Long-term complications following an outbreak of giardiasis

Background: The association between certain acute infections and long-term complications is well known, with gastroenteritis and subsequent irritable bowel syndrome (IBS) as one established example. In 2004 there was a large outbreak of Giardia lamblia in Bergen, Norway, due to contaminated drinking-water. An estimated 5000 inhabitants fell ill with giardiasis. Before this outbreak, the knowledge on long-term complications following giardiasis was scarce. Aims: The overall aim of the studies constituting this thesis was to investigate long-term consequences of having had a Giardia lamblia infection in 2004. Methods: All three papers in this thesis are reports from a controlled cohort study. In Bergen, Norway, 1252 persons had a verified Giardia lamblia infection by detection of cysts in their stools during the outbreak. These were defined as the exposed population in the study and were matched 2:1 on sex and age to a control group from the Bergen area. Questionnaires were mailed to the participants three, six and ten years after the outbreak. In paper 1 the main outcome was perceived food intolerance and its association with exposure to giardiasis three years after the outbreak. We also investigated the relation with IBS. Perceived food intolerance was measured by two unvalidated questions. IBS was defined by the Rome III criteria. In paper 2 the main outcomes were IBS and chronic fatigue (CF). We investigated the association between giardiasis and IBS/CF ten years later, and changes in prevalence from three to ten and six to ten years. CF was defined by the Fatigue Questionnaire. In paper 3 the main outcome was quality of life (QoL), as measured by the short-form 12 version 2. We investigated the association between giardiasis and QoL ten years later, and further, the relationship with IBS/CF. Results: Response rates among exposed were 66%, 61% and 50% after three, six and ten years, respectively. Among controls the corresponding numbers were 35%, 36% and 30%. Perceived food intolerance three years after the outbreak was associated with giardiasis, with an adjusted odds ratio (aOR) of 2.00 (95% confidence interval (CI) 1.65 to 2.42), as compared to the control group. Dairy products was the most frequently reported intolerance, with an aOR for exposure of 1.95 (95% CI 1.51 to 2.51). We found no interaction between exposure to giardiasis and IBS on perceived food intolerance in stratified analyses. We found a prevalence of IBS after ten years that was 43% (248/576) among exposed and 14% (94/685) among controls (aOR 4.74; 95% CI: 3.61 to 6.23). For CF the prevalence was 26% (153/587) and 11% (73/692), respectively (aOR 3.01; 95% CI 2.22 to 4.08). There were no changes in the prevalence of IBS among the exposed from six (40%) to ten (43%) years (aOR for the change 1.03; 95% CI: 0.87 to 1.22). The prevalence of CF decreased from 31% to 26% among exposed from six to ten years (aOR for the change 0.74; 95% CI: 0.61 to 0.90). Exposure to giardiasis was associated with a lower QoL. The mean physical component summary T-score among the exposed (51.4; 95% CI: 50.6-52.1) was 2.8 points (95% CI: −3.8 to −1.9; P < 0.001) lower than among controls (54.2; 95% CI: 53.7-54.8). The mean mental component summary T-score was also 2.8 points (95% CI: −3.8 to −1.9, P < 0.001) lower among the exposed (48.9; 95% CI: 48.2-49.6) than among controls (51.7; 95% CI: 51.1-52.4). Adjusting for IBS and CF in regression analyses resulted in no effect of Giardia exposure on the physical component T-score, with an estimated difference of -0.5 points (95% CI: -1.4 to 0.40; P-value: 0.28). Corresponding numbers for the mental component summary in this model were -0.75 (95% CI: −1.7 to 0.22; P-value: 0.13). Discussion: We found that giardiasis was associated with perceived food intolerance after three years. This is a novel finding. Stratified analyses with IBS and exposure status as independent variables and perceived food intolerance as the outcome indicated a strong association between IBS and food intolerance. The association between IBS and food intolerance is well established, and our findings were relatively consistent with findings from other studies. The strong association between giardiasis and both IBS and CF ten years after the outbreak is surprising and unprecedented in the literature on long-term complications after gastroenteritis. The prevalence of IBS was unchanged from six to ten years, contrary to findings from studies on bacterial gastroenteritis, where post-infectious IBS has been found to subside with time. The lower QoL among exposed than controls was statistically significant, but the clinical significance is questionable. We found no effect of exposure on QoL after adjusting for IBS and CF, indicating that these complications were the basis for the reduced QoL among the exposed. The main methodological problems with our data were the low response rate among the exposed after ten years, and the consistently low response rates among controls, as well as a lack of baseline information about study participants. Analyses were performed to assess selection bias, and the main results from paper 2 would be significant even in the unlikely event of an extreme selection bias. A strength of all the studies was the high number of participants and the inclusion of a control group. Conclusions: Exposure to Giardia lamblia was associated with long-term complications up to ten years later

