DOI: 10.1111/hiv.12191 HIV Medicine (2015), 16, 168–175
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ORIGINAL RESEARCH
Shigella flexneri serotype 1 infections in men who have sex with men in Vancouver, Canada A Wilmer,1 MG Romney,1,2 R Gustafson,3 J Sandhu,4 T Chu,4 C Ng,5 L Hoang,1,5 S Champagne1,2 and MW Hull6,7 Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada, 2Department of Pathology & Laboratory Medicine, Division of Medical Microbiology, St. Paul’s Hospital, Vancouver, BC, Canada, 3 Communicable Disease Control, Vancouver Coastal Health, Vancouver, BC, Canada, 4Public Health Surveillance Unit, Vancouver Coastal Health, Vancouver, BC, Canada, 5British Columbia Centre for Disease Control, Public Health Microbiology & Reference Laboratory, Division of Mycology and Bacteriology, Vancouver, BC, Canada, 6Department of Medicine, University of British Columbia, Vancouver, BC, Canada and 7BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada 1
Objectives
Outbreaks of shigellosis have been documented in men who have sex with men (MSM), associated with interpersonal transmission and underlying HIV infection. We observed a rise in Shigella flexneri isolates identified in a downtown tertiary-care hospital laboratory located within the city centre community health area (CHA-1) of Vancouver, Canada. The objectives of this study were to evaluate clinical outcomes of shigellosis cases among MSM admitted to hospital and to evaluate trends in Shigella cases within Vancouver, Canada. Methods
Adult rates of shigellosis were analysed by gender and health region, from 2005 to 2011, followed by retrospective chart review of all hospital laboratory-identified S. flexneri cases from 2008 to 2012. Serotyping and pulsed-field gel electrophoresis (PFGE) were performed on these isolates. Results
Although shigellosis rates in men within CHA-1 did not change from 2005 to 2011 (range 33.4–68.5 per 100 000; P = 0.74), they were significantly higher than in other regions within the city of Vancouver (P ≤ 0.001) and the province of British Columbia (P ≤ 0.001). Shigella flexneri rates in men within CHA-1 increased significantly (range 2.3–51.4 per 100 000; P < 0.001), starting in 2008, and were higher than in other regions within Vancouver (P ≤ 0.01). Seventy-nine isolates of S. flexneri from 72 patients were identified by a single hospital laboratory. All patients were male and predominantly MSM (91.7%) and HIV-infected (86.1%), with most (92.6%) demonstrating CD4 counts ≥ 200 cells/μL. In total, 38.0% required hospitalization. Most (87.3%) had S. flexneri serotype 1 infection, with 72.9% of these representing a single PFGE pattern. Conclusions
We identified high levels of transmission of a primarily clonal strain of S. flexneri serotype 1 in our local MSM population, resulting in a substantial burden of illness and health care resource use secondary to hospital admissions. Keywords: HIV, homosexuality, male, Shigella Accepted 9 July 2014
Introduction Shigellosis is an acute intestinal infection caused by Shigella species, including Shigella flexneri, Shigella sonnei, Shigella dysenteriae and Shigella boydii [1]. These organisms are
Correspondence: Dr Mark Hull, BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel: 604 806 8640; fax: 604 806 8527; e-mail: [email protected]
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transmitted via direct or indirect faecal−oral contact, and are highly transmissible, with as few as 100 organisms able to establish infection [1,2]. The incubation period is typically 12 to 96 hours, followed by the onset of watery, bloody or mucoid diarrhoea, abdominal cramps, nausea and fever, which last 4 to 7 days [1]. Rare complications of shigellosis include sepsis, reactive arthritis and haemolytic uraemic syndrome (HUS) [1]. Shigellosis has long been recognized as a possible sexually transmitted infection (STI) in men who have sex with men (MSM) [3–5]. From 1970 to 1985, a significant demographic shift occurred in the USA with respect to S. flexneri infection, with a more than fivefold increase in the infection rate in men 30 to 39 years old, despite no change in women of comparable age [6]. MSM transmission was felt to be a likely explanation for this change, with acquisition thought to be related to sexual practices of oral−anal and oral−genital contact [6]. In 1996, HIV was also identified as an important risk factor for shigellosis, after higher rates of Shigella infection were noted in a population that was significantly more likely to be adult, male and HIV-infected [7]. A case−control study was performed in the San Francisco area during a nonoutbreak period from 1998 to 1999, with multivariate analysis demonstrating a significant association of shigellosis with MSM, HIV infection, direct oral−anal contact and foreign travel [8]. Shigella flexneri appeared to be the predominant species in MSM during that period and, compared with S. sonnei, was significantly associated with MSM, HIV infection, direct anal contact, and lack of foreign travel [8]. Despite numerous MSM shigellosis outbreaks documented in the literature, little is known regarding the clinical course and outcomes of infections in this population. Additionally, for the HIV-infected patients involved in these outbreaks, use of antiretroviral therapy (ART) and degree of CD4 lymphopaenia have not been described. We observed a sustained rise in the number of S. flexneri isolates and related hospital admissions in an urban tertiary-care hospital, and hypothesized that increased transmission may be occurring in the local MSM population. We performed a retrospective review to define the at-risk population and evaluated the clinical courses and outcomes of their infections. Subsequently, and in cooperation with our local Public Health department, we reviewed epidemiological surveillance data for our city and province to identify any changes in shigellosis rates at these levels.
