Introduction

The City of Stockton, California operates a wastewater treatment facility that discharges treated effluent to the San Joaquin River. Beneficial uses of the San Joaquin River include body contact recreation, agricultural irrigation, and municipal uses. The California Regional Water Quality Control Board, Sacramento Region (RWQCB), recently indicated that the effluent may have a reasonable potential to cause an unacceptably high health risk for body contact recreation in the San Joaquin River in the vicinity of the discharge related to exposure to pathogenic microorganisms (CA RWQCB, 1994).

To date, operation of the treatment facility has included secondary treatment via stabilization ponds followed by filtration and disinfection (tertiary treatment) between the months of May and October and secondary treatment between November and April. To address the concerns raised by the RWQCB, an investigation was initiated to characterize the risk to public health via body contact recreation in the San Joaquin River under various flow and treatment scenarios at the treatment facility (Soller et al., 2003a). Based on the available options to reduce the risk to public health, the investigation focused on determining if the addition of tertiary treatment to the facility's operation during the winter season would substantially reduce the risk the public faces via recreation in the river for existing and potential future effluent flows.

Quantifying the human health risk associated with the ingestion of waterborne pathogens is a rapidly developing field. Until relatively recently, quantitative microbial risk assessment investigations were carried out by employing static models that calculated the probability of infection or disease resulting from a single exposure event (Fuhs, 1975; Haas, 1983; Regli et al., 1991; Anderson et al., 1998). Static model assessments are based on an approach that was developed for the assessment of risk associated with exposure to chemical agents (National Research Council, 1983). Thus, fundamental properties that are unique to the transmission of infectious diseases, such as immunity to infection and the potential for person-to-person transmission of infection, are not accounted for in those assessments. There are, however, limitations of addressing the transmission of infectious diseases as a static process (Koopman et al., 1991; Koopman and Longini, 1994; Eisenberg et al., 1996).

Dynamic models of disease transmission (Hethcote, 1976; Anderson and May, 1991) are able to account for human exposures to contaminated media such as water, exposures to infected individuals that may result in person-to-person transmission of infection (Eisenberg et al., 2002), and protection from infection (immunity) from prior exposures (Soller et al., 2002b). Nevertheless, until recently, few researchers or risk assessors have employed an epidemiology- based disease transmission framework to characterize the risk to human health associated with waterborne pathogens (Cooper et al., 1986; EOA Inc., U.C. Berkeley, 1995,1999; Eisenberg et al., 1996,1998; Soller et al., 2003a,2003b.

In this investigation, a disease transmission model was applied to characterize quantitatively the relative risk associated with various treatment and flow scenarios for the City of Stockton's wastewater treatment facility (Soller et al., 2003a). A schematic representation of the conceptual model for disease transmission is provided in Figure 1 (Soller et al., 2003a). The investigation focused on risk of gastroenteritis associated with viral contamination, as numerous investigations of waterborne illness in developed countries indicate that the common etiological agents are more likely to be viruses than other pathogens (Cabelli et al., 1982; Levine and Stephenson, 1990; Palmateer et al., 1991; Sobsey et al., 1995; Fankhauser et al., 1998; Mead et al., 1999; World Health Organization, 1999). Further, the California Department of Health Services requested that the investigation determine the feasibility of characterizing the risk to sensitive subpopulations for the exposure scenario under consideration.

Figure 1.

Conceptual model for disease transmission in a microbial risk assessment for the city of Stockton.

Full figure and legend (31K)

Incorporating differential susceptibility into a quantitative microbial risk assessment has been under discussion for several years (Balbus et al., 2000,2002). There have been a few attempts to quantitatively incorporate differential susceptibility into microbial risk assessments (e.g., Miller and Pegues, 1995; Perz et al., 1998; Makri et al., 2002). However, variations in risk may be less related to differences in interindividual susceptibility than to variations in characteristics of pathogens, even those between strains within species (Okhuysen et al., 1999).

The purpose of this paper is to report the results of a comprehensive, risk assessment-oriented evaluation of the literature on sensitive subpopulations' exposures to enteroviruses in recreational water, noting that our project involved river water. The review focused on determining the nature, severity, and extent of adverse health responses experienced by sensitive individuals, especially children; examining the available qualitative and quantitative health data; evaluating the data's usefulness for risk assessment purposes; and recommending research needed to fill key data gaps. The family Picornaviridae is divided into genuses, one of which is for enteroviruses. The serotypes for this genus have been organized into subclassifications including coxsackievirus (A and B), echoviruses, human enteroviruses, and polioviruses. As a group, the enteroviruses are relatively hardy in the environment, especially in the presence of neutral pHs, moist environments, and low temperatures. They survive for long periods on hands and fomites, in water, and on crops exposed to night-soil fertilizers (Morens and Pallansch, 1995).