Consultations for gastroenteritis in general practice and out-of-hours services in Norway 2006–15

Background: Most of the patients with gastroenteritis seeking health care services are managed in primary care; yet, little is known about these consultations. Syndromic-based surveillance of gastrointestinal infections is used in several countries, including Norway. Aim: To investigate the extent of, and explore characteristics associated with, consultations for gastroenteritis in primary care and to compare consultations in daytime general practice and out-of-hours (OOH) services in Norway. Design and Setting: Registry-based study using reimbursement claims data from all consultations in general practice and OOH services in Norway over the 10-year period, 2006–15. Methods: The main outcome variable was whether the consultation took place in general practice or OOH services. Possible associations with patient age and sex, time and use of point-of-care C-reactive protein (CRP) testing and sickness certificate issuing were investigated. Results: Gastroenteritis consultations (n = 1 281 048) represented 0.9% of all consultations in primary care (n = 140 199 637), of which 84.4% were conducted in general practice and 15.6% in OOH services. Young children and young adults dominated among the patients. Point-of-care CRP testing was used in 36.1% of the consultations. Sickness certificates were issued in 43.6% of consultations with patients in working age. Age-specific time variations in consultation frequencies peaking in winter months were observed. Conclusions: The proportion of gastroenteritis consultations was higher in the OOH services when compared with daytime general practice. Young children and young adults dominated among the patients. The seasonal variation in consultation frequency is similar to that shown for gastroenteritis caused by norovirus.publishedVersio

Antibiotics for gastroenteritis in general practice and out-of-hours services in Norway 2006-15

Background When patients with gastroenteritis (GE) seek health care, they are generally managed in primary care. Little is known about the use of antibiotic treatment in these cases. Objective The aim of this study was to investigate time trends and patient characteristics associated with antibiotic treatment for GE in Norwegian primary care in a 10-year period. Methods We linked data from two nationwide registries, reimbursement claims data from Norwegian primary care (the KUHR database) and The Norwegian Prescription Database, for the period 2006–15. GE consultations were extracted, and courses of systemic antibiotics dispensed within 1 day were included for further analyses. Results Antibiotic treatment was linked to 1.8% (n = 23 663) of the 1 279 867 consultations for GE in Norwegian primary care in the period 2006–15. The proportion of GE consultations with antibiotic treatment increased from 1.4% in 2006 to 2.2% in 2012 and then decreased to 1.8% in 2015. Fluoroquinolones (28.9%) and metronidazole (26.8%) were most frequently used. Whereas the number of fluoroquinolones courses decreased after 2012, the number of metronidazole courses continued to increase until year 2015. The antibiotic treatment proportion of GE consultations was lowest in young children and increased with increasing age. Conclusion Antibiotic treatment is infrequently used in GE consultations in Norwegian primary care. Although there was an overall increase in use during the study period, we observed a reduction in overall use after year 2012. Young children were treated with antibiotics in GE consultations less frequent than older patients.publishedVersio

Clinical features of gastroenteritis during a large waterborne Campylobacter outbreak in Askøy, Norway