Methods Setting This study took place at St Paul’s Hospital (SPH), a 435-bed tertiary care centre in downtown Vancouver, British
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Columbia (BC), Canada. SPH has a dedicated 20-bed HIV medical ward. SPH also houses the BC Centre for Excellence in HIV/AIDS, which provides medical services via primary care and specialty clinics for a large proportion of HIV-infected patients in BC and dispenses ART for the entire province. The Medical Microbiology Laboratory at SPH serves the hospital and associated out-patient clinics, and accepts out-patient community specimens from nearby clinics. From a Public Health perspective, Vancouver is considered a health service delivery area (HSDA) within the Vancouver Coastal Health (VCH) region, and is divided geographically into six community health areas (CHAs). CHA-1 represents the Vancouver city centre region in which SPH is located, and where a large population of MSM reside [9]. Shigellosis is a reportable communicable disease in BC; as such all laboratory-diagnosed cases are reported to (and followed up by) the regional Environmental Health Officer, using a standardized case report form [10].
Study design Shigella cases in Vancouver residents 20 to 59 years old were extracted from the Vancouver Coastal Health Reportable Communicable Diseases Information System from 2005 to 2011, based on episode date. The patient’s residential postal code was used to define the geographical area in Vancouver in which they resided. The provincial count of BC cases was extracted from the BC Annual Summary of Reportable Diseases for 2005−2011 [11]. For S. flexneri isolates collected from 2008 to 2012 at SPH, a hospital chart review was performed using a standardized data extraction tool. Information collected included demographics, travel and sexual history. HIV status was also collected, as were use of ART at time of shigellosis and CD4 count and HIV plasma viral load taken from most recent blood work within 6 months prior to the episode of shigellosis, if available, and at the time of shigellosis if not. Additionally, if available in the health record, symptoms, vital signs, serum creatinine values, and white blood cell count (WBC) at presentation were collected. Complications of shigellosis such as bacteraemias, reactive arthritis and death were examined, as was health care use with respect to emergency department (ED) visits and hospitalizations. VCH Public Health shigellosis case forms were reviewed for available cases, with symptoms at presentation, antibiotic use, travel within 4 days prior to onset and sexual history being extracted. This study was performed with the approval of the Providence Health Care and University of British Columbia research ethics boards.
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170 A Wilmer et al.
Microbiology Stool and blood culture specimens were routinely worked up as per established guidelines [12]. Isolates underwent identification and susceptibility testing by Vitek2 (bioMérieux, Marcy l’Etoile, France), with confirmation via antisera for somatic O antigen (Remel, Lenexa, KS). Shigella flexneri serotyping was performed at the BC Public Health Microbiology and Reference Laboratory (BCPHMRL) (Denka Seiken, Tokyo, Japan). Pulsed-field gel electrophoresis (PFGE) was also performed, using the XbaI enzyme, at the BCPHRML and results were interpreted according to standards set by PulseNet Canada [13]. Serotyping data for all adult patients in the province with S. flexneri isolates submitted to the BCPHMRL for testing were extracted from 2008 to 2012, with the proportion of serotype 1 isolates compared with the proportions of serotype 3 isolates and other serotypes.
Data analysis Case counts were summarized by age, sex and CHA. To calculate the population rate of shigellosis in each strata by age, sex, and geographical area in Vancouver and BC, population estimates in each given time period were used, provided by BC Stats [14]. The χ2 test was used to determine the statistical significance of differences between rates. We also compared the risk for shigellosis infection between residents of CHA-1, Vancouver (excluding CHA-1)
and BC (excluding CHA-1) using relative risk and its corresponding 95% confidence interval (CI) from Woolf’s estimate, by sex and health region. Analyses of proportion trends were performed using a user-written program PTREND to regress the proportion on time period. SPH S. flexneri cases were analysed comparing admitted versus nonadmitted patients. All tests were two-tailed and were carried out at a significance level of α = 0.05. All analyses were conducted with STATA 12 software, version 12.1 (Statacorp, College Station, TX, USA).
Results From 2005 to 2011, rates of shigellosis in adult male individuals in the CHA-1 region remained elevated (range 33.4 to 68.5 per 100 000) and did not change significantly (P = 0.74 for trend) (Fig. 1). However, these rates were significantly higher than rates for men residing in other regions of Vancouver as well as other regions of BC (Table 1), in whom shigellosis rates were actually declining in this period (P = 0.02 and P = 0.003 for trends, respectively) (Fig. 1). The male to female relative risk in the CHA-1 region varied from 3.1 (95% CI 1.2 to 7.7) in 2008 to 18.8 (95% CI 2.5 to 139.9) in 2011, with values for all years being statistically significant (P ≤ 0.01). Shigella flexneri rates in adult male individuals in the CHA-1 region increased significantly from 2.3 per 100 000 of population in 2005 to a peak of 51.4 per 100 000 in
Fig. 1 Incidence of Shigella flexneri infection (a) and overall shigellosis (b) in men 20–59 years old in Vancouver city centre (community health area 1), other regions of Vancouver and the province of British Columbia from 2005 to 2011.
