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Case-Control Study of Shigellosis in San Francisco: The Role of Sexual Transmission and HIV Infection; oral-anal sex, MSM
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Clinical Infectious Diseases Feb 1, 2007;44:327-334
Tomas J. Aragon,1,2 Duc J. Vugia,3,4 Sue Shallow,4 Michael C. Samuel,4 Arthur Reingold,2,4 Frederick J. Angulo,5 and Williamson Z. Bradford4
1San Francisco Department of Public Health, City and County of San Francisco, San Francisco, 2School of Public Health, University of California at Berkeley, Berkeley, 3California Department of Health Services, Richmond, and 4California Emerging Infections Program, Oakland, California; and 5Centers for Disease Control and Prevention, Atlanta, Georgia
(See the editorial commentary by Daskalakis and Blaser below): "....Aragon et al. [13] have demonstrated a convincing association between Shigella species, specific sexual activities between men, and HIV status. The elements that combine to create this "perfect storm" of disease transmission already allow public health recommendations to permit their interdiction...."
ABSTRACT
Background. Shigella species infect about 450,000 persons annually in the United States. Person-to-person transmission of Shigella species, which have a low infectious dose, occurs frequently, particularly in areas with poor sanitation and hygiene. Sexual transmission of Shigella species among men who have sex with men (MSM) has been inferred from outbreaks of shigellosis among that population, and limited studies have suggested the importance of human immunodeficiency virus (HIV) infection as a risk factor for shigellosis. No population-based study of sporadic shigellosis has evaluated the role of sexual practices (especially among MSM) and HIV infection along with other established risk factors for shigellosis.
Methods. We conducted a population-based case-control study of shigellosis in adults in San Francisco, California, during the period 1998-1999. Cases of Shigella infection were identified through laboratory-based active surveillance conducted by the California Emerging Infections Program. Seventy-six case patients were matched by sex with 146 control subjects. Exposure data were collected on established risk factors, sexual practices, and HIV infection status. Bivariable and multivariable analyses were conducted. Population-attributable fractions were calculated.
Results. From the multivariable analysis, for men, shigellosis was associated with MSM (odds ratio [OR], 8.24; 95% confidence interval [CI], 2.70-25.2), HIV infection (OR, 8.17; 95% CI, 2.71-24.6), direct oral-anal contact (OR, 7.50; 95% CI, 1.74-32.3), and foreign travel (OR, 20.0; 95% CI, 5.26-76.3), with population-attributable fractions of 0.72, 0.42, 0.31, and 0.18, respectively. For women, shigellosis was associated only with foreign travel (OR, 21.0; 95% CI, 2.52-899), with a population-attributable fraction of 0.37.
Conclusions. Among MSM, shigellosis is predominantly a sexually transmitted disease, with direct oral-anal contact conferring the highest risk and HIV infection likely contributing to increased host susceptibility.
Background
Each year, an estimated 450,000 persons in the United States are infected with Shigella species, resulting in 6200 hospitalizations and 70 deaths [1]. Humans and other primates are the only natural reservoirs for Shigella species [2]. Shigella species are transmitted by the fecal-oral route, and most infections are transmitted from person to person, reflecting the low infectious dose [3]; as few as 10 viable organisms can result in clinical infection [4]. In areas in which infection is prevalent, risk for Shigella infection increases with poor hand hygiene, ingestion of contaminated food or water, inadequate sanitation and toileting, overcrowding, and sexual contact [5-13].
Among reported culture-confirmed infections in the United States during the period 1989-2002, 72% were due to Shigella sonnei, 18% were due to Shigella flexneri, 1.6% were due to Shigella boydii, and 0.7% were due to Shigella dysenteriae [3]. Most reported cases occurred in children <10 years of age, followed by women 20-39 years of age; the high rate of infection in the latter group was presumably related to caring for infected children. In the mid-1970s, shigellosis was recognized as a potentially sexually transmitted disease among men who have sex with men (MSM) [7, 14, 15]. In the late 1970s and early 1980s, the increased incidence of S. flexneri infection in men was attributed to the sexual practices of MSM, which frequently include anal contact [16].
