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Gut Online First, published on June 12, 2015 as 10.1136/gutjnl-2015-309460 Neurogastroenterology
ORIGINAL ARTICLE
Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis Mira Wouters,1 Sander Van Wanrooy,1 Anh Nguyen,2,3 James Dooley,2,3 Javier Aguilera-Lizarraga,1 Winde Van Brabant,1 Josselyn E Garcia-Perez,2,3 Lukas Van Oudenhove,1 Marc Van Ranst,4 Jan Verhaegen,5 Adrian Liston,2,3 Guy Boeckxstaens1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ gutjnl-2015-309460). 1
Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium 2 Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium 3 Autoimmune Genetics Laboratory, VIB, Leuven, Belgium 4 Laboratory of Clinical Virology, Rega Institute for Medical Research, University Hospital Leuven, Leuven, Belgium 5 Department of Microbiology, University Hospital Leuven, KU Leuven, Leuven, Belgium Correspondence to Professor Guy Boeckxstaens Translational Research Center for Gastrointestinal Disorders (TARGID), Center of Neuroimmune interaction and Mucosal Immunology, KU Leuven, University Hospital of Leuven, Herestraat 49, Leuven 3000, Belgium; guy.boeckxstaens@med. kuleuven.be MW, SVW and AN contributed equally. Received 25 February 2015 Revised 18 May 2015 Accepted 19 May 2015
ABSTRACT Objective Psychological factors increase the risk to develop postinfectious IBS (PI-IBS), but the mechanisms involved are unclear. As stress affects the immune system, we investigated the potential interaction between psychological factors, the immune response against infectious gastroenteritis (IGE) and the development of IGE and PI-IBS in a large cohort exposed to contaminated drinking water. Design 18 620 people exposed to contaminated drinking water (norovirus, Giardia lamblia, Campylobacter jejuni) were invited to participate in a prospective controlled cohort study. They were asked to complete questionnaires assessing demographic, psychological and clinical data during the outbreak and 1 year later. At both time points, in-depth immune function ( peripheral blood and rectal biopsies) was studied in a subgroup of subjects. Results 1379 subjects completed the questionnaires during the outbreak, of which 271 developed IGE. Risk factors for IGE included younger age, pre-existing dyspepsia-like symptoms, anxiety and drinking contaminated tap water. Anxiety scores before the outbreak inversely correlated with interleukin-2expressing CD4+ T cells (r=0.6, p=0.01, n=23). At follow-up, 34 of 172 (20%) IGE subjects developed IBS compared with 24/366 exposed participants (7%, p10 were considered to be abnormal.27 28 Statistical analysis, gene expression studies, PBMC immunephenotyping and cytokine analysis in plasma and in supernatants of stimulated PBMCs are described in online supplementary material and methods.
Fifty-six faecal samples were collected from subjects clinically diagnosed with IGE, of which 26 specimens tested positive for an infectious pathogenic agent. Norovirus (NoV) GI.4, GII.4, GII.14 and GII.7 was most frequently detected (15/56), followed by Giardia lamblia (5/56), Campylobacter ssp. (4/56), adenovirus (1/56) and rotavirus A (1/56). Two patients were positive for more than one infectious agent: one with NoV GI.4 and GII.4, and one with C. jejuni and NoV GI.4 and GII.7.
Risk factors underlying the susceptibility to develop IGE Participants were asked to provide information on their consumption and use of the drinking water. Thirty-nine per cent of inhabitants drank tap water with an average of 3.7 glasses per day while almost all subjects used tap water to brush their teeth (98%) or to wash vegetables and fruit (97%). As previous studies indicated psychological factors as risk factor to develop PI-IBS, subjects were asked to complete the HADS and PHQ-12 questionnaires to assess anxiety, depression and somatisation 2 and 4 weeks before the outbreak, respectively.