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Table 1 Relative risk (RR) of shigellosis in men 20 to 59 years old in Vancouver city centre [community health area 1 (CHA-1)] compared with other regions in Vancouver and the province of British Columbia
Year
CHA-1 vs. other regions of Vancouver [RR (95% CI)]
CHA-1 vs. other regions of province [RR (95% CI)]
2005 2006 2007 2008 2009 2010 2011
3.9 8.7 2.1 2.5 7.5 6.3 4.8
10.6 (7.0, 16.3) 10.6 (5.8, 19.3) 8.1 (5.3, 12.2) 7.0 (4.3, 11.5) 14.8 (9.6, 22.8) 12.9 (8.2, 20.3) 13.3 (7.8, 22.8)
(2.3, (3.4, (1.3, (1.4, (4.0, (3.4, (2.5,
6.6) 22.4) 3.4) 4.4) 13.8) 11.7) 9.4)
CI, confidence interval.
Table 2 Relative risk (RR) of Shigella flexneri in individuals 20 to 59 years old in Vancouver city centre [community health area 1 (CHA-1)] compared with other regions in Vancouver
Year
Male patients in CHA-1 vs. other regions of Vancouver [RR (95% CI)]
Male to female ratio in CHA-1 vs. other regions of Vancouver [RR (95% CI)]
2005 2006 2007 2008 2009 2010 2011
1.8 3.5 3.4 3.1 6.4 6.7 5.3
*
(0.2, (0.5, (0.2, (1.3, (3.2, (3.4, (2.4,
19.5) 24.7) 55.0) 7.7) 12.9) 13.1) 11.4)
1.8 (0.2, 20.4) * 8.4 (1.1, 66.3) 6.9 (2.1, 23.0) 22.6 (3.1, 167.1) *
CI, confidence interval. *Unable to estimate as no cases in women in CHA-1 during these years.
2010 (P < 0.001 for trend) (Fig. 1). From 2008 onwards, the relative risk for S. flexneri infection was significantly higher in men in the CHA-1 region compared with other regions of Vancouver (Table 2). Additionally, the relative risk of cases in the CHA-1 region compared with other regions of Vancouver was significantly higher for men than women from 2008 onwards (Table 2). From 2008 to 2012, 343 of 403 (85.1%) provincial S. flexneri isolates were referred to the BCPHMRL for serotyping, with 237 identified from adults 20 to 59 years old, 72.6% of whom were male. In men, the proportion of serotype 1 isolates peaked at 75.0% in 2010, then declined, while the proportion of serotype 3 isolates increased from 2010 onwards, and peaked at 43.6% in 2012 (data not shown). From 2008 to 2012, 79 unique S. flexneri isolates from 72 patients were identified at SPH, representing 43.1% of male patients with S. flexneri infection reported to VCH Public Health from 2008 to 2011. All 72 patients were male, with 66 (91.7%) identified in the health record as MSM. Sixty-two of 72 patients (86.1%) were HIV-infected at the time of shigellosis, with an additional patient diagnosed as
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Table 3 Characteristics of St Paul’s Hospital patients with shigellosis, comparing admitted versus not admitted patients, 2008 to 2012
Patient characteristics
Admitted (n = 30)
Not admitted (n = 49)
P-value
Age (years) [median (range)] Male sex MSM High-risk travel HIV-infected Antiretroviral therapy CD4 < 200 cells/μL CD4 > 500 cells/μL Viral load undetectable Viral load > 1000 copies/mL Creatinine > 120 mmol/L WBC ≥ 12 or ≤ 4 giga/L Blood culture drawn Blood cultures positive SBP < 90 mm Hg T > 38°C HR > 90 beats/min Death Shigella flexneri serotype 1 Shigella flexneri serotype 3
43.5 (27–70) 30/30 (100.0) 29/29 (100.0) 1/30 (3.3) 28/30 (93.3) 22/28 (78.6) 0/28 (0.0) 10/28 (35.7) 16/28 (57.1) 7/28 (25.0) 5/30 (16.7) 10/30 (33.3) 26/30 (86.7) 3/30 (10.0) 3/29 (10.3) 11/29 (37.9) 26/29 (89.7) 0/30 (0.0) 20/21 (95.2) 1/21 (4.8)
45 (26–66) 49/49 (100.0) 44/44 (100.0) 1/29 (3.4) 41/49 (83.7) 35/41 (85.4) 5/40 (12.5) 16/40 (40.0) 29/41 (70.7) 8/41 (19.5) 0/18 (0.0) 4/21 (19.0) 4/49 (8.2) 0/4 (0.0) 1/19 (5.3) 2/19 (10.5) 9/19* (47.4) 0/49 (0.0) 28/34 (82.4) 6/34 (17.6)
NS NS NS NS NS NS NS NS NS NS NS NS 200 cells/μL in over 90% of cases and > 500 cells/μL in nearly 40% of cases. A review of cases of individuals with Shigella sterile site infection admitted to sentinel surveillance hospitals in South Africa from 2003 to
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2009 demonstrated that 67% (80 of 120) of patients with HIV testing available were positive, of whom 55 (69%) were female and 56 (70%) were adults [16]. Of these adult patients, only two were on ART, and 75% (18 of 24) of patients with available CD4 counts had values < 50 cells/μL. In total, 39% of adult patients died. The predominance of adult female patients in the study was postulated to reflect the role of women in child care practices in South Africa, with caregivers acquiring infection from children, in whom shigellosis was most prevalent. As no other cause of immunocompromise was significantly associated with invasive shigellosis in the predominantly female adult patients in this study, this suggests that more advanced HIV infection increases susceptibility to invasive shigellosis. Similar to the South African study, most reports of Shigella bloodstream infection in the literature describe invasive infection in patients with AIDS in the era before access to highly active ART [17–23]. In our study, although HIV infection was more prevalent (87.3%), only three cases of bloodstream infection were detected and no mortality was observed. Given the high prevalence of HIVinfected individuals, our study is consistent with other studies which have shown an association between increased susceptibility to shigellosis and HIV infection. However, patients in our study were relatively immunocompetent, suggesting that shigellosis may have been related more to unprotected sexual activities. While multiple reports of shigellosis in MSM populations