A study conducted in the San Francisco Bay area in 1996 showed a correlation between an increased prevalence of HIV infection and increased incidence of shigellosis, suggesting that Shigella infection may be more severe among HIV-infected persons or that HIV infection may be an important risk factor for shigellosis in the MSM community [17]. Among persons infected with Salmonella or Campylobacter species, HIV-infected persons have more-severe infections [18].
How risk factors contribute to Shigella transmission dynamics can be conceptualized using the equation for the per capita infection rate among susceptible individuals: I = cpP, where c is the contact rate of susceptible individuals to a potentially infectious source, p is the probability that the agent is transmitted from this contact, and P is the probability that the source is infectious [19]. The transmission probability (p) is influenced by host susceptibility, source infectiousness, and factors that modify transmission risk independent of susceptibility or infectiousness (e.g., barrier methods). This simple model illustrates that all of these factors must come together in place and time for infections to be transmitted, propagated, and sustained.
For example, if a man has sex with a man, there are several factors to consider. First, did this man engage in behavior that put him in direct or indirect contact with fecal material (e.g., anal fisting, oral-anal contact)? Second, does he have a condition (e.g., HIV infection) that might increase susceptibility to Shigella infection or disease? Third, was his partner shedding Shigella species in his feces? The likelihood that his partner was shedding Shigella species may be reflected by the prevalence of shigellosis in the local MSM community and the prevalence of conditions that may increase or prolong shedding. For example, although not established, if HIV infection increased or prolonged fecal shedding, then a higher prevalence of HIV infection in the MSM community could increase the prevalence of Shigella infection.
To date, no population-based analytic epidemiological study of sporadic shigellosis has been reported that evaluated the role of HIV infection and sexual behavior in the transmission of Shigella species. To assess the role of sexual behavior and HIV infection in the transmission of Shigella species in adults in San Francisco during a nonoutbreak period, we conducted a population-based case-control study. We used the conceptual approach described above to guide our analysis and interpretations.
DISCUSSION
This is the first population-based study of sporadic shigellosis in adults that evaluated the role of sexual acts (including oral-anal contact), the sex of sex partners, and HIV infection along with other established risk factors for infection. In men and women, foreign travel outside the United State in the prior week was the strongest single factor associated with shigellosis (for both men and women, the OR was >20; P < .001). Among men, being MSM, having HIV infection, and having direct oral-anal contact were independently associated with shigellosis (ORs were about 8 for each risk factor; P < .001). Among MSM only, HIV infection and direct oral-anal contact remained independently associated with shigellosis (ORs were about 9 for both risk factors; P <.01).
Our epidemiological study corroborates previous research [7, 14-16] that suggests that shigellosis is a sexually transmitted disease among MSM and that sexual practices among MSM that include anal contact are risky. We also found that sexual practices among MSM involving direct oral-anal contact are particularly risky for shigellosis. Although these findings may have been generally assumed by some, they have not been well documented in a population-based study of sporadic shigellosis. Foreign travel, on the other hand, has been well documented as a risk factor for shigellosis [23, 24].
Is HIV infection a contributing factor in shigellosis? This could be true in 2 ways: HIV infection may increase the shedding of Shigella species or may increase the susceptibility of the host. At an individual level, if an HIV-infected person is more susceptible to Shigella infection, then contact with a person who is infected is more likely to result in infection. At a group level, if HIV-infected persons with shigellosis are more likely to shed Shigella species and if HIV-infected persons are more likely to have sexual contact with other HIV-infected persons (assortative mixing by HIV status), then the HIV infection group membership can be a causal risk factor. In fact, this phenomenon of sexual "serological sorting" has been well described: MSM who know their HIV status are more likely to seek serologically concordant sex partners [25]. Finally, it is possible that knowledge of the discordant HIV status of sex partners may promote the substitution of behaviors that increase the risk of transmitting HIV with behaviors that increase the risk of transmitting enteric pathogens.