RESULTS Characterisation of patient cohort: Early phase Patient cohort Between 6 and 9 December 2010, 18 620 residents in 7711 households in Hemiksem and Schelle were exposed to contaminated tap water and asked to participate in our study. A total of 1379 subjects completed the questionnaires, of which 411 were excluded (figure 1). Of the 968 eligible subjects, 271 (28%) reported IGE: 62% presented with classic IGE, 19% with moderate IGE and 19% with abdominal symptoms but without diarrhoea (IGE w/o diarrhoea). The number of IGE cases followed a steep incline from 6 to 8 December and peaked on 8 December (figure 2). Other main IGE symptoms included nausea (reported by 54%), vomiting (61%), abdominal cramping (55%) and abdominal pain (69%). The mean duration of illness was 7.7±8.2 days, and the mean duration of diarrhoea was 5.2±8.4 days. Also, 9 out of 270 individuals (3%, n=1 missing data on rectal bleeding) reported rectal blood loss. Wouters M, et al. Gut 2015;0:1–10. doi:10.1136/gutjnl-2015-309460
Figure 2 Incidence of gastroenteritis. Individuals who developed infectious gastroenteritis (IGE) between December 6 and 19 were included in the study. 3
Downloaded from http://gut.bmj.com/ on June 15, 2015 - Published by group.bmj.com
Neurogastroenterology
Figure 3 Prevalence of psychological conditions prior to infectious gastroenteritis (IGE) and correlation with interleukin (IL)-2-expressing T cells in acute infectious phase. (A) Psychological status 2 weeks before the outbreak was assessed by Hospital Anxiety and Depression Scale (HADS)-anxiety and depression questionnaires and the Patient Health Questionnaire (PHQ)-12 somatisation questionnaire. (B) HADS-anxiety, depression and somatisation were inversely correlated with IL-2-expressing CD4+ cells. (C) Relative mRNA expression levels of inflammatory genes in rectal biopsies were increased in subjects with IGE compared with non-infected, healthy volunteers (HV; relative expression to HPRT1 housekeeping gene). Infected subjects suffered significantly more from increased anxiety and somatisation compared with exposed subjects who would not develop symptoms of gastroenteritis (no IGE). As shown in figure 3A, the proportion of subjects with abnormal anxiety scores (>10) was increased in the IGE group (11%) compared with the exposed group (4%, p χ2=0.0001). Also, PHQ-12 somatisation scores were increased in the IGE group Table 1
(median=3 IQR (2–7)) compared with the exposed group (median=2.5 IQR (1–5), Mann–Whitney U test, p=0.0001). The proportion of subjects with abnormal depression scores was not different between the IGE (4%) and the exposed group (5%)
Risk factors to develop infectious gastroenteritis (IGE)
Acute phase Female, N (%) Age, mean (SD) Pre-existing dyspepsia-like symptoms, N (%) Exposure to tap water: Not reported, N (%) Drinking tap water, N (%) Psychological factors: Anxiety HADS score (mean, 95% CI) Depression HADS score (mean, 95% CI) Somatisation score (PHQ-12) (mean, 95% CI)
Total
IGE+
IGE−
Univariate Pearson’s χ2 p OR (95% CI)
968 496 (51%) 52 (16) 213 (22%)
271 156 (59%) 49 (16) 93 (35%)
697 340 (49%) 53 (16) 120 (19%)
0.015
Gut Online First, published on June 12, 2015 as 10.1136/gutjnl-2015-309460 Neurogastroenterology
ORIGINAL ARTICLE
Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis Mira Wouters,1 Sander Van Wanrooy,1 Anh Nguyen,2,3 James Dooley,2,3 Javier Aguilera-Lizarraga,1 Winde Van Brabant,1 Josselyn E Garcia-Perez,2,3 Lukas Van Oudenhove,1 Marc Van Ranst,4 Jan Verhaegen,5 Adrian Liston,2,3 Guy Boeckxstaens1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ gutjnl-2015-309460). 1
Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium 2 Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium 3 Autoimmune Genetics Laboratory, VIB, Leuven, Belgium 4 Laboratory of Clinical Virology, Rega Institute for Medical Research, University Hospital Leuven, Leuven, Belgium 5 Department of Microbiology, University Hospital Leuven, KU Leuven, Leuven, Belgium Correspondence to Professor Guy Boeckxstaens Translational Research Center for Gastrointestinal Disorders (TARGID), Center of Neuroimmune interaction and Mucosal Immunology, KU Leuven, University Hospital of Leuven, Herestraat 49, Leuven 3000, Belgium; guy.boeckxstaens@med. kuleuven.be MW, SVW and AN contributed equally. Received 25 February 2015 Revised 18 May 2015 Accepted 19 May 2015
ABSTRACT Objective Psychological factors increase the risk to develop postinfectious IBS (PI-IBS), but the mechanisms involved are unclear. As stress affects the immune system, we investigated the potential interaction between psychological factors, the immune response against infectious gastroenteritis (IGE) and the development of IGE and PI-IBS in a large cohort exposed to contaminated drinking water. Design 18 620 people exposed to contaminated drinking water (norovirus, Giardia lamblia, Campylobacter jejuni) were invited to participate in a prospective controlled cohort study. They were asked to complete questionnaires assessing demographic, psychological and clinical data during the outbreak and 1 year later. At both time points, in-depth immune function ( peripheral blood and rectal biopsies) was studied in a subgroup of subjects. Results 1379 subjects completed the questionnaires during the outbreak, of which 271 developed IGE. Risk factors for IGE included younger age, pre-existing dyspepsia-like symptoms, anxiety and drinking contaminated tap water. Anxiety scores before the outbreak inversely correlated with interleukin-2expressing CD4+ T cells (r=0.6, p=0.01, n=23). At follow-up, 34 of 172 (20%) IGE subjects developed IBS compared with 24/366 exposed participants (7%, p10 were considered to be abnormal.27 28 Statistical analysis, gene expression studies, PBMC immunephenotyping and cytokine analysis in plasma and in supernatants of stimulated PBMCs are described in online supplementary material and methods.