exist, documentation of related hospitalizations has been limited. In our hospital-based study, which describes almost half of all cases of S. flexneri infection in adult male individuals occurring in Vancouver during the study period, we found that 30 of 79 (38.0%) cases resulted in hospitalization over a 5-year period, with a median stay of 3 days (range 1 to 23 days). Laboratory-based surveillance data from San Francisco county described hospitalization in 11% of cases, in a population that was 51% MSM and 39% HIV-infected [7]. In non-MSM foodborne or waterborne shigellosis outbreaks, the proportion of individuals hospitalized varies widely in the literature, ranging from 15% to upwards of 70% in patients over the age of 65 years [24–27]. Length of hospitalization was described in a foodborne outbreak of S. sonnei infection in Norway in 1994, during which 17% of interviewed patients were hospitalized, for a median of 4 days [25]. Patients with invasive shigellosis in South Africa, in whom the HIV prevalence was 67%, were hospitalized for a median of 7 days. The proportion of patients hospitalized and the duration of hospitalization appear to be considerable in both HIV-infected and noninfected patients with shigellosis. Shifts in Shigella species (species or subtype replacement) causing outbreaks in MSM have been described in several parts of the world [28–31]. In London, over the
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period 2004 − 2005, an outbreak of S. sonnei infection occurred in the MSM population, and nearly all the individuals with S. sonnei infection were also found to be HIV-infected [28]. More recently (2009–2011), and in contrast to previous reports, an outbreak of S. flexneri serotype 3 infection was demonstrated in the MSM population in the UK [29]. Interestingly, in our population, S. flexneri serotype 1 infection peaked initially in 2009–2010, followed by a rise in serotype 3 infection starting in 2010. In Montreal, Canada, analysis of public health surveillance data revealed that S. flexneri had become the predominant cause of shigellosis in MSM in 2009, after an outbreak of S. sonnei infection in the MSM population ended in 2008 [30]. Investigators in Toronto have also reported a shift towards dominance of S. flexneri in their MSM population in 2009 [31]. The reason for this shift is unknown, although development of herd immunity to S. sonnei in the MSM population has been previously hypothesized [32]. Because our study focused on laboratory-based surveillance, the number of cases presented probably underestimates the true burden of S. flexneri infection in the community, as only cases in which patients had stool cultures submitted for testing would have been detected and subsequently reported to the local Public Health department. Additionally, some outbreak investigations have described asymptomatically colonized individuals with Shigella, who would not be detected through our passive surveillance methods [33,34]. However, previous rectal cultures in asymptomatic MSM presenting to a sexually transmitted disease clinic in an outbreak setting did not detect additional cases, suggesting that the prevalence of asymptomatically colonized MSM is low [35]. In addition to rectal screening cultures in asymptomatic MSM, other public health interventions have been described during previous outbreaks. Most of these measures have common themes, including raising awareness through media releases to the general public, as well as targeted communication to both relevant medical practitioners and the MSM community [29,35,36]. In our region, a public health bulletin was distributed in January 2009, alerting clinicians to increased S. flexneri transmission in the MSM population, and promoting treatment of these patients. Since that point, ongoing transmission has occurred, with no significant changes in shigellosis rates within this population. In our region, shigellosis cases are followed up by environmental health officers (EHOs), who are primarily trained in the detection of foodborne and waterborne outbreaks of enteric infections with no formal training related to follow-up of sexually transmitted infections. Although prompted to ask about oral−anal activity in shigellosis cases, the EHOs do not provide any standardized educational messaging specific to MSM or
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perform sexual contact tracing for these cases. Conversely, follow-up and contact tracing of other sexually transmitted infections in the region is performed by public health nurses with specialized training. Shigellosis continues to be a challenge, as a sexually transmitted enteric infection, and requires further study to develop an optimal approach to follow-up and interruption of disease transmission. In conclusion, we have demonstrated a significant change in the epidemiology of shigellosis in Vancouver, with transmission of a primarily clonal strain of S. flexneri serotype 1 replacing the previously circulating S. sonnei in 2009. Nearly all documented S. flexneri infections occurred in HIV-infected patients, resulting in significant complications, including hospitalizations and bacteraemias. Focused public health interventions may be required to control shigellosis in this population.
Acknowledgements Thanks to Anna Wong for assisting in data extraction and James Chan for assisting with data management. There was no financial support for this work.