Some case reports and case series suggest more-severe shigellosis among HIV-infected patients [26-31]. One case-control study from Zambia, conducted during an epidemic of dysentery (most of it due to S. dysenteriae), found an association between dysentery and HIV infection (crude OR, 9.2; 95% CI, 5.0-16.9) [32]. Case patients and control subjects were similar in age, sex, and distance from the clinic. No other factors were associated with dysentery, although the study did not collect behavioral data or control for potential confounders. This study suggested that HIV infection may contribute to disease transmission and/or disease expression. Our study found a similar association (adjusted OR, 8.50; 95% CI, 2.79-25.9), suggesting that HIV infection does play an important causal role. Although we do not know the mechanism, our study is more consistent with increased susceptibility to infection as an explanation.
Among men, the PAFs for being MSM, having HIV infection, and having direct and indirect oral-anal contact were 0.72, 0.42, and 0.31, respectively. Therefore, up to that fraction of cases might have been prevented if a causal and modifiable risk factor had been removed. For example, if HIV infection were causal through increased susceptibility, then up to 42% of shigellosis in men in San Francisco might have been prevented if there had been no HIV infection. Although being MSM is not a modifiable factor, it can be causal at the population level as a sexual network group with a higher prevalence of Shigella infection. Again, prevalence of infection operates through the relationship I = cpP. Reducing any component (c, p, or P) results in lowering the infection rate among susceptible individuals (I). Therefore, if the prevalence of Shigella infection in MSM had been reduced to near zero in San Francisco, then up to 72% of Shigella infections in men might have been prevented. Naturally, because HIV-infected men may be more susceptible to infection, this would also benefit them, because >90% of the HIV-infected men with shigellosis were MSM.
The strengths of this study include the following: the case patients and control subjects were population-based, we studied sporadic shigellosis (in the absence of an outbreak), and we collected data on oral-anal sexual exposures, HIV status, and established risk factors for Shigella infection. To control for factors associated with being MSM, we also evaluated risk factors among MSM only. Our results represent the baseline epidemiological characteristics of Shigella transmission in San Francisco. Although we applied a traditional case-control study design, we incorporated our understanding of Shigella transmission dynamics to guide the analysis and interpretation of the data. Other studies of Shigella outbreaks among MSM did not use population-based control subjects, did not collect detailed oral-anal contact histories, did not (or could not) collect data on or control for HIV-infection status, or did not consider how transmission risk factors can be interdependent and dynamic [7, 9, 14-17, 32-38].
There are limitations in conducting epidemiological risk factor studies of communicable infections when the risk factors are dynamic, interdependent, and dependent on location and calendar time. For example, a high frequency of risk behavior (e.g., direct oral-anal contact) is a risk factor only if a subject is selecting partners with a high prevalence of infection (i.e., if the P is high). In addition, of course, prevalence of infection differs by location and varies over time. In the terminology of Rothman and Greenland [39], for a risk factor to be a component cause, it must be part of a sufficient cause in which all of the components of the causal "pie" are present. Therefore, readers must be cautious in interpreting risk factor studies of communicable diseases. These risk factors can be naturally interdependent and, in this case, highly correlated, making traditional interpretation of regression coefficients more challenging.
Another limitation is that the association of HIV infection with shigellosis may in part be caused by a diagnostic bias among HIV-infected patients. HIV-infected patients are more likely to receive regular medical care, are more likely to seek medical evaluation for a diarrheal illness, and are more likely to be evaluated with stool cultures to rule out treatable conditions. However, even if such a diagnostic bias was operating, it would not likely account for the association we detected (ORs >8; P < .001) (table 5).