Methods

Risk Assessment Methodology

The fundamental risk assessment methodology was to integrate a hydraulic model of the San Joaquin River and a dynamic model of disease transmission to conservatively estimate, via numerical simulation, the difference in disease incidence in the population attributable to the City of Stockton's wastewater treatment facility under various treatment conditions. A detailed description of the modeling effort and the results of the simulation study are described under separate cover (Soller et al., 2003a). Briefly, the hydraulic modeling was carried out to simulate water quality of the river near the discharge and provides estimated concentrations of a model virus to the disease transmission model at hourly time steps. The disease transmission model dynamically tracks the epidemiological status of the population, and provides to the hydraulic model virus loading data from infected recreators on the river (Figure 1). The simulation results estimate, for the population at-large, the risk of viral disease from recreation in the San Joaquin River attributable to the wastewater treatment facility under secondary and tertiary treatment conditions. The incremental benefit of tertiary treatment is also computed. Sensitivity analysis was employed to demonstrate how potentially important attributes of the model virus and the environmental exposure may impact the overall findings of the investigation. As noted above, it was also of interest to determine if estimates of risk could be estimated for sensitive subpopulations separately from the population-at-large.

Literature Review to Determine Differential Susceptibility among Subpopulations

To address the risk to sensitive subpopulations, we conducted an extensive literature search using Medline and other online scientific databases. We used keywords and combinations including recreation, water, viruses, outbreak, and specific virus nomenclature. Data from articles dated prior to 1966, the limit of Medline, were gathered using citations from previous articles and searches of library resources. We also reviewed waterborne disease outbreak surveillance reports from the Centers for Disease Control and Prevention (CDC) and others, with particular focus on outbreaks of unknown etiologic origin in recreational waters (Taylor et al., 1972; Harris et al., 1983; CDC, 1988,1990,1991,1993,1996,1998,2000).

We then screened the literature gathered for reports involving enterovirus occurrence and/or health-related information. We evaluated the final set of papers on a detailed basis for type of recreational water (river, lake, or swimming pool); pathogen type and strain; demographic data; study design; methods of exposure assessment; and health outcomes. We looked for both qualitative and quantitative information that could be useful for our modeling purposes. For example, qualitative information was extracted on microbial pathogen characteristics (species, strain, or serotype); types of illness (e.g., enteric, aural, dermal infections, etc.); symptoms reported; and outcomes (e.g., recovery, outpatient case, hospitalized case, death) in the outbreaks. We recorded quantitative data on the numbers and ages of persons exposed, incubation periods, rates of infection and illness, secondary attack rates, duration of illness, hospitalization rates, and associations between a pathogen and illness. We synthesized the data across studies as shown in this paper to develop the results and conclusions for our modeling project.

Results

Fewer than 15 epidemiological studies were identified, which provided information and data on exposures to enteroviruses in recreational water. These papers included data on infants, children, and adults through elderly ages; there were no papers on immune-compromised persons. Not all of the recreational settings in these studies were relevant to our risk assessment, but we summarize all studies here to place the investigations we focused on in a broader exposure assessment context.

Occurrence

Enteroviruses are commonly detected in sewage and water; some researchers have detected enteroviruses in recreational waters. Polioviruses, coxsackievirus A and B, and echoviruses have been found in rivers (e.g., Payment et al., 1988; Miyama et al., 1992; Tani et al., 1995), but coxsackievirus A and B and echoviruses have also been reported in lakes (D'Alessio et al., 1981) and swimming pools (Kee et al., 1994). Sources of waterborne enteroviruses suggested in the scientific literature include sewage (Oostvort et al., 1994; Van der Avoort et al., 1995), storm sewer discharge and runoff (D'Alessio et al., 1981), human activities (Payment et al., 1988; Kee et al., 1994), and diapers and sullage (Field et al., 1968).

Few articles provide sufficient temporal information to allow conclusions about whether the viruses detected in recreational water were present before illnesses. Van der Avoort et al. (1995) reported that in The Netherlands, wild poliovirus type 3 (PV3) was in river water 3 weeks before the index case of illness occurred. However, they also indicated that the initial source of the virus was probably a traveler who had been on another continent. Interpersonal contacts within a largely unvaccinated population, and not water, were reportedly responsible for the outbreak.