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ORIGINAL RESEARCH
Shigella flexneri serotype 1 infections in men who have sex with men in Vancouver, Canada A Wilmer,1 MG Romney,1,2 R Gustafson,3 J Sandhu,4 T Chu,4 C Ng,5 L Hoang,1,5 S Champagne1,2 and MW Hull6,7 Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada, 2Department of Pathology & Laboratory Medicine, Division of Medical Microbiology, St. Paul’s Hospital, Vancouver, BC, Canada, 3 Communicable Disease Control, Vancouver Coastal Health, Vancouver, BC, Canada, 4Public Health Surveillance Unit, Vancouver Coastal Health, Vancouver, BC, Canada, 5British Columbia Centre for Disease Control, Public Health Microbiology & Reference Laboratory, Division of Mycology and Bacteriology, Vancouver, BC, Canada, 6Department of Medicine, University of British Columbia, Vancouver, BC, Canada and 7BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada 1
Objectives
Outbreaks of shigellosis have been documented in men who have sex with men (MSM), associated with interpersonal transmission and underlying HIV infection. We observed a rise in Shigella flexneri isolates identified in a downtown tertiary-care hospital laboratory located within the city centre community health area (CHA-1) of Vancouver, Canada. The objectives of this study were to evaluate clinical outcomes of shigellosis cases among MSM admitted to hospital and to evaluate trends in Shigella cases within Vancouver, Canada. Methods
Adult rates of shigellosis were analysed by gender and health region, from 2005 to 2011, followed by retrospective chart review of all hospital laboratory-identified S. flexneri cases from 2008 to 2012. Serotyping and pulsed-field gel electrophoresis (PFGE) were performed on these isolates. Results
Although shigellosis rates in men within CHA-1 did not change from 2005 to 2011 (range 33.4–68.5 per 100 000; P = 0.74), they were significantly higher than in other regions within the city of Vancouver (P ≤ 0.001) and the province of British Columbia (P ≤ 0.001). Shigella flexneri rates in men within CHA-1 increased significantly (range 2.3–51.4 per 100 000; P < 0.001), starting in 2008, and were higher than in other regions within Vancouver (P ≤ 0.01). Seventy-nine isolates of S. flexneri from 72 patients were identified by a single hospital laboratory. All patients were male and predominantly MSM (91.7%) and HIV-infected (86.1%), with most (92.6%) demonstrating CD4 counts ≥ 200 cells/μL. In total, 38.0% required hospitalization. Most (87.3%) had S. flexneri serotype 1 infection, with 72.9% of these representing a single PFGE pattern. Conclusions
We identified high levels of transmission of a primarily clonal strain of S. flexneri serotype 1 in our local MSM population, resulting in a substantial burden of illness and health care resource use secondary to hospital admissions. Keywords: HIV, homosexuality, male, Shigella Accepted 9 July 2014
Introduction Shigellosis is an acute intestinal infection caused by Shigella species, including Shigella flexneri, Shigella sonnei, Shigella dysenteriae and Shigella boydii [1]. These organisms are
Correspondence: Dr Mark Hull, BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital, 608-1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel: 604 806 8640; fax: 604 806 8527; e-mail: [email protected]
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transmitted via direct or indirect faecal−oral contact, and are highly transmissible, with as few as 100 organisms able to establish infection [1,2]. The incubation period is typically 12 to 96 hours, followed by the onset of watery, bloody or mucoid diarrhoea, abdominal cramps, nausea and fever, which last 4 to 7 days [1]. Rare complications of shigellosis include sepsis, reactive arthritis and haemolytic uraemic syndrome (HUS) [1]. Shigellosis has long been recognized as a possible sexually transmitted infection (STI) in men who have sex with men (MSM) [3–5]. From 1970 to 1985, a significant demographic shift occurred in the USA with respect to S. flexneri infection, with a more than fivefold increase in the infection rate in men 30 to 39 years old, despite no change in women of comparable age [6]. MSM transmission was felt to be a likely explanation for this change, with acquisition thought to be related to sexual practices of oral−anal and oral−genital contact [6]. In 1996, HIV was also identified as an important risk factor for shigellosis, after higher rates of Shigella infection were noted in a population that was significantly more likely to be adult, male and HIV-infected [7]. A case−control study was performed in the San Francisco area during a nonoutbreak period from 1998 to 1999, with multivariate analysis demonstrating a significant association of shigellosis with MSM, HIV infection, direct oral−anal contact and foreign travel [8]. Shigella flexneri appeared to be the predominant species in MSM during that period and, compared with S. sonnei, was significantly associated with MSM, HIV infection, direct anal contact, and lack of foreign travel [8]. Despite numerous MSM shigellosis outbreaks documented in the literature, little is known regarding the clinical course and outcomes of infections in this population. Additionally, for the HIV-infected patients involved in these outbreaks, use of antiretroviral therapy (ART) and degree of CD4 lymphopaenia have not been described. We observed a sustained rise in the number of S. flexneri isolates and related hospital admissions in an urban tertiary-care hospital, and hypothesized that increased transmission may be occurring in the local MSM population. We performed a retrospective review to define the at-risk population and evaluated the clinical courses and outcomes of their infections. Subsequently, and in cooperation with our local Public Health department, we reviewed epidemiological surveillance data for our city and province to identify any changes in shigellosis rates at these levels.