In this study, S. flexneri was the predominant strain occurring among MSM. This association has been previously noted [16]. Beginning in June 2000, 6 months after data collection for this study, San Francisco started experiencing a large, sustained outbreak of shigellosis among MSM in which S. sonnei was the predominant strain [9]. It is unlikely that the prevalence of HIV infection and fecal-oral risk behaviors changed significantly in San Francisco during this time interval. A more likely explanation is that the sufficient introduction of S. sonnei into this community changed the transmission dynamics of Shigella infection in this group, such that the prevalence of infectious cases exceeded some threshold, resulting in a sustained, explosive outbreak. This is plausible, because S. sonnei is less pathogenic and less virulent than S. flexneri [40] and could result in a higher number of asymptomatic and less severely ill (yet infectious) individuals circulating in the community, thereby increasing transmission and driving the outbreak. Subsequently, similar outbreaks among MSM were reported in Canada, Australia, London, and Chicago [33, 34, 36, 38, 41].
Among MSM, shigellosis is predominantly a sexually transmitted disease, with direct oral-anal contact conferring the highest risk, and HIV infection likely contributes to transmission through increased host susceptibility. Given the continuing outbreaks of shigellosis among MSM [41], we believe that there is enough evidence and biological plausibility to recommend that MSM avoid direct oral-anal sexual contact, especially if sex partners are ill or if there are community outbreaks of enteric infection.
Scientific knowledge gaps in this area remain. Are HIV-infected persons more susceptible to Shigella infection or more likely to experience severe disease? Do HIV-infected persons with shigellosis shed more bacteria or shed bacteria for longer periods (with or without treatment)? Will barrier methods (e.g., dental dams) reduce the risk of transmission from direct oral-anal sexual contact? Answers to these and other questions will help medical and public health authorities to design better clinical and public health control interventions.
Another Perfect Storm: Shigella, Men Who Have Sex with Men, and HIV
EDITORIAL
Demetre C. Daskalakis1 and Martin J. Blaser1,2
1Division of Infectious Diseases and Immunology, Department of Medicine, and 2Department of Microbiology, New York University School of Medicine, New York
Shigella species are a significant cause of bacterial dysentery worldwide, with 165 million cases every year, leading to 1 million deaths annually [1]. Nearly 450,000 Shigella infections, causing significant morbidity, are reported each year in the United States [2]. Many of these cases occur in children or in health care institutions or are imported through travel abroad. In the mid-1970s, outbreaks of Shigella infection among adults in New York and San Francisco raised the possibility that Shigella species may be sexually transmitted, with most infections occurring in men who have sex with men (MSM) [3, 4]. Since these early observations, Shigella infection appears to be more frequent among MSM than among other adult populations, via direct fecal-oral transmission either through accidental inoculation of contaminated stool or through direct oral-anal contact [5-9].
The efficiency of this sexual transmission is likely fueled by several elements, both biological and behavioral in nature (figure 1). A very small inoculum of Shigella-as low as 10 organisms-is able to cause disease [10]. Even the accidental ingestion of minute amounts of fecal material during sexual activity could deliver a sufficient inoculum. Often transmitted through ingestion of contaminated food or water, Shigella species survive the chemical barriers of the stomach and thrive in the colon, leading to tissue invasion and disease [11]. Biological factors in the host likely also participate in the apparent frequency of Shigella infection among MSM; the immunodeficiencies related to the high prevalence of HIV infection among these men may drive transmission [8, 12]. Social adaptation by MSM in the age of HAART may affect behaviors that influence transmission of enteric pathogens, and travel-related infections may introduce Shigella species to networks of susceptible persons.
The study by Aragon et al. [13] is a significant contribution to our knowledge of sexually transmitted enteric infections among MSM. Their analysis of shigellosis in San Francisco through a case-control study deepens our understanding of the association between Shigella infection and specific sexual behaviors. The authors extend the work of Baer at al. [8], associating specific behaviors with risk for shigellosis among MSM, and strengthen the connection between HIV infection and this enteric pathogen. By analyzing cases in women and men separately, the authors highlight the likely efficient transmission of Shigella species in MSM. They also raise important questions about the role of HIV infection in the venereal transmission of this pathogen. The model of Shigella infection offered by this study represents a "perfect biological storm": a highly infectious organism imported into a behavioral setting in which continuing transmission can occur among a particularly susceptible population (figure 1).