Purpose: Outbreaks of Campylobacter infection are common, but studies exploring the clinical features of acute illness in the outbreak setting are scarce in existing literature. The main purpose of the present study was to investigate the clinical features of self-reported acute illness in gastroenteritis cases during a large waterborne Campylobacter outbreak in Askøy municipality, Norway, in 2019. Methods: A web-based self-administered questionnaire, and invitation to participate was sent by the municipality of Askøy as text message to mobile phones using the municipality’s warning system to the inhabitants during the ongoing outbreak. Results. Out of 3624 participants, 749 (20.7%) were defined as cases, of which 177 (23.6%) reported severe gastroenteritis. The most common symptoms were loose stools (90.7%), abdominal pain (89.3%) and diarrhea (88.9%), whereas 63.8% reported fever, 50.2% joint pain and 14.2% bloody stools. Tiredness, a symptom non-specific to gastroenteritis, was the overall most common symptom (91.2%). Conclusion: About one in four of the cases reported symptoms consistent with severe gastroenteritis. We found more joint pain and less bloody stools than reported in published studies of laboratory confirmed campylobacteriosis cases. Tiredness was common in the current study, although rarely described in previous literature of acute illness in the outbreak setting.publishedVersio

Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: A controlled prospective cohort study

Objectives To investigate whether acute infection with Giardia lamblia is associated with fibromyalgia 10 years after infection and whether fibromyalgia is associated with irritable bowel syndrome (IBS) and chronic fatigue (CF) in this setting. Methods A cohort study was established after an outbreak of G. lamblia in Bergen, Norway, 2004. Laboratory-confirmed cases and a matched control group were followed for 10 years. The main outcome was fibromyalgia 10 years after giardiasis, defined by the 2016 revisions of the fibromyalgia diagnostic criteria using the Fibromyalgia Survey Questionnaire (FSQ). Results The prevalence of fibromyalgia was 8.6% (49/572) among Giardia exposed compared to 3.1% (21/673) in controls (p<0.001). Unadjusted odds for having fibromyalgia was higher for Giardia exposed compared to controls (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.72, 4.91), but adjusted for IBS and CF it was not (OR: 1.05, 95% CI: 0.57, 1.95). Among participants without CF the odds for fibromyalgia was 6.27 times higher for participants with IBS than those without (95% CI: 3.31, 11.91) regardless of exposure. Among participants without IBS the odds for fibromyalgia was 4.80 times higher for those with CF than those without (95% CI: 2.75, 8.37). Conclusions We found a higher prevalence of fibromyalgia among Giardia exposed compared to controls 10 years after the acute infection. Fibromyalgia was strongly associated with IBS and CF, and the difference between the exposed and controls can be attributed to the high prevalence of IBS and CF among the Giardia exposed. Notably, this study was not designed to establish causality between Giardia exposure and the outcomes.publishedVersio

Rastløse bein – en studie fra allmennpraksis

BAKGRUNN Forekomsten av rastløse bein er rundt 5–10 % blant voksne i den generelle befolkningen. Få studier er gjort om forekomsten blant pasienter som oppsøker fastlege. Det er også få studier om sammenheng med andre vanlige plager som irritabel tarm, kronisk utmattelse eller kronisk muskel- og ryggsmerte. MATERIALE OG METODE Studien ble gjennomført som en spørreskjemaundersøkelse ved legekontorer på Sør- og Vestlandet høsten 2017 og våren 2018, der pasienter som ventet på time hos fastlegen fortløpende ble invitert til å delta. 2 634 personer deltok (62,2 % kvinner, gjennomsnittsalder 49,6 år). Svarprosenten var 86,8. Rastløse bein ble definert basert på internasjonale kriterier. Assosiasjoner mellom rastløse bein og irritabel tarm, kronisk utmattelse og kronisk muskel- og ryggsmerte ble analysert med khikvadrattester og logistisk regresjon. RESULTATER OG FORTOLKNING Andelen pasienter med rastløse bein var 14,3 %. Blant pasientene med rastløse bein rapporterte 44,8 % at symptomene var moderate til veldig plagsomme, og 85,8 % at de ikke brukte medikamenter for dette. Andelen pasienter med rastløse bein var signifikant høyere blant pasienter med irritabel tarm (21,8 % versus 13,6 %, p = 0,009), kronisk utmattelse (18,2 % versus 13,1 %, p = 0,003) og kronisk muskel- og ryggsmerte (23,2 % versus 12,2 %, p < 0,0005). Fastleger bør være oppmerksomme på at mange pasienter har rastløse bein og at tilstanden er assosiert med andre vanlige plager. HOVEDFUNN Forekomsten av rastløse bein var 14,3 % blant pasienter som oppsøker fastlegen. Rundt halvparten av dem oppga mye og hyppige plager, men et fåtall benyttet medikamentell behandling. Rastløse bein var hyppigere blant pasienter med andre plager som irritabel tarm (justert oddsratio (OR) 1,73), kronisk utmattelse (OR 1,48) og kronisk muskel- og ryggsmerte (OR 2,06), sammenliknet med pasienter uten disse tilstandene.publishedVersio