Methods Setting This study took place at St Paul’s Hospital (SPH), a 435-bed tertiary care centre in downtown Vancouver, British
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Columbia (BC), Canada. SPH has a dedicated 20-bed HIV medical ward. SPH also houses the BC Centre for Excellence in HIV/AIDS, which provides medical services via primary care and specialty clinics for a large proportion of HIV-infected patients in BC and dispenses ART for the entire province. The Medical Microbiology Laboratory at SPH serves the hospital and associated out-patient clinics, and accepts out-patient community specimens from nearby clinics. From a Public Health perspective, Vancouver is considered a health service delivery area (HSDA) within the Vancouver Coastal Health (VCH) region, and is divided geographically into six community health areas (CHAs). CHA-1 represents the Vancouver city centre region in which SPH is located, and where a large population of MSM reside [9]. Shigellosis is a reportable communicable disease in BC; as such all laboratory-diagnosed cases are reported to (and followed up by) the regional Environmental Health Officer, using a standardized case report form [10].
Study design Shigella cases in Vancouver residents 20 to 59 years old were extracted from the Vancouver Coastal Health Reportable Communicable Diseases Information System from 2005 to 2011, based on episode date. The patient’s residential postal code was used to define the geographical area in Vancouver in which they resided. The provincial count of BC cases was extracted from the BC Annual Summary of Reportable Diseases for 2005−2011 [11]. For S. flexneri isolates collected from 2008 to 2012 at SPH, a hospital chart review was performed using a standardized data extraction tool. Information collected included demographics, travel and sexual history. HIV status was also collected, as were use of ART at time of shigellosis and CD4 count and HIV plasma viral load taken from most recent blood work within 6 months prior to the episode of shigellosis, if available, and at the time of shigellosis if not. Additionally, if available in the health record, symptoms, vital signs, serum creatinine values, and white blood cell count (WBC) at presentation were collected. Complications of shigellosis such as bacteraemias, reactive arthritis and death were examined, as was health care use with respect to emergency department (ED) visits and hospitalizations. VCH Public Health shigellosis case forms were reviewed for available cases, with symptoms at presentation, antibiotic use, travel within 4 days prior to onset and sexual history being extracted. This study was performed with the approval of the Providence Health Care and University of British Columbia research ethics boards.
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Microbiology Stool and blood culture specimens were routinely worked up as per established guidelines [12]. Isolates underwent identification and susceptibility testing by Vitek2 (bioMérieux, Marcy l’Etoile, France), with confirmation via antisera for somatic O antigen (Remel, Lenexa, KS). Shigella flexneri serotyping was performed at the BC Public Health Microbiology and Reference Laboratory (BCPHMRL) (Denka Seiken, Tokyo, Japan). Pulsed-field gel electrophoresis (PFGE) was also performed, using the XbaI enzyme, at the BCPHRML and results were interpreted according to standards set by PulseNet Canada [13]. Serotyping data for all adult patients in the province with S. flexneri isolates submitted to the BCPHMRL for testing were extracted from 2008 to 2012, with the proportion of serotype 1 isolates compared with the proportions of serotype 3 isolates and other serotypes.
Data analysis Case counts were summarized by age, sex and CHA. To calculate the population rate of shigellosis in each strata by age, sex, and geographical area in Vancouver and BC, population estimates in each given time period were used, provided by BC Stats [14]. The χ2 test was used to determine the statistical significance of differences between rates. We also compared the risk for shigellosis infection between residents of CHA-1, Vancouver (excluding CHA-1)
and BC (excluding CHA-1) using relative risk and its corresponding 95% confidence interval (CI) from Woolf’s estimate, by sex and health region. Analyses of proportion trends were performed using a user-written program PTREND to regress the proportion on time period. SPH S. flexneri cases were analysed comparing admitted versus nonadmitted patients. All tests were two-tailed and were carried out at a significance level of α = 0.05. All analyses were conducted with STATA 12 software, version 12.1 (Statacorp, College Station, TX, USA).
Results From 2005 to 2011, rates of shigellosis in adult male individuals in the CHA-1 region remained elevated (range 33.4 to 68.5 per 100 000) and did not change significantly (P = 0.74 for trend) (Fig. 1). However, these rates were significantly higher than rates for men residing in other regions of Vancouver as well as other regions of BC (Table 1), in whom shigellosis rates were actually declining in this period (P = 0.02 and P = 0.003 for trends, respectively) (Fig. 1). The male to female relative risk in the CHA-1 region varied from 3.1 (95% CI 1.2 to 7.7) in 2008 to 18.8 (95% CI 2.5 to 139.9) in 2011, with values for all years being statistically significant (P ≤ 0.01). Shigella flexneri rates in adult male individuals in the CHA-1 region increased significantly from 2.3 per 100 000 of population in 2005 to a peak of 51.4 per 100 000 in
Fig. 1 Incidence of Shigella flexneri infection (a) and overall shigellosis (b) in men 20–59 years old in Vancouver city centre (community health area 1), other regions of Vancouver and the province of British Columbia from 2005 to 2011.
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Table 1 Relative risk (RR) of shigellosis in men 20 to 59 years old in Vancouver city centre [community health area 1 (CHA-1)] compared with other regions in Vancouver and the province of British Columbia
Year
CHA-1 vs. other regions of Vancouver [RR (95% CI)]
CHA-1 vs. other regions of province [RR (95% CI)]
2005 2006 2007 2008 2009 2010 2011
3.9 8.7 2.1 2.5 7.5 6.3 4.8
10.6 (7.0, 16.3) 10.6 (5.8, 19.3) 8.1 (5.3, 12.2) 7.0 (4.3, 11.5) 14.8 (9.6, 22.8) 12.9 (8.2, 20.3) 13.3 (7.8, 22.8)
(2.3, (3.4, (1.3, (1.4, (4.0, (3.4, (2.5,
6.6) 22.4) 3.4) 4.4) 13.8) 11.7) 9.4)
CI, confidence interval.
Table 2 Relative risk (RR) of Shigella flexneri in individuals 20 to 59 years old in Vancouver city centre [community health area 1 (CHA-1)] compared with other regions in Vancouver
Year
Male patients in CHA-1 vs. other regions of Vancouver [RR (95% CI)]
Male to female ratio in CHA-1 vs. other regions of Vancouver [RR (95% CI)]
2005 2006 2007 2008 2009 2010 2011
1.8 3.5 3.4 3.1 6.4 6.7 5.3
*
(0.2, (0.5, (0.2, (1.3, (3.2, (3.4, (2.4,
19.5) 24.7) 55.0) 7.7) 12.9) 13.1) 11.4)
1.8 (0.2, 20.4) * 8.4 (1.1, 66.3) 6.9 (2.1, 23.0) 22.6 (3.1, 167.1) *
CI, confidence interval. *Unable to estimate as no cases in women in CHA-1 during these years.
2010 (P < 0.001 for trend) (Fig. 1). From 2008 onwards, the relative risk for S. flexneri infection was significantly higher in men in the CHA-1 region compared with other regions of Vancouver (Table 2). Additionally, the relative risk of cases in the CHA-1 region compared with other regions of Vancouver was significantly higher for men than women from 2008 onwards (Table 2). From 2008 to 2012, 343 of 403 (85.1%) provincial S. flexneri isolates were referred to the BCPHMRL for serotyping, with 237 identified from adults 20 to 59 years old, 72.6% of whom were male. In men, the proportion of serotype 1 isolates peaked at 75.0% in 2010, then declined, while the proportion of serotype 3 isolates increased from 2010 onwards, and peaked at 43.6% in 2012 (data not shown). From 2008 to 2012, 79 unique S. flexneri isolates from 72 patients were identified at SPH, representing 43.1% of male patients with S. flexneri infection reported to VCH Public Health from 2008 to 2011. All 72 patients were male, with 66 (91.7%) identified in the health record as MSM. Sixty-two of 72 patients (86.1%) were HIV-infected at the time of shigellosis, with an additional patient diagnosed as
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Table 3 Characteristics of St Paul’s Hospital patients with shigellosis, comparing admitted versus not admitted patients, 2008 to 2012
Patient characteristics
Admitted (n = 30)
Not admitted (n = 49)
P-value
Age (years) [median (range)] Male sex MSM High-risk travel HIV-infected Antiretroviral therapy CD4 < 200 cells/μL CD4 > 500 cells/μL Viral load undetectable Viral load > 1000 copies/mL Creatinine > 120 mmol/L WBC ≥ 12 or ≤ 4 giga/L Blood culture drawn Blood cultures positive SBP < 90 mm Hg T > 38°C HR > 90 beats/min Death Shigella flexneri serotype 1 Shigella flexneri serotype 3
43.5 (27–70) 30/30 (100.0) 29/29 (100.0) 1/30 (3.3) 28/30 (93.3) 22/28 (78.6) 0/28 (0.0) 10/28 (35.7) 16/28 (57.1) 7/28 (25.0) 5/30 (16.7) 10/30 (33.3) 26/30 (86.7) 3/30 (10.0) 3/29 (10.3) 11/29 (37.9) 26/29 (89.7) 0/30 (0.0) 20/21 (95.2) 1/21 (4.8)
45 (26–66) 49/49 (100.0) 44/44 (100.0) 1/29 (3.4) 41/49 (83.7) 35/41 (85.4) 5/40 (12.5) 16/40 (40.0) 29/41 (70.7) 8/41 (19.5) 0/18 (0.0) 4/21 (19.0) 4/49 (8.2) 0/4 (0.0) 1/19 (5.3) 2/19 (10.5) 9/19* (47.4) 0/49 (0.0) 28/34 (82.4) 6/34 (17.6)
NS NS NS NS NS NS NS NS NS NS NS NS 200 cells/μL in over 90% of cases and > 500 cells/μL in nearly 40% of cases. A review of cases of individuals with Shigella sterile site infection admitted to sentinel surveillance hospitals in South Africa from 2003 to
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2009 demonstrated that 67% (80 of 120) of patients with HIV testing available were positive, of whom 55 (69%) were female and 56 (70%) were adults [16]. Of these adult patients, only two were on ART, and 75% (18 of 24) of patients with available CD4 counts had values < 50 cells/μL. In total, 39% of adult patients died. The predominance of adult female patients in the study was postulated to reflect the role of women in child care practices in South Africa, with caregivers acquiring infection from children, in whom shigellosis was most prevalent. As no other cause of immunocompromise was significantly associated with invasive shigellosis in the predominantly female adult patients in this study, this suggests that more advanced HIV infection increases susceptibility to invasive shigellosis. Similar to the South African study, most reports of Shigella bloodstream infection in the literature describe invasive infection in patients with AIDS in the era before access to highly active ART [17–23]. In our study, although HIV infection was more prevalent (87.3%), only three cases of bloodstream infection were detected and no mortality was observed. Given the high prevalence of HIVinfected individuals, our study is consistent with other studies which have shown an association between increased susceptibility to shigellosis and HIV infection. However, patients in our study were relatively immunocompetent, suggesting that shigellosis may have been related more to unprotected sexual activities. While multiple reports of shigellosis in MSM populations exist, documentation of related