HIV infection has several effects on Shigella transmission. Immunocompromised persons may have extended carriage of Shigella species and may have prolonged symptomatic or asymptomatic shedding at high titer. HIV infection also may have nonbiological effects on behaviors that may influence the transmission of Shigella infection and other sexually transmitted infections among HIV-positive MSM. Whether as a result of increased high-risk activity among HIV-positive persons or of efforts among HIV-positive men to prevent the spread of HIV infection by limiting risky sexual behaviors to partners who are already HIV positive, in the post-HAART era, Shigella infection, like other sexually transmitted infections, may follow specific MSM sexual networks [14]. Behaviors such as serosorting, strategic positioning, and intentional unsafe anal intercourse with others who are HIV positive may create sexual and behavioral networks of HIV-positive men that potentially enhance sexually transmitted infections among themselves but limit transmission to those who are seronegative for HIV [15].
Are HIV-positive MSM more susceptible to shigellosis, or do the specific behaviors of HIV-positive men create sexual networks that facilitate transmission to other HIV-positive men? Or are both true? Several recent studies have shown that unsafe sexual behavior has been increasing among both HIV-positive and HIV-negative MSM [16-18]. Whether this increase is influenced by optimism regarding HIV treatment, increased sex partnering through the Internet, or the impact of crystal methamphetamine use, some MSM are exhibiting higher-risk behaviors [19]. In recent years, improved sanitation and hygiene have reduced waterborne and foodborne Shigella species transmission and have led to a marked reduction in endemic infections in the developed world, except in certain special populations [20]. In contrast, diminished "sexual hygiene" in the form of a resurgence of high-risk behavior with multiple and concurrent partners may create endemicity for shigellosis among some groups of MSM and may generate efficient and sustained transmission networks among them [21].
An alternative possibility is that some MSM may be engaging in activities, such as serosorting or strategic positioning, that create separate sexual networks that are based on perceived HIV status. Serosorting is defined as having sex with partners of the same HIV status. Strategic positioning is changing specific sexual practices on the basis of an assumed understanding of the magnitude of the HIV infection risk that these practices incur. An example of strategic positioning is the conscious decision of an HIV-negative person to avoid receptive sex with HIV-positive partners but to still participate with them in other sexual activities that are perceived to be lower risk. The 2004 outbreak of lymphogranuloma venereum in The Netherlands, which occurred among predominantly HIV-positive MSM engaging in "leather parties," and its subsequent spread to a similar US population highlights the need for further study of the transmission of sexually transmitted infections among MSM networks to interrupt and prevent such occurrences [22].
As was the case in the 2004 lymphogranuloma venereum outbreak, travel likely plays an important role in introducing Shigella species to populations at risk. The predominant species of Shigella causing disease in MSM reported by Aragon et al. [13] was Shigella flexneri; however, there was an outbreak of shigellosis due to Shigella sonnei in San Francisco after their data collection was complete, predominantly among HIV-positive MSM [5]. This outbreak broadens our view of the transmission dynamics of Shigella species in that population: S. sonnei was likely imported via travel into a sexual network, allowing for biobehavioral amplification into an outbreak. The replacement of S. flexneri by S. sonnei may reflect some degree of herd immunity in the core population. In association with import through travel, factors including immunodeficiency, seropositive sexual networks, and Shigella virulence likely synergize to create conditions that facilitate the transmission of Shigella species to outbreak levels among HIV-positive MSM (figure 1).
This study raises several questions that merit further investigation. Do CD4 cell counts and other measures of immune status affect why HIV-positive MSM are more likely to develop shigellosis? Are there other behavioral or biological correlates of susceptibility to Shigella species in this population? Does HIV infection status affect the frequency of direct or indirect anal contact by MSM? Which steps are needed to interrupt transmission of enteric pathogens through sexual networks? How do serosorting, strategic positioning, and other behavioral cofactors influence transmission of Shigella species? Are HIV-positive women at increased risk for shigellosis?
Aragon et al. [13] have demonstrated a convincing association between Shigella species, specific sexual activities between men, and HIV status. The elements that combine to create this "perfect storm" of disease transmission already allow public health recommendations to permit their interdiction.
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