Epidemiology

There is no single epidemiology for all enteroviruses; the patterns for each serotype relate to the microorganism's characteristics and its interactions with the human host, the environment, and the mode of transmission. The primary route of transmission for most enteroviruses is fecal–oral, but oral–oral and several other routes occur (Morens and Pallansch, 1995; Modlin, 2000). Contaminated water can be an intermediary between infected and susceptible individuals (Morens and Pallansch, 1995). Serotype is important in determining whether infected people become symptomatic and how long they may shed viruses that could present exposures to others. Enteroviral replication is detectable within 3 days after ingestion of the viruses. Although many people exposed do not become symptomatic, they may shed viruses for up to 4 weeks from the pharynx and for over 5 months in feces (Modlin, 2000).

Age is one of the most important determinants of the incidence and severity of enterovirus infections. Newborns have some of the highest rates of infection, while children 2- to 9-years old have been identified as the most important transmitters of enteroviruses. Additionally, males rather than females have been reported to get more enteroviral infections and tend to have more severe illnesses as a result of their infections (Gelfand et al., 1963). Urban and crowded environments have been identified as areas with higher transmission rates, particularly where there are many children present (Morens and Pallansch, 1995).

The secondary attack rate for enteroviruses and the probability of experiencing symptoms vary by serotype. Owing to their longer shedding periods, polio and some coxsackieviruses tend to have higher secondary infection rates than do other enteroviruses. Secondary infection rates are generally highest among mothers (78%) and lower for fathers (47%), family members, or other close contacts of initial cases (Morens and Pallansch, 1995).

Sensitive Subpopulations

There is evidence that persons with abnormal cell-mediated immunity with accompanying B-cell dysfunction may be more susceptible to chronic, severe enteroviral infections (Modlin, 2000). However, it is widely accepted that age is the primary determining factor related to the type and severity of health outcomes from enterovirus exposures. In general, coxsackievirus A, coxsackievirus B, and echovirus infections result in more severe consequences in young children, while polioviruses cause more serious illnesses in older children and adults. Factors thought to influence susceptibility by age include variations in cell receptor sites, inoculums, host behavior patterns, and related routes of exposure (Morens and Pallansch, 1995). Since age is the most important indicator known for enteroviral illness risks among sensitive subpopulations, and since no studies on immune-compromised persons were found, this review focused on children (under age 19 years) as the group of concern.

Evaluation of the Data

We sought scientific literature on children infected by any enteroviral serotypes found in recreational waters. The search resulted in a collection of studies reporting on the following serotypes: coxsackieviruses A1, 6, 9, and 16; coxsackieviruses B1–5, and undetermined; echoviruses 1–7, 9, 11, 14, 16, 18, 19, 21, 24, 25, 30, and undetermined; enterovirus 71; polioviruses 1–3; and nontypable enteroviruses. Not all of these reports concluded that recreational water was the source of infection. There is more evidence that rules out waterborne transmission (Field et al., 1968; Hawley et al., 1973; Danes et al., 1983; Oostvort et al., 1994; Mulders et al., 1997, Rodriguez et al., 1997; Gosbell et al., 2000) or is not definitive (Matsura et al., 1984; Rumke et al., 1995) than there is evidence that is suggestive (D'Alessio et al., 1981) or definitive (Kee et al., 1994) for transmission of enteroviruses through recreational water.

Qualitative Data

Nature of Illnesses

A few studies of children with enteroviral infections associated with recreational water described the type but not the severity of symptoms experienced. The symptoms included headache, fever, vomiting, abdominal cramps, diarrhea, unspecified gastrointestinal symptoms, and pharyngitis (Hawley et al., 1973; D'Alessio et al., 1981; Kee et al., 1994).

Extent of Illnesses

Danes et al. (1983) stated that there was a high incidence of enteroviral infections among children aged 5–16 years, but did not provide data for the incidence to be calculated. Some patterns can be seen among cases reported by age (D'Alessio et al., 1981; Miyama et al., 1992; Oostvort et al., 1994), gender (Oostvort et al, 1994; Rodriguez et al., 1997), and proximity to the index case (Hawley et al., 1973; Oostvort et al., 1994; Van der Avoort et al., 1995). Typically, cases were younger children, men, or persons in close contact with index cases.

Secondary transmission reportedly occurred in coxsackievirus B5 (Hawley et al., 1973) and echovirus type 30 (Gosbell et al., 2000) outbreaks and was probably low in a set of cases with coxsackievirus A and B and/or echovirus infections (D'Alessio et al., 1981). Kee et al. (1994) indicated that 26% (12 of 46) of their echovirus type 30 cases were probably secondary cases.