hospitalizations has been limited. In our hospital-based study, which describes almost half of all cases of S. flexneri infection in adult male individuals occurring in Vancouver during the study period, we found that 30 of 79 (38.0%) cases resulted in hospitalization over a 5-year period, with a median stay of 3 days (range 1 to 23 days). Laboratory-based surveillance data from San Francisco county described hospitalization in 11% of cases, in a population that was 51% MSM and 39% HIV-infected [7]. In non-MSM foodborne or waterborne shigellosis outbreaks, the proportion of individuals hospitalized varies widely in the literature, ranging from 15% to upwards of 70% in patients over the age of 65 years [24–27]. Length of hospitalization was described in a foodborne outbreak of S. sonnei infection in Norway in 1994, during which 17% of interviewed patients were hospitalized, for a median of 4 days [25]. Patients with invasive shigellosis in South Africa, in whom the HIV prevalence was 67%, were hospitalized for a median of 7 days. The proportion of patients hospitalized and the duration of hospitalization appear to be considerable in both HIV-infected and noninfected patients with shigellosis. Shifts in Shigella species (species or subtype replacement) causing outbreaks in MSM have been described in several parts of the world [28–31]. In London, over the
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period 2004 − 2005, an outbreak of S. sonnei infection occurred in the MSM population, and nearly all the individuals with S. sonnei infection were also found to be HIV-infected [28]. More recently (2009–2011), and in contrast to previous reports, an outbreak of S. flexneri serotype 3 infection was demonstrated in the MSM population in the UK [29]. Interestingly, in our population, S. flexneri serotype 1 infection peaked initially in 2009–2010, followed by a rise in serotype 3 infection starting in 2010. In Montreal, Canada, analysis of public health surveillance data revealed that S. flexneri had become the predominant cause of shigellosis in MSM in 2009, after an outbreak of S. sonnei infection in the MSM population ended in 2008 [30]. Investigators in Toronto have also reported a shift towards dominance of S. flexneri in their MSM population in 2009 [31]. The reason for this shift is unknown, although development of herd immunity to S. sonnei in the MSM population has been previously hypothesized [32]. Because our study focused on laboratory-based surveillance, the number of cases presented probably underestimates the true burden of S. flexneri infection in the community, as only cases in which patients had stool cultures submitted for testing would have been detected and subsequently reported to the local Public Health department. Additionally, some outbreak investigations have described asymptomatically colonized individuals with Shigella, who would not be detected through our passive surveillance methods [33,34]. However, previous rectal cultures in asymptomatic MSM presenting to a sexually transmitted disease clinic in an outbreak setting did not detect additional cases, suggesting that the prevalence of asymptomatically colonized MSM is low [35]. In addition to rectal screening cultures in asymptomatic MSM, other public health interventions have been described during previous outbreaks. Most of these measures have common themes, including raising awareness through media releases to the general public, as well as targeted communication to both relevant medical practitioners and the MSM community [29,35,36]. In our region, a public health bulletin was distributed in January 2009, alerting clinicians to increased S. flexneri transmission in the MSM population, and promoting treatment of these patients. Since that point, ongoing transmission has occurred, with no significant changes in shigellosis rates within this population. In our region, shigellosis cases are followed up by environmental health officers (EHOs), who are primarily trained in the detection of foodborne and waterborne outbreaks of enteric infections with no formal training related to follow-up of sexually transmitted infections. Although prompted to ask about oral−anal activity in shigellosis cases, the EHOs do not provide any standardized educational messaging specific to MSM or
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perform sexual contact tracing for these cases. Conversely, follow-up and contact tracing of other sexually transmitted infections in the region is performed by public health nurses with specialized training. Shigellosis continues to be a challenge, as a sexually transmitted enteric infection, and requires further study to develop an optimal approach to follow-up and interruption of disease transmission. In conclusion, we have demonstrated a significant change in the epidemiology of shigellosis in Vancouver, with transmission of a primarily clonal strain of S. flexneri serotype 1 replacing the previously circulating S. sonnei in 2009. Nearly all documented S. flexneri infections occurred in HIV-infected patients, resulting in significant complications, including hospitalizations and bacteraemias. Focused public health interventions may be required to control shigellosis in this population.
Acknowledgements Thanks to Anna Wong for assisting in data extraction and James Chan for assisting with data management. There was no financial support for this work.
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