To Örebro University

Background: Celiac disease (CD) is a chronic immune-mediated enteropathy affecting about 1% of the population worldwide. CD is triggered by ingestion of gluten in genetically predisposed individuals but additional factors (e.g. infections) are required for the disease to develop. CD also seems to be associated with infectious complications.

Aim: The main objective of this thesis was to increase the knowledge about the associations between CD and infections.

Methods: Epidemiological and laboratory approaches. Studies I-III used a data set consisting of small intestinal biopsy reports. The biopsies were taken in 1969-2008 and collected in 2006-2008. A total of 29,096 individuals with CD, 13,306 with inflammation and 3,719 with potential CD were identified. Each individual was matched with up to 5 controls from the general population (n= 228,632). Through linkage of the data to the Patient Register study I examined the risk of hospital visits due to respiratory syncytial virus (RSV) in children <2 years prior to onset of CD. Study II used the Patient Register and Cause of Death Register to assess whether CD affects the outcome in sepsis. Study III linked the data to microbiological data bases and the Public Health Agency to estimate risk of invasive pneumococcal disease (IPD) in CD. In study IV children with CD and controls were recruited from Kalmar County Hospital. Complement activation (C3a and sC5b-9) in plasma were analysed after incubation with pneumococci.

Results: Study I found that children with CD were more likely than controls to have attended hospital due to RSV infection prior to diagnosis (odds ratio 1.46; 95% confidence interval (CI)=1.02-2.07). CD did not seem to influence survival in sepsis (adjusted hazard ratio (HR) 1.10 95%CI=0.72-1.69) (study II). Study III indicated a 46% risk increase for individuals with CD to acquire IPD (HR 1.46; 95%CI=1.05-2.03) but study IV did not reveal any differences in complement response in regard to CD status (p=0.497and p=0.724), explaining this excess risk.

Conclusion: This thesis supports associations between CD and infections preceding and complicating diagnosis. However, CD does not seem to influence the outcome in a severe infection like sepsis and altered complement function is unlikely to be responsible for the excess IPD risk in CD.

Severe infections are recognized complications of coeliac disease (CD). In the present study we aimed to examine whether individuals with CD are at increased risk of invasive pneumococcal disease (IPD). To do so, we performed a population-based cohort study including 29 012 individuals with biopsy-proven CD identified through biopsy reports from all pathology departments in Sweden. Each individual with CD was matched with up to five controls (n = 144 257). IPD events were identified through regional and national microbiological databases, including the National Surveillance System for Infectious Diseases. We used Cox regression analyses to estimate hazard ratios (HRs) for diagnosed IPD. A total of 207 individuals had a record of IPD whereas 45/29 012 had CD (0.15%) and 162/144 257 were controls (0.11%). This corresponded to a 46% increased risk for IPD [HR 1.46, 95% confidence interval (CI) 1.05-2.03]. The risk estimate was similar after adjustment for socioeconomic status, educational level and comorbidities, but then failed to attain statistical significance (adjusted HR 1.40, 95% CI 0.99-1.97). Nonetheless, our study shows a trend towards an increased risk for IPD in CD patients. The findings support results seen in earlier research and taking that into consideration individuals with CD may be considered for pneumococcal vaccination.

Background: Individuals with celiac disease (CD) are at increased risk of sepsis. The aim of this study was to examine whether CD influences survival in sepsis of bacterial origin.

Methods: Nationwide longitudinal registry-based study. Through data on small intestinal biopsies from Sweden's 28 pathology departments, we identified 29,096 individuals with CD (villous atrophy, Marsh stage III). Each individual with CD was matched with five population-based controls. Among these, 5,470 had a record of sepsis according to the Swedish Patient Register (1,432 celiac individuals and 4,038 controls). Finally we retrieved data on mortality in sepsis patients through the Swedish Cause of Death Registry.

Results: CD was associated with a 19% increase in overall mortality after sepsis (95% confidence interval (CI) = 1.09-1.29), with the highest relative risk occurring in children (adjusted hazard ratio (aHR) = 1.62; 95%CI = 0.67-3.91). However, aHR for death from sepsis was lower (aHR = 1.10) and failed to reach statistical significance (95%CI = 0.72-1.69). CD did not influence survival within 28 days after sepsis (aHR = 0.98; 95%CI = 0.80-1.19).

Conclusions: Although individuals with CD seem to be at an increased risk of overall death after sepsis, that excess risk does not differ from the general excess mortality previously seen in celiac patients in Sweden. CD as such does not seem to influence short-term or sepsis-specific survival in individuals with sepsis and therefore is not an independent risk factor for poor prognosis in sepsis.

Background and Aim: The purpose of this study was to examine the association between celiac disease (CD) and prior respiratory syncytial virus (RSV) infection or any viral bronchiolitis.

Methods: This was a retrospective case–control study. During 2006–2008 small intestinal biopsy data were collected from Sweden’s 28 pathology departments. We identified 3,835 children diagnosed with CD (villous atrophy, Marsh stage 3) before the age of 2 years in 1987 or later. Using conditional logistic regression we calculated odds ratios (ORs) for having a prior diagnosis of respiratory syncytial virus or other viral bronchiolitis compared to 19,102 age- and sex-matched controls.

Results: Of the 3,835 children with CD, 36 (0.9 %) had a prior diagnosis of RSV compared to 117/19,102 (0.6 %) matched controls. This corresponded to an OR of 1.46 (95 % CI 1.03–2.07). ORs were similar in girls and boys. The highest ORs were seen in children developing early CD (before 1 year of age (OR 1.82; 95 % CI 0.91–3.62). Prior record of any type of viral bronchiolitis was found in 3.4 % (132/3,835) of individuals with CD and in 2.0 % (390/19,102) of the matched controls corresponding to an OR of 1.60 (95 % CI 1.33–1.92).

Conclusions: Children with CD diagnosed\2 years of age were more likely to have attended hospital for a prior RSV infection or any viral bronchiolitis than other children.

OBJECTIVE: The goal was to examine whether parent-reported infection at the time of gluten introduction increases the risk of future celiac disease (CD).

METHODS: Through the population-based All Infants in Southeast Sweden study, parents recorded data on feeding and infectious disease prospectively. Complete data on gluten introduction and breastfeeding duration were available for 9408 children. Those children had 42 826 parent-reported episodes of infectious disease in the first year of life (including 4003 episodes of gastroenteritis). We identified 44 children with biopsy-verified CD diagnosed after 1 year of age, and we used Cox regression to estimate the risk of future CD for children with infection at gluten introduction.

RESULTS: Eighteen children with CD (40.9%) had an infection at the time of gluten introduction, compared with 2510 reference individuals (26.8%; P = .035). Few children had gastroenteritis at the time of gluten introduction (1 child with CD [2.3%] vs 166 reference individuals [1.8%]; P = .546). With adjustment for age at gluten introduction and breastfeeding duration, we found no association between a future diagnosis of CD and either any infection (adjusted hazard ratio: 1.8 [95% confidence interval: 0.9-3.6]) or gastroenteritis (adjusted hazard ratio: 2.6 [95% confidence interval: 0.2-30.8]) at the time of gluten introduction. We found no associations between breastfeeding duration, age at gluten introduction, and future CD.

CONCLUSION: These results indicate that parent-reported infection at the time of gluten introduction is not a major risk factor for CD.