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Long-term complications following an outbreak of giardiasis

Background: The association between certain acute infections and long-term complications is well known, with gastroenteritis and subsequent irritable bowel syndrome (IBS) as one established example. In 2004 there was a large outbreak of Giardia lamblia in Bergen, Norway, due to contaminated drinking-water. An estimated 5000 inhabitants fell ill with giardiasis. Before this outbreak, the knowledge on long-term complications following giardiasis was scarce. Aims: The overall aim of the studies constituting this thesis was to investigate long-term consequences of having had a Giardia lamblia infection in 2004. Methods: All three papers in this thesis are reports from a controlled cohort study. In Bergen, Norway, 1252 persons had a verified Giardia lamblia infection by detection of cysts in their stools during the outbreak. These were defined as the exposed population in the study and were matched 2:1 on sex and age to a control group from the Bergen area. Questionnaires were mailed to the participants three, six and ten years after the outbreak. In paper 1 the main outcome was perceived food intolerance and its association with exposure to giardiasis three years after the outbreak. We also investigated the relation with IBS. Perceived food intolerance was measured by two unvalidated questions. IBS was defined by the Rome III criteria. In paper 2 the main outcomes were IBS and chronic fatigue (CF). We investigated the association between giardiasis and IBS/CF ten years later, and changes in prevalence from three to ten and six to ten years. CF was defined by the Fatigue Questionnaire. In paper 3 the main outcome was quality of life (QoL), as measured by the short-form 12 version 2. We investigated the association between giardiasis and QoL ten years later, and further, the relationship with IBS/CF. Results: Response rates among exposed were 66%, 61% and 50% after three, six and ten years, respectively. Among controls the corresponding numbers were 35%, 36% and 30%. Perceived food intolerance three years after the outbreak was associated with giardiasis, with an adjusted odds ratio (aOR) of 2.00 (95% confidence interval (CI) 1.65 to 2.42), as compared to the control group. Dairy products was the most frequently reported intolerance, with an aOR for exposure of 1.95 (95% CI 1.51 to 2.51). We found no interaction between exposure to giardiasis and IBS on perceived food intolerance in stratified analyses. We found a prevalence of IBS after ten years that was 43% (248/576) among exposed and 14% (94/685) among controls (aOR 4.74; 95% CI: 3.61 to 6.23). For CF the prevalence was 26% (153/587) and 11% (73/692), respectively (aOR 3.01; 95% CI 2.22 to 4.08). There were no changes in the prevalence of IBS among the exposed from six (40%) to ten (43%) years (aOR for the change 1.03; 95% CI: 0.87 to 1.22). The prevalence of CF decreased from 31% to 26% among exposed from six to ten years (aOR for the change 0.74; 95% CI: 0.61 to 0.90). Exposure to giardiasis was associated with a lower QoL. The mean physical component summary T-score among the exposed (51.4; 95% CI: 50.6-52.1) was 2.8 points (95% CI: −3.8 to −1.9; P < 0.001) lower than among controls (54.2; 95% CI: 53.7-54.8). The mean mental component summary T-score was also 2.8 points (95% CI: −3.8 to −1.9, P < 0.001) lower among the exposed (48.9; 95% CI: 48.2-49.6) than among controls (51.7; 95% CI: 51.1-52.4). Adjusting for IBS and CF in regression analyses resulted in no effect of Giardia exposure on the physical component T-score, with an estimated difference of -0.5 points (95% CI: -1.4 to 0.40; P-value: 0.28). Corresponding numbers for the mental component summary in this model were -0.75 (95% CI: −1.7 to 0.22; P-value: 0.13). Discussion: We found that giardiasis was associated with perceived food intolerance after three years. This is a novel finding. Stratified analyses with IBS and exposure status as independent variables and perceived food intolerance as the outcome indicated a strong association between IBS and food intolerance. The association between IBS and food intolerance is well established, and our findings were relatively consistent with findings from other studies. The strong association between giardiasis and both IBS and CF ten years after the outbreak is surprising and unprecedented in the literature on long-term complications after gastroenteritis. The prevalence of IBS was unchanged from six to ten years, contrary to findings from studies on bacterial gastroenteritis, where post-infectious IBS has been found to subside with time. The lower QoL among exposed than controls was statistically significant, but the clinical significance is questionable. We found no effect of exposure on QoL after adjusting for IBS and CF, indicating that these complications were the basis for the reduced QoL among the exposed. The main methodological problems with our data were the low response rate among the exposed after ten years, and the consistently low response rates among controls, as well as a lack of baseline information about study participants. Analyses were performed to assess selection bias, and the main results from paper 2 would be significant even in the unlikely event of an extreme selection bias. A strength of all the studies was the high number of participants and the inclusion of a control group. Conclusions: Exposure to Giardia lamblia was associated with long-term complications up to ten years later

Consultations for gastroenteritis in general practice and out-of-hours services in Norway 2006–15

Background: Most of the patients with gastroenteritis seeking health care services are managed in primary care; yet, little is known about these consultations. Syndromic-based surveillance of gastrointestinal infections is used in several countries, including Norway. Aim: To investigate the extent of, and explore characteristics associated with, consultations for gastroenteritis in primary care and to compare consultations in daytime general practice and out-of-hours (OOH) services in Norway. Design and Setting: Registry-based study using reimbursement claims data from all consultations in general practice and OOH services in Norway over the 10-year period, 2006–15. Methods: The main outcome variable was whether the consultation took place in general practice or OOH services. Possible associations with patient age and sex, time and use of point-of-care C-reactive protein (CRP) testing and sickness certificate issuing were investigated. Results: Gastroenteritis consultations (n = 1 281 048) represented 0.9% of all consultations in primary care (n = 140 199 637), of which 84.4% were conducted in general practice and 15.6% in OOH services. Young children and young adults dominated among the patients. Point-of-care CRP testing was used in 36.1% of the consultations. Sickness certificates were issued in 43.6% of consultations with patients in working age. Age-specific time variations in consultation frequencies peaking in winter months were observed. Conclusions: The proportion of gastroenteritis consultations was higher in the OOH services when compared with daytime general practice. Young children and young adults dominated among the patients. The seasonal variation in consultation frequency is similar to that shown for gastroenteritis caused by norovirus

Characteristics of hospitalized patients during a large waterborne outbreak of Campylobacter jejuni in Norway

Very few reports describe all hospitalized patients with campylobacteriosis in the setting of a single waterborne outbreak. This study describes the demographics, comorbidities, clinical features, microbiology, treatment and complications of 67 hospitalized children and adults during a large waterborne outbreak of Campylobacter jejuni in Askoy, Norway in 2019, where more than 2000 people in a community became ill. We investigated factors that contributed to hospitalization and treatment choices. Data were collected from electronic patient records during and after the outbreak. Fifty adults and seventeen children were included with a biphasic age distribution peaking in toddlers and middle-aged adults. Most children, 14 out of 17, were below 4 years of age. Diarrhea was the most commonly reported symptom (99%), whereas few patients (9%) reported bloody stools. Comorbidities were frequent in adults (63%) and included cardiovascular disease, pre-existing gastrointestinal disease or chronic renal failure. Comorbidities in children (47%) were dominated by pulmonary and gastrointestinal diseases. Adult patients appeared more severely ill than children with longer duration of stay, higher levels of serum creatinine and CRP and rehydration therapy. Ninety-two percent of adult patients were treated with intravenous fluid as compared with 12% of children. Almost half of the admitted children received antibiotics. Two patients died, including a toddler. Both had significant complicating factors. The demographic and clinical findings presented may be useful for health care planning and patient management in Campylobacter outbreaks both in primary health care and in hospitals.publishedVersio