Parechovirus Infection in Early Childhood and Association With Subsequent Celiac Disease.

INTRODUCTION: To test whether parechovirus and anellovirus, frequent enteric viruses, were associated with subsequent celiac disease (CD). We hypothesized that children who later developed CD would have increased frequency of parechovirus infections before transglutaminase 2 (TG2) antibody development. Anellovirus testing was exploratory, as a potential marker of immune status. METHODS: Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk of CD (carrying the human leukocyte antigen genotype DR4-DQ8/DR3-DQ2, recruited throughout Norway during 2001-2007). We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually, to determine when TG2 antibodies developed. Of 220 genetically at-risk children tested, 25 were diagnosed with CD (cases; ESPGHAN 2012 criteria) and matched for follow-up time, birthdate, and county of residence with 2 randomly selected children free from CD (controls) from the cohort. Viruses were quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time polymerase chain reaction methods. RESULTS: Parechovirus was detected in 222 of 2,005 stool samples (11.1%) and was more frequent in samples from cases before developing TG2 antibodies (adjusted odds ratio 1.67, 95% confidence interval 1.14-2.45, P = 0.01). The odds ratio was higher when a sample was positive for both parechovirus and enterovirus (adjusted odds ratio 4.73, 95% confidence interval 1.26-17.67, P = 0.02). Anellovirus was detected in 1,540 of 1,829 samples (84.2%), but did not differ significantly between case and control subjects. DISCUSSION: Early-life parechovirus infections were associated with development of CD in genetically at-risk children.

Maternal Infections, Antibiotics, and Paracetamol in Pregnancy and Offspring Celiac Disease: A Cohort Study.

OBJECTIVES: Infections in pregnancy are common, may affect fetal development, and have been linked to offspring autoimmunity. We aimed to determine whether maternal infections, the use of antibiotics, and use of paracetamol in pregnancy are associated with the risk of offspring celiac disease (CD). METHODS: The nationwide Norwegian Mother and Child Cohort Study includes 84,274 children born in the period from 2000 to 2009 with prospectively collected questionnaire data on maternal infections and medication use in pregnancy. CD was identified through questionnaires and the Norwegian Patient Register. Logistic regression yielded odds ratios adjusted for age and sex (aORs). RESULTS: During a median follow-up of 8.5 years, 617 children (0.7%) were diagnosed with CD. The aOR for offspring CD per increase in number of maternal infections was 1.07 (95% confidence interval [CI] = 1.01-1.13), but not significantly increased for categories 1 infection (1.01 [95% CI = 0.82-1.25]) and ≥2 infections (1.22 [95% CI = 1.00-1.49]) versus no infection. We found the same pattern for respiratory tract infections, but not for gastrointestinal infections. The aORs were broadly consistent across pregnancy periods of exposure. The use of antibiotics and paracetamol was, compared with no use, not associated with offspring CD (aOR = 1.16 [95% CI = 0.94-1.43] and aOR = 1.13 [95% CI = 0.96-1.33], respectively; P values for trend >0.2). CONCLUSIONS: In this large pregnancy cohort we found no clear association between maternal infections in pregnancy and offspring CD, but considering the marginal significance in some of our results maternal infections cannot be ruled out as a risk factor. Reassuringly for both parents-to-be and clinicians, the use of antibiotics and paracetamol in pregnancy was not a significant risk factor.

Infections and risk of celiac disease in childhood: a prospective nationwide cohort study.

OBJECTIVES: Studies on early life infections and risk of later celiac disease (CD) are inconsistent but have mostly been limited to retrospective designs, inpatient data, or insufficient statistical power. We aimed to test whether early life infections are associated with increased risk of later CD using prospective population-based data. METHODS: This study, based on the Norwegian Mother and Child Cohort Study, includes prospective, repeated assessments of parent-reported infectious disease data up to 18 months of age for 72,921 children born between 2000 and 2009. CD was identified through parental questionnaires and the Norwegian Patient Registry. Logistic regression was used to estimate odds ratios adjusted for child's age and sex (aOR). RESULTS: During a median follow-up period of 8.5 years (range, 4.5-14.5), 581 children (0.8%) were diagnosed with CD. Children with ≥10 infections (≥fourth quartile) up to age 18 months had a significantly higher risk of later CD, as compared with children with ≤4 infections (≤first quartile; aOR=1.32; 95% confidence interval (CI)=1.06-1.65; per increase in infectious episodes, aOR=1.03; 95% CI=1.02-1.05). The aORs per increase in specific types of infections were as follows: upper respiratory tract infections: 1.03 (95% CI=1.02-1.05); lower respiratory tract infections: 1.12 (95% CI=1.01-1.23); and gastroenteritis: 1.05 (95% CI=0.99-1.11). Additional adjustments for maternal CD, education level, smoking, birth weight, prematurity, infant feeding practices, birth season, and antibiotic treatment yielded largely unchanged results. CONCLUSIONS: This is the first large-scale population-based cohort study of this association. Our results are in line with immunological data suggesting that early life infections may have a role in CD development. However, non-causal explanations for this association due to surveillance bias and reverse causation cannot be excluded.

Review article: exposure to microbes and risk of coeliac disease.

BACKGROUND: Coeliac disease is an immune-mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous. AIMS: To review human observational studies on microbes and coeliac disease METHODS: We identified 135 publications judged relevant. Most studies were cross-sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review. RESULTS: Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies , whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, including Helicobacter pylori (four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross-sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case-control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome. CONCLUSIONS: Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted.

Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort.

OBJECTIVE: To determine whether infection with human enterovirus or adenovirus, both common intestinal viruses, predicts development of coeliac disease. DESIGN: Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016. SETTING: Norwegian population. PARTICIPANTS: Children carrying the HLA genotype DR4-DQ8/DR3-DQ2 conferring increased risk of coeliac disease. EXPOSURES: Enterovirus and adenovirus detected using real time polymerase chain reaction in monthly stool samples from age 3 to 36 months. MAIN OUTCOME MEASURE: Coeliac disease diagnosed according to standard criteria. Coeliac disease antibodies were tested in blood samples taken at age 3, 6, 9, and 12 months and then annually. Adjusted odds ratios from mixed effects logistic regression model were used to assess the relation between viral infections before development of coeliac disease antibodies and coeliac disease. RESULTS: Among 220 children, and after a mean of 9.9 (SD 1.6) years, 25 children were diagnosed as having coeliac disease after screening and were matched to two controls each. Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls (adjusted odds ratio 1.49, 95% confidence interval 1.07 to 2.06; P=0.02). The association was restricted to infections after introduction of gluten. High quantity samples (>100 000 copies/µL) (adjusted odds ratio 2.11, 1.24 to 3.60; P=0.01) and long lasting infections (>2 months) (2.16, 1.16 to 4.04; P=0.02) gave higher risk estimates. Both the commonly detected enterovirus species Enterovirus A and Enterovirus B were significantly associated with coeliac disease. The association was not found for infections during or after development of coeliac disease antibodies. Adenovirus was not associated with coeliac disease. CONCLUSIONS: In this longitudinal study, a higher frequency of enterovirus, but not adenovirus, during early childhood was associated with later coeliac disease. The finding adds new information on the role of viral infections in the aetiology of coeliac disease.

Endothelial function in highly endurance-trained men: effects of acute exercise.

Exercise training reverses endothelial dysfunction, but the effect in young, healthy subjects is less clear. We determined the influence of maximal oxygen uptake (VO2max) and a single bout of high-intensity exercise on flow-mediated dilatation (FMD), brachial artery diameter, peak blood flow, nitric oxide (NO) bioavailability, and antioxidant status in highly endurance-trained men and their sedentary counterparts. Ten men athletes (mean +/- SEM age 23.5 +/- 0.9 years, height 182.6 +/- 2.4 cm, weight 72.5 +/- 2.4 kg, VO2max 75.9 +/- 0.8 mL.kg.min) and seven healthy controls (age 25.4 +/- 1.2 years, height 183.9 +/- 3.74 cm, weight 92.8 +/- 3.9 kg, VO2max 47.7 +/- 1.7 mL.kg.min) took part in the study. FMD, brachial artery diameter, and peak blood flow were measured using echo-Doppler before, 1 hour, 24 hours, and 48 hours after a single bout of interval running for 5 x 5 minutes at 90% of maximal heart rate. NO bioavailability and antioxidant status in blood were measured at all time points. Maximal arterial diameter and peak flow were 10-15% (P < 0.02) and 28-35% (P < 0.02) larger, respectively, in athletes vs. controls at all time points, and similar FMD were observed, apart from a transient decay of FMD in athletes 1 hour post exercise. NO bioavailability increased significantly after exercise in both groups and decreased to baseline levels after 24 hours in controls but remained increased 80% and 93% above baseline 24 and 48 hours post exercise in athletes. Antioxidant status was equal in the two groups at baseline and increased by approximately 10% 1 hour post exercise, an effect that lasted for 24 hours. Athletes had larger arterial diameter but similar FMD as untrained subjects, i.e., athletes had larger capacity for blood transport compared with their untrained counterparts. The observed FMD, bioavailability of NO, and antioxidant status in blood were highly dependent on the time elapsed after the exercise session.

Antibiotics, acetaminophen and infections during prenatal and early life in relation to type 1 diabetes.

Background: Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D. Methods: Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D. Results: Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D. Conclusions: Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases.

Early growth in children with coeliac disease: a cohort study.

OBJECTIVES: We aimed to study growth during the first 2 years of life in children later diagnosed with coeliac disease compared with children without, in a time with changing epidemiology and improved diagnostics. DESIGN: A prospective population-based pregnancy cohort study. SETTING: The nationwide Norwegian Mother and Child Cohort Study. PATIENTS: 58 675 children born between 2000 and 2009 with prospectively collected growth data. Coeliac disease was identified through combined data from questionnaires and the Norwegian Patient Register. MAIN OUTCOME MEASURES: The differences in height and weight at age 0, 3, 6, 8, 12, 15-18 and 24 months using internally standardised age and gender-specific z-scores. Linear regression and mixed models were used. RESULTS: During a median follow-up of 8.6 years (range 4.6-14.2), 440 children (0.8%) were diagnosed with coeliac disease at a mean age of 4.4 years (range 1.5-8.5). Children with coeliac disease had significantly lower z-scores for height from 12 months (-0.09 standard deviation scores (SDS), 95% CI -0.18 to -0.01) and weight from 15 to 18 months of life (-0.09 SDS, 95% CI -0.18 to -0.01) compared with cohort controls. The longitudinal analysis from 0 to 24 months yielded a significant reduction in height z-score per year (-0.07 SDS, 95% CI -0.13 to -0.01) but not for weight among children with coeliac disease. Excluding children diagnosed before age 2 years gave similar results. CