estimates. Many of the same risk factors identified worldwide are present in poor communities throughout the United States. Raw sewage contamination has been documented in Lowndes County, Alabama,245 where a recent study documents the presence of S. stercoralis, hookworm, and E. histolytica.14 As reported in Chapter 1, a central Texas community is at unusually (for the US) high risk for strongyloidiasis and Blastocystis, owing to widespread septic failure. As was reported in Malaysian playgrounds, helminth egg contamination has also been documented in the American northeast, with distinctly higher degrees of contamination in poorer neighborhoods.249 The US is also home to many of the same populations vulnerable to STH and IP infection characterized globally. Pregnant women and children living in poverty, especially refugees and immigrants are at increased risk, although poverty and not immigration status is believed to be the single most important determinant of STH in the
78 US.1 The nature, context, and consequences of poverty in the US also differ significantly from that of the countries studied in the literature. Indigenous people in the US, particularly those living on reservations where homes lack indoor plumbing, are at heightened risk. American MSM, immunocompromised people, and deployed military personnel all share the risks identified elsewhere. Presumably due to the lack of surveillance to justify a public health response, the US has not conducted any program of STH control for decades. Post-treatment parasite infection levels are known to bounce back to their pre-treatment equilibrium in a predictable manner absent other changes to the environment.250 Thus, reinfection is a given.251,252 In the most destitute, disadvantaged and neglected pockets of America, there have not been substantial changes to the environment to unequivocally consider that the effects of any prior deworming initiatives would persist today.3,244,245 While sophisticated modeling studies can suggest burden and distribution of STH and IP and predict treatment needs and costs to control and eliminate parasitic intestinal infections, the need for a national survey for accurate and updated mapping cannot be circumvented where data are scarce, as was the conclusion for Chammartin and colleagues when they provided the same estimates for Bolivia.187 The recent report by Hlavsa et al. highlights the use of CryptoNet, the first US molecularly-based surveillance system for a parasitic disease. CryptoNet data can further elucidate cryptosporidiosis epidemiology and can be used to inform and optimize prevention strategies.21 Similar systems can be developed for the more neglected parasitic infections endemic to the US.
US health system awareness and capacity building
Clinical preparedness and capacity amongst US medical professionals to address
STH, IP and other infections of poverty remains to be explored systematically, but is
79 assumed to be insufficient. General practitioners should be familiar with the diagnosis, clinical management, treatment and control of these infections, not only in the case of migrants and returning travelers but also in the case of people without a travel history. Particular clinical attention is required in the case of strongyloidiasis, the STH that is capable of autoinfection and the diagnosis for which is especially challenging.253 The migration of S. stercoralis worms to any organ carries the risk of septicemia, with a high fatality rate. Dissemination may occur even decades after initial infection, so that absence of recent travel to known endemic areas is never sufficient to rule it out,221,254 and, given its historical endemicity in the US, strongyloidiasis may occur in cases with no travel history at all (as we see in Chapters 1 and 2).
Limitations
The premise of this study is to use evidence from other countries to inform development of a policy agenda to address neglected parasitic infections in the United States. This review is intended to be a first step in US policy formulation towards that aim. Studies of surveillance for infectious disease in the US were considered as a part of this review to demonstrate existing practices that could be built upon. A vast body of international evidence exists for best practices, innovative strategies, and case studies of how to address intestinal parasitic infections. However, even considering this evidence, an unavoidable limitation of this study is that there are questions of transferability of policies and practices from a given country to the US, given the potential vast differences in context. The reader may have understandable concerns or objections to the problem of external validity or generalizability from a given developing country context to the US. Certain examples drawn from the international literature may or may not apply in particular American localities, states, and territories.
As demonstrated in this review, reporting requirements for parasitic infections vary
80 widely across states, as do environments, populations, risk factors, and resources. However, the US is in a nascent stage in addressing the threat of these diseases and has not yet determined the extent of the problem. As with any literature review that relies solely on published literature, this study is susceptible to publication bias. Studies with minimal or negative results may not have been included. Many studies only reported a point estimate of prevalence; it was therefore not possible to ascertain the certainty around these estimates. Prevalence estimates are only as good as the diagnostic methods and survey/sampling strategies used to obtain them. Likewise, some studies compare their updated prevalence estimates to those obtained from historical surveys, which may or may not have used similar methods, limiting comparability and determination of program success due to uncertain baseline estimates. Bias is introduced whenever studies attempt to assess success based on prior prevalence estimates that used different or unknown methods, whether for diagnostic approaches or sampling strategies. Many studies relied on a single stool screening exam and utilized a suboptimal diagnostic approach that likely lead to systematic underreporting of distribution and prevalence of STH and IP. As for bias within the review, every attempt was made to offer transparency about the search and the process. The full protocol was pre-registered and can be publicly accessed on PROSPERO.
Lastly, this study is not able to assess empirically the capacities for carrying out suggested policies and practices for neglected disease control at the local, state, or federal levels. The conversation around intestinal parasitic infections in the US has only begun.
81 Conclusions and future work
This review has described a neglected public health concern in the United States and appraised examples of successful STH and IP surveillance and control globally to suggest an appropriate policy framework for the US. As a resource-rich country, the US is uniquely positioned to adopt and integrate intestinal parasite control and elimination strategies through strengthening existing public health systems. While STH are not viewed as candidates for elimination in resource-poor settings due to economic and epidemiological constraints, including high prevalence and ability to survive in soil and animal hosts,255 the opportunity to eliminate STH in the US is more viable. Advocacy and political will are required for sustainable and equitable control of these debilitating diseases that are rooted in and propel poverty. Active surveillance, case finding, and parasitological surveys are needed to characterize the problem of STH and IP in the US. Future work should also investigate why the promising Neglected Infections of Impoverished Americans Act of 2011 failed and empirically assess state capacity and political willpower to protect all and especially the most vulnerable Americans from intestinal parasitic infections. The extent of knowledge and capacity of US clinicians and laboratory professionals to detect and diagnose STH and IP should be evaluated. The utility and feasibility of mandating reporting of these infections should be studied through interviews with state health officials and The Council of State and Territorial Epidemiologists, who review and modify the list of nationally notifiable diseases with the CDC annually. In raising these issues, we must consider the social and political implications, as well as the potential ramifications, of public interventions. These concerns are especially relevant in the current climate of xenophobia and intolerance. Surveillance may reveal that certain communities are disproportionately affected. The civil rights of these vulnerable communities and their human rights to privacy, health, sanitation, and safety must be protected.
82
Conclusions
THEORETICAL AND EPIDEMIOLOGICAL CONTRIBUTIONS
Conversations about health disparities in the United States most often focus on chronic disease. The notion that disparities in infectious disease, especially those labeled tropical disease, are prevalent domestically is scarce in academic, clinical, and policy domains. Yet neglected infections of poverty are culpable in disease-poverty traps nationwide, with socioeconomic sequelae potentially rippling through generations. The research presented in this dissertation adds to the increasing weight of evidence of the prevalence, scope, and burden of neglected intestinal parasitic infections in the US, and offers a framework for their surveillance and control. Chapter 1 documents the prevalence of intestinal parasites in a central Texas community suffering from sanitation failure, finding that the helminth Strongyloides stercoralis and the heterokont Blastocystis spp. are present to an unprecedented and alarming degree for autochthonous transmission in the US. Chapter 2 explores the predicted ecological range for S. stercoralis nationally, extending current knowledge about the extent of epidemiological risk to ten states beyond the southeast. To our knowledge, no prior study has utilized reported cases and records of the parasite to predict a risk map in the US, where strongyloidiasis epidemiology is poorly characterized but from which a majority of states report deaths. Chapter 3 demonstrates the value in zooming outward and taking advantage of the decades of experience cultivated by low- and middle-income countries in the surveillance and control of intestinal parasitic infections. Lessons learned include heeding special attention to vulnerable populations, building basic epidemiological profiles of particular
83 helminth and protozoal species, and developing strategies for integrated programming and health systems strengthening. The assessment of current intestinal parasitic disease reporting in the US should provide called-for introspection about a critical gap in our state and national surveillance capacity and associated repercussions for the epidemiology of these infections, especially for the soil-transmitted helminths. Beyond the more pragmatic epidemiological and policy pieces this research offers, there is hopefully a salient substantive political value to this work, highlighting the lens of collaborative science for social, racial, economic, and environmental justice at a time when such a lens is acutely morally justified, though justified and necessary it has always been.
IMPLICATIONS FOR POLICY
The epidemiological insights we have gained about intestinal parasitic infections in the US suggest several public health, clinical, and policy strategies that may help to address the burden of disease: (1) Augmentation of reporting requirements at both state and national levels; (2) Accurate and targeted prevalence estimation; (3) Increased clinical suspicion and amelioration of systemic barriers to accessing care; (4) Investment in NTD R&D; (5) Equitable provision of and access to effective sanitation infrastructure;
(6) Cohesion and universality of solid organ transplant donor/recipient screening for strongyloidiasis; and, (7) Adoption and integration of intestinal parasite control and elimination strategies through strengthening existing public health systems. It is possible that this confluence of empirical epidemiological data (the problem), the aforementioned public health, clinical, and environmental proposals (possible solutions to the problems), and current global protests for racial justice in the United States in the wake of Breonna Taylor’s and George Floyd’s murders by police, combined with awareness that the novel coronavirus pandemic represents a deadly health disparity
84 for people of color259–262 (political circumstances) will create a policy window that moves a neglected disease-focused agenda forward in the policymaking process.263 Present political circumstances, however, may also be viewed as competitors for policy attention, especially in light of the urgency of sustained protests and the Covid-19 death toll. With the immediacy of current events, longstanding neglected health issues like the infections of poverty may seem orthogonal, but the ties to fractured, inequitable, and systematically racist health systems and disparities in chronic and infectious disease are inextricable. In the same way that Black, Latinx, and Indigenous people in the US are at much higher risk for severe disease and death from Covid-19 due to underlying health disparities rooted in structural racism in the health care system and the environment, Black, Latinx, and Indigenous people in the US suffer disproportionate rates of infections of poverty stemming from the same aspects of structural racism, particularly lack of access to safe sanitation.69,145 Even though the evidence –– historic and contemporary –– merits a shift in the way we think and act about health equity in the US, a pragmatic perspective requires that we consider the serious barriers to policy change that would address neglected infections of poverty. As Longest points out, the existence of systemic health problems alone is not sufficient to spur the policies intended to address them; beyond existent solution proposals, sufficient political will is required to enact legislation specific to implementing those solutions (Chapter 5, p136).264 Baker et al. argue that evidence gathering and calls for action often do not suffice to systematically attenuate health inequities via actionable response to social determinants of health. In exploring substantial political and policy challenges in the way of including the social determinants of health inequities in policy agendas, the following constraints were identified: institutional norms and path dependency; limited evidence for interventional alternatives and their misalignment with existing policy and institutional arrangements; a biomedical paradigm featuring the medicalization of health; pervasive racism; obstructive power of interest groups; and a
85 neoliberal ideology emphasizing individualism over equity, which is highly antithetical to an agenda inclusive of social determinants of health.265 First, it will be useful to question why neglected diseases are so –– to examine the root of the neglect. In some cases at both federal and state levels, policies aimed at neglected diseases have appeared to make it onto the policy agenda, but often not in the tangible sense that Kingdon defined a governmental agenda –– issues to which government officials and people associated with them are paying serious attention and which are the focus of attention.266 Second, it will be productive to explore the reasons for past policy failures at times when these diseases are pulled out of the shadow of neglect, when particular legislators explicitly attempt to highlight them. In the absence of a more complete understanding of these sociopolitical underpinnings, it would seem unlikely for any of the above policy proposals to succeed. So how do neglected infections really make it onto the policy agenda? The types of problems that ultimately lead to policy development tend to be those that policymakers identify as important and urgent; those that do not meet these criteria wither at the bottom of a long list and may never make it on the agenda (Chapter 5, p138).264 In addition to their established morbidity, which in and of itself should attract policy attention equal to that held by non-neglected intestinal diseases (e.g., causative agents of foodborne illness routinely targeted by local health departments), the neglected intestinal parasitic infections are key players in insidious cycles of poverty and disease, as previously described. The health consequences and economic sequelae of this group of infections would seem to satisfy the importance criterion. Whether or not these ancient diseases267,268 are viewed as an urgent problem perhaps depends on how much the policymakers value the health and economic well being of those afflicted; it may also depend on the degree to which their constituents are aware of the problem and how mobilized, organized, and empowered they become in response.
86 According to the analysis by Baker et al., factors that increase the probability of health equity reaching a policy agenda include the mobilization of civil society and interest groups, particularly when it involves a combination of participation by affected groups and a grassroots base of support among the general public, interest groups, and opinion leaders, as well as tactical flexibility and opportunism for influencing government. Other enabling factors include leadership and influential policy entrepreneurs and health equity champions that function as liaison between advocacy, research and policy; and, in some cases, bureaucratic institutions that play an important role in sustaining issues on the policy agenda and make policy alternatives appear more feasible to policymakers, (e.g., a new public health unit within an existing department).265 One way for some problems to secure a place on the agenda is for them to be tied to other issues that already occupy a fixed spot (Chapter 5, p139).264 In the case of Community A (chapter 1), a proposed new development bordering on the community caught the attention of the local government as an opportunity for substantial economic development. Results were shared with members of Community A at the conclusion of the study and prior to community notification of the proposed development. Community leaders, feeling threatened by the impending development and anxious to protect their families and neighbors from strongyloidiasis and other intestinal parasitic infections, saw an opportunity to use the epidemiological evidence from the study as an integral part of a political and legal strategy to improve conditions in their community. Residents successfully organized, formed a non-profit community organization, and earned the service of a regional legal aid organization to defend Community A in a zoning case to protect residents from negative consequences of the development and to argue for improved services access. At the time of this writing, the legal case is pending and details are confidential.
Since the new development will require wastewater infrastructure, and both the development and Community A are within the nearest municipality’s extraterritorial
87 jurisdiction, one objective is for the municipality to extend sewer lines and services to Community A at the time of provision of the same services to the proposed adjacent development. Multiple stakeholders, including the city, the county, the developer, the community, and possibly state and/or federal agencies will have to engage together to work out a manner in which the new service provision will be affordable to low-income residents. While the coordination of various jurisdictions and departments is critical to services extension, their competing roles and priorities will likely present challenges, as has been noted in the process to secure services for other communities.269 In initial public hearings on the proposed development, community members successfully voiced their concerns about the sanitation failure and associated disease documented throughout their community –– planning and zoning officials spent the remainder of the meeting discussing the issue and in the end included conditions supportive of facilitating access to city wastewater services in their official recommendation to city council. This response is consistent with that prompted by unincorporated communities in North Carolina who reported to city officials the extent of their septic system failure.269 As a researcher-activist, I seek to engage with the study population in this way to help them use their data to drive positive change. I view the researcher’s role in health disparities work to extend beyond academic outcomes, and towards fostering community- driven policy change. Rather than disengaging with the community upon conclusion of the study, results and implications were shared with residents; ultimately, residents were mobilized to cultivate an empowered, data-driven response to the story their data tell: one of an inequitable and unhealthy built environment that contains the threat of a potentially deadly parasite, for which their more affluent neighbors and other area taxpayers needn’t be concerned. The case of Community A poses a compelling policy problem: how do you provide safe water and sanitation for an informal, unincorporated settlement when the onus for service provision is on neither the county nor city and where is no Municipal
88 Utility District in place? Solutions to this type of problem require collaboration across multiple disciplines. In addition to community leaders and tropical medicine experts at the National School of Tropical Medicine, this project has led to partnerships with colleagues at University of Texas Schools of Law and Engineering. A similar initiative was carried out in a historically Black unincorporated community, Rogers-Eubanks, in Orange County, North Carolina, where concerned community members organized a community-driven research partnership with university scientists and local organizations, and similarly detected high rates of septic system failure, providing evidence of their need for improved sanitation services, among several other needs for improvement.270 As in Community A, the community-driven research approach in Rogers-Eubanks empowered residents there to establish a non-profit community-based organization, which enabled them to further their agenda for community improvement. The results of these and other studies suggest the persistence of racial and socioeconomic disparities in the geographic distribution of regulated water and wastewater services, and underscore the challenges of identifying accountability for services provision and facilitating access.14,134,145,270 In communities like Community A, Rogers-Eubanks, and rural Lowndes County, Alabama, many households cannot afford construction costs to tap into municipal water and wastewater lines if they become available. More fundamental institutional barriers to extending adequate services to low- income communities of color predate the present-day affordability issue, and persist at the local level in communities nationwide –– these barriers have been characterized as environmental racism tied to systematic inequities in local planning and zoning practices.130,270–276 The important differences and similarities between communities underscore the need to adapt solutions to the local setting rather than force a one-size-fits-all approach.129 For example, while both rural Lowndes County, Alabama residents and Community A residents in central Texas experience widespread sanitation failure and a
89 concomitant burden of intestinal parasites, the communities live in different climates with different geological characteristics and have different demographics and built environments –– Lowndes County residents are predominantly Black and have straight pipes and cesspools for on-site sewage disposal14 whereas Community A residents are predominantly Latinx and have septic systems –– which will need to be explicitly accounted for in any solution. The model from chapter 2 predicts that ecological risk for strongyloidiasis is present in various Texas locales and many others throughout the US, and epidemiological models tell us that infection with STH, IP, and the heterokont Blastocystis will be most prevalent where humans live with sanitation failure. Further, sociological and spatial models tell us that sanitation failure is most prevalent where humans live in poverty, which correlates strongly with Indigenous, Black, and Latinx racial and ethnic groups.145 New policy proposals to prohibit development of communities without provision of adequate basic services do not rectify past abuses with enduring present-day impacts. Instead, the strategy of in-place upgrading, which has been the primary policy approach in Texas, relies on local participation and community inclusion, and is most effective when participatory versus top-down approaches are practiced.129,270,274,277 Often, though, services do not improve until the communities become annexed by nearby municipalities.129,130
Annexation and services provision come with significant costs to residents. Indeed, financing water and wastewater systems emerged as the primary factor that influenced local decisions to extend services to three unincorporated communities in North Carolina; the health consequences of sanitation failures were a minor factor for city officials in deciding whether to extend services.269 However, in one county, data pertinent to health risks of septic failure was collected and allowed health officials to present a strong, ultimately persuasive argument to approve service extension to an unincorporated community in their jurisdiction. Importantly, this county effectively handled the common
90 challenge to local oversight of sewage disposal –– that homeowners fear the consequences of septic system failure, including high repair costs or possibly condemnation of their homes –– by anonymous surveying and environmental quality monitoring.269 When a positive right such as the rights to health and sanitation is created and recognized, who can and should pay for the implementation of that right, particularly in the context of a low-income unincorporated community? In the case of Community A, the power to provide the right to sanitation lies with the city and developer. It’s possible to draw a parallel between the problem of financing R&D innovation for NTDs therapeutics, diagnostics, and vaccines (chapter 3), which lack a financial incentive due to a low-income target population, and the problem of funding municipal wastewater services to Community A (and unincorporated communities nationwide). One successful approach in the NTD R&D arena has been the establishment of public-private partnerships.235,236,240,241 The corresponding partnership in services provision for Community A would be between the local government and the developer. Although, unlike R&D for NTDs, wastewater services provision to unincorporated communities is not without financial incentive to local government or the developer. If services are provided through annexation, the city will gain taxes. Regardless of the jurisdictional requirements or arrangement for service provision, both the local government and the developer would benefit by mitigating public health risks to nearby communities, including the new development itself, which may have a difficult time selling homes to buyers aware of the local threat of strongyloidiasis. Acknowledging that framing health disparities as rights violations invokes governmental neglect, tying government inaction to shame and blame, Yamin argues that international law offers standards for evaluating the US government’s conduct as well as mechanisms to assess accountability.38 Indeed, an array of international treaties consider the right to health extending far beyond a right to health care (which tends to dominate
91 the discourse in the US), and to include basic preconditions for health, including adequate sanitation.38 Under international law, the ultimate accountability for state and local policy resides with the federal government, and so when state or local governments fail to meet a standard (such as eliminating health disparities or racial discrimination), the federal government is not absolved of ultimate responsibility.278 The US is party to the International Convention on the Elimination of all Forms of Racial Discrimination (Race Convention), which legally obligates the US to assume measures to eliminate racial disparities in public health.36 Yet, of all industrialized countries, the US is alone in lacking a plan for universal health care coverage and in legally recognizing a right to care or even accepting international human rights standards.38,279,280 Given the entrenched racial disparities in access to functioning sanitation and related infectious disease, it seems clear that the US has long been in violation of the Race Convention. Indeed, this violation was noted in the UN committee’s report on US compliance in 2001.281 As social determinants of health, civil rights must be enforced to eliminate disparities in health and housing; the failure to enforce civil rights to housing has resulted in persistent discrimination, with enduring impacts on health.282 Once a country has legally recognized the right, what matters most is the way a nation implements and enforces the right to health; because this is dependent on legislative and judicial action at the federal level,38 the success of congressional bills to address neglected diseases in the US such as the one most recently sponsored by Senator Cory Booker,59 would be critically important. However, in the absence of accepting international human rights standards, the US does not conform its laws to satisfy those standards. Perhaps this aversion to adopting international human rights norms is the core of why past proposals to codify laws aimed specifically at addressing neglected diseases in America have repeatedly failed.