Fifty-six faecal samples were collected from subjects clinically diagnosed with IGE, of which 26 specimens tested positive for an infectious pathogenic agent. Norovirus (NoV) GI.4, GII.4, GII.14 and GII.7 was most frequently detected (15/56), followed by Giardia lamblia (5/56), Campylobacter ssp. (4/56), adenovirus (1/56) and rotavirus A (1/56). Two patients were positive for more than one infectious agent: one with NoV GI.4 and GII.4, and one with C. jejuni and NoV GI.4 and GII.7.
Risk factors underlying the susceptibility to develop IGE Participants were asked to provide information on their consumption and use of the drinking water. Thirty-nine per cent of inhabitants drank tap water with an average of 3.7 glasses per day while almost all subjects used tap water to brush their teeth (98%) or to wash vegetables and fruit (97%). As previous studies indicated psychological factors as risk factor to develop PI-IBS, subjects were asked to complete the HADS and PHQ-12 questionnaires to assess anxiety, depression and somatisation 2 and 4 weeks before the outbreak, respectively.
RESULTS Characterisation of patient cohort: Early phase Patient cohort Between 6 and 9 December 2010, 18 620 residents in 7711 households in Hemiksem and Schelle were exposed to contaminated tap water and asked to participate in our study. A total of 1379 subjects completed the questionnaires, of which 411 were excluded (figure 1). Of the 968 eligible subjects, 271 (28%) reported IGE: 62% presented with classic IGE, 19% with moderate IGE and 19% with abdominal symptoms but without diarrhoea (IGE w/o diarrhoea). The number of IGE cases followed a steep incline from 6 to 8 December and peaked on 8 December (figure 2). Other main IGE symptoms included nausea (reported by 54%), vomiting (61%), abdominal cramping (55%) and abdominal pain (69%). The mean duration of illness was 7.7±8.2 days, and the mean duration of diarrhoea was 5.2±8.4 days. Also, 9 out of 270 individuals (3%, n=1 missing data on rectal bleeding) reported rectal blood loss. Wouters M, et al. Gut 2015;0:1–10. doi:10.1136/gutjnl-2015-309460
Figure 2 Incidence of gastroenteritis. Individuals who developed infectious gastroenteritis (IGE) between December 6 and 19 were included in the study. 3
Downloaded from http://gut.bmj.com/ on June 15, 2015 - Published by group.bmj.com
Neurogastroenterology
Figure 3 Prevalence of psychological conditions prior to infectious gastroenteritis (IGE) and correlation with interleukin (IL)-2-expressing T cells in acute infectious phase. (A) Psychological status 2 weeks before the outbreak was assessed by Hospital Anxiety and Depression Scale (HADS)-anxiety and depression questionnaires and the Patient Health Questionnaire (PHQ)-12 somatisation questionnaire. (B) HADS-anxiety, depression and somatisation were inversely correlated with IL-2-expressing CD4+ cells. (C) Relative mRNA expression levels of inflammatory genes in rectal biopsies were increased in subjects with IGE compared with non-infected, healthy volunteers (HV; relative expression to HPRT1 housekeeping gene). Infected subjects suffered significantly more from increased anxiety and somatisation compared with exposed subjects who would not develop symptoms of gastroenteritis (no IGE). As shown in figure 3A, the proportion of subjects with abnormal anxiety scores (>10) was increased in the IGE group (11%) compared with the exposed group (4%, p χ2=0.0001). Also, PHQ-12 somatisation scores were increased in the IGE group Table 1
(median=3 IQR (2–7)) compared with the exposed group (median=2.5 IQR (1–5), Mann–Whitney U test, p=0.0001). The proportion of subjects with abnormal depression scores was not different between the IGE (4%) and the exposed group (5%)
Risk factors to develop infectious gastroenteritis (IGE)
Acute phase Female, N (%) Age, mean (SD) Pre-existing dyspepsia-like symptoms, N (%) Exposure to tap water: Not reported, N (%) Drinking tap water, N (%) Psychological factors: Anxiety HADS score (mean, 95% CI) Depression HADS score (mean, 95% CI) Somatisation score (PHQ-12) (mean, 95% CI)
Total
IGE+
IGE−
Univariate Pearson’s χ2 p OR (95% CI)
968 496 (51%) 52 (16) 213 (22%)
271 156 (59%) 49 (16) 93 (35%)
697 340 (49%) 53 (16) 120 (19%)
0.015