Other

Related risk factors noted in the epidemiological literature on recreational water exposures include swimming, frequency of swimming, head immersion during swimming, and swallowing recreational water (Hawley et al., 1973; Denis et al., 1974; D'Alessio et al., 1981). It should be noted that these factors tend to be age-related behaviors and may be more common among young males.

Quantitative Data

Children as a Sensitive Subpopulation

Two studies provided quantitative epidemiological evidence that children are at increased risk of enteroviral illnesses following contact with recreational waters (D'Alessio et al., 1981; Kee et al., 1994). In a study of lake beach users, D'Alessio et al. reported that 90% of 134 ill children under age 16 years tested positive for nonpolio enteroviruses (coxsackievirus A (34%), coxsackievirus B (22%), echoviruses (29%), untypable enteroviruses (4%), and other viruses (11%)) compared with 7% of the 27 well children (D'Alessio et al., 1981). In a study where 96% of the cases were children, 18% were infected with echovirus 30 following swimming in an insufficiently chlorinated outdoor pool (Kee et al., 1994).

In many of the other studies, child and adult data were combined, so that it was not possible to analyze data for children specifically. Field et al.'s (1968) echovirus type 1 cases were aged 2 weeks – 8 years, with most under the age of 2 years. Oostvort et al. (1994) stated that in a largely unvaccinated population, the median for their child and adult wild PV3 cases was age 18 years (ranging from 10 days – 61 years). Rodriguez et al. (1997) presented data on 79 cases (predominantly echovirus type 9) that ranged in age from infancy to 66 years old, with a median of 21 years. Similarly, 30 echovirus type 30 cases had a median age of 25 years (8 months – 51 years) (Gosbell et al., 2000).

Severity of Illnesses

The current literature offers a limited amount of quantitative information that can be used to estimate the severity of children's illnesses resulting from enterovirus infections. Field et al. (1968) reported that 3 of 55 childhood cases (6%) of echovirus type 1 infections died. Oostvort et al. (1994) found 2 deaths among 71 cases (3%) of child and adult cases of wild PV3, but did not indicate the ages of the fatalities. Of the 30 echovirus type 30 cases in Gosbell et al. (2000), 26 cases stayed in the hospital and were there for a median of 2.8 days (1–9 days). Field et al. (1968) noted that the median duration of hospitalization for their 58 hospitalized echovirus type 1 cases was 13 days. Rodriguez et al. (1997) reported that among 79 hospitalized cases with coxsackievirus A or B and/or echovirus infections, 15 (19%) were treated as outpatients, and the rest (81%) were admitted; no duration of stay data were presented. No articles reported the total duration of illnesses.

The incubation period for an enteroviral infection was reported by only one set of authors (Kee et al., 1994). They noted that the incubation period for echovirus type 30 among lake bathers had a median of less than 36 h (0–72 h) and for secondary cases had a median of 78 h (Kee et al., 1994).

Extent of Illnesses

No study provided quantitative evidence sufficient to estimate the incidence of enteroviral illnesses among children or the proportion of their illnesses attributable to a recreational water source. Also, several of the studies combined data for adults and children (Field et al., 1968; Kee et al., 1994; Rodriguez et al., 1997; Gosbell et al., 2000), did not report the age range of the cases (Mulders et al., 1997), or did not otherwise clarify the number of ill cases who were children (Van der Avoort et al., 1995). As a result, it is not possible to determine, in exact terms, the proportion of infections and illnesses that occurred among children.

D'Alessio et al. (1994) were the only authors to report odds ratios (ORs) by age. Combining all of their confirmed nonpolio enterovirus cases, they found that children under the age of 4 years who were exclusive lake beach swimmers were the most likely to become ill (OR=10.63). Children aged 10–15 years had the second highest odds ratio (OR=3.93), but no significance or confidence intervals were provided. Oostvort et al. (1994) reported that 32.9% of the children in schools with siblings of PV3 positive cases had antibodies for the serotype, while only 4.9% of children in schools without such siblings were infected. The numbers of children sampled in each school and the numbers of children found to be positive and negative for PV3 were not reported. As a result, the data needed to calculate an OR are not available in the article.

Dose–response

No study reported a dose–response relation for any of the enteroviral illnesses in children.

Discussion

Applicability of Existing Data

The available evidence is quite limited for childhood illnesses associated with enteroviruses contracted through recreational water exposures. Two studies have suggested that enteroviral illnesses are associated with recreational water exposures (D'Alessio, 1981; Kee et al., 1994), but far more studies have not been able to establish a link.

The qualitative data offer limited insights for risk assessment modeling purposes. They suggest that young males who swim frequently and who immerse their heads or swallow water while swimming may be at higher risk for enteroviral infections. For some echoviral illnesses, cases may result in death or hospitalization of up to 2 weeks.

Most of the studies reviewed were descriptive and did not include data from comparison populations. Other important limitations of the research have been the inability to determine the total number of children at risk, difficulties in identifying all cases (particularly the milder cases), and the inability to determine the impacts of recall bias on exposure status. The lack of reporting data on the number of people at risk, either each case individually or data separated by child and adult cases, prevented independent calculations of incidence rates, attributable incidence rates, or ORs. Another limitation for risk assessors is the lack of any dose–response data for children infected with enteroviruses. We determined that the available studies did not provide sufficient data on susceptible subpopulations' exposures to enteroviruses for use in improving our model. Our exposure assessment showed that the most likely initial susceptible population was approximately 2.8 million people. The impact of the size of the initial susceptible population on the risk analysis was investigated via sensitivity analysis. These analyses indicated that the size of the initial susceptible population does not substantially affect the predicted number of cases of enterovirus disease attributable to the treatment plant discharge (EOA Inc., 2002).

Data Needs

In theory, exposure assessments could be improved with enhanced virus monitoring in recreational waters. However, the quantification of animal viruses in water remains technically difficult, time consuming, and expensive. Further, the viruses that are most likely the etiological agents of primary interest for exposure to ambient waters are still difficult or impossible to quantify in water. It is for these reasons that many public agencies rely on indicator organisms to establish a qualitative or semiquantitative link between water quality data and risk to public health. Although many published studies have questioned the utility of bacterial organisms as indicators for viral pathogens (Gantzer et al., 2000; McLaughlin and Rose, 2000) and recent studies indicate that alternative organisms show promise as viral indicators (Brion et al., 2002), there is still little consensus on the best indicator organism for viral pathogens in ambient waters. Thus, in many cases risk assessors must still develop estimates of exposure based on indicator organism and/or epidemiological data when the exposure of interest is due to recreational contact with ambient waters.

Reviews of sensitive subpopulations have typically focused on a dichotomy of risk factors, including genetic and acquired factors, which may place individuals at increased risk of infection or disease. However, we have recently proposed a new framework to expand and clarify evaluations of risk factors for sensitive subpopulations (Embrey et al., 2002). For example, the stage of an individual's physiological development may have important impacts on how microorganisms and their related toxins are metabolized. Acquired physiological factors such as chronic diseases and nutritional states may influence uptake, metabolism, and excretion. The impacts of gender may be related to hormonal or behavioral factors, potentially adding to the effects of physiological development. As more knowledge is gained about the health effects of enteroviruses, the use of such a framework may facilitate more rapid insights into the critical risk factors that put children or other groups at increased risk, thereby making them "susceptible subpopulations."

To make more data accessible for risk assessments of children's health outcomes, researchers should report health and exposure data for child and adult cases separately. Information on the age and gender of cases, along with incubation period and symptom duration data, would allow risk assessors to develop more effective models for the population. Evaluation of risks by age subgroups (e.g., <1 year 1–4, 5–9, and >9 years) may yield some important insights into risk factors (such as behaviors and physiological development) and strategies for risk assessment modeling.

Additionally, more complete ascertainment of the numbers of people at risk for infection and detection of all cases, including mild cases, would provide more reliable bases on which to estimate incidence and prevalence of illness and to calculate relevant ORs for recreational water exposures. Authors should routinely comment on the accuracy of their efforts to enumerate the population at risk and all cases. With this information, risk assessors can analyze the degree of uncertainty inherent in reported data. In retrospective studies, efforts are needed to improve the evaluation of the extent to which recall bias may explain reported exposure status, particularly of behaviors such as head immersion and swallowing while swimming.

Without more effective investigations and documentation of enteroviral outbreaks among children and more thorough consideration of the sources of their infections, risk assessments specifically designed to address susceptible subpopulations such as children will remain difficult to conduct or, when conducted, will be quite uncertain in their outcomes. The exposure assessment lessons we learned are likely to be relevant to other microbial pathogens and susceptible subpopulations, but testing the wider applicability of these lessons was not within the scope of this project.

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Acknowledgements

Funding for this investigation was provided by the City of Stockton, Municipal Utilities Department. We thank Mr. Don Dodge and Mr. Morris Allen for their support of this investigation and Mr. Robert Hultquist, Dr. Steven Book, and Mr. Carl Lischeske of the California Department of Health Services for their constructive input and review. We also acknowledge Lisa Ragain, Martha Embrey, and Bridget Ambrose for their technical assistance in preparing this publication.