At this unique junction in American history, the US may be facing an opportunity to realign the debate about people’s health in this country towards one explicitly focused
92 on the bottom line: until the US government accepts international human rights standards for itself, the rights to health and healthy environments will perpetually be afforded strictly along socioeconomic and racial divides. The policy window created by this fundamental reframing, in the context of one of the top wealthiest countries in the world, has the potential to stimulate innovative solutions responsive to entrenched inequities, both shared and unique, among vulnerable communities nationwide. With the reframing of health as a right, debates about government and market roles and accountability shift; the government’s obligations surrounding that right become solidified in both society and law.38,279,280 The legal scholar Cass Sunstein insists that these basic rights belong within US constitutional commitments (p108), and suggests that public consciousness –– at a heightened state in the throes of today’s dual crises –– can promote legal recognition of economic and social rights.283 Pointing out that the constitutional recognition of the right to basic education is only several decades old, Yamin suggests that American awareness of health as a right may be susceptible to a similarly pronounced shift.38 Despite important differences between communities that must be considered in local decisionmaking, these communities suffer from the same root societal causes, inequities stemming from pathologies of power at play in US federal, state, and local settings, which converge on the disease poverty trap for the most vulnerable populations. In this view, a common solution towards addressing and rectifying racial and economic disparities would need to arise at the national level. In the current political climate, this widespread reckoning towards equality is what the people are demanding.
FUTURE RESEARCH DIRECTIONS
A research area centered on neglected diseases is rife with questions to address, both scientific and sociopolitical. I will actively pursue the following questions as part of
93 my postdoctoral and professional research agenda. Questions stemming from Chapter 1 include: (1) Does the prevalence of intestinal parasites in the environment spatially correlate with that of infected hosts in Community A? An analysis of soil samples, as well as serological study of the cat and dog roundworms, Toxocara cati and Toxocara cani, will help address this question. (2) What barriers to accessing treatment for strongyloidiasis do people face and how can they be mitigated? Unfortunately, albeit not surprisingly, residents who tested seroreactive to S. stercoralis generally had difficulty obtaining treatment from their local providers, who were apparently unaware of the existence of this infection and the potentially fatal complications that can result.
Questions stemming from Chapter 2 include: (1) What do the species distribution models look like for the other soil-transmitted helminths in the US: A. lumbricoides, T. trichiura, and N. americanus? What areas are at risk and in which communities should resources be allocated to extend active surveillance? Additional modeling studies can help inform where the next surveillance studies should occur and where public health surveillance should be concentrated, with the ultimate aim of further clarifying the
epidemiology of intestinal parasitic infections in the US. (2) What are the risks of healthcare-associated strongyloidiasis in the US? How effective and efficient would the implementation of a universal screening policy be in preventing healthcare-associated strongyloidiasis? What does strongyloidiasis epidemiology in the US look like –– how many cases of hyperinfection and disseminated disease occur nationally and what factors are
pertinent to patient survival? Questions emerging from Chapter 3 include:
94 (1) To what extent is there political will to address infections of poverty in the US? Why and how have prior legislative attempts to codify protection from these diseases been thwarted? (2) To what extent is there public health and clinical capacity to address infections of poverty in the US? What effect, if any, would reform to medical education in the US and inclusive disease reporting policies have on the incidence and prevalence of intestinal parasitic infection? These questions should be investigated through qualitative studies, including in-depth interviews with public health officials, infectious disease experts, and policymakers. Analyses of any policy changes should follow, along with monitoring and evaluation of any control programming that may eventually be implemented.
Neglect is silence, inaction. No change will ever stem from it. As Yamin and Farmer wrote, to apply a human rights-based framework to health takes more than elucidating the relevant biology; it requires recognition that disparities in health and suffering ultimately reflect pathological relationships of power. The systematization of health disparities can be used to public health advantage: on some level, we already know where to look for these diseases. We also know how to prevent them. Poverty, inequality, and violations of human rights are not legitimately ascribed to predestined forces, though these weak explanations do make it easier to neglect others and their problems. Mirroring the present moment in US history, time is overdue to critically examine and remedy the toxic interplay of injustice, disease, power, and privilege, and to prescribe a new world free from parasitic pathology, biological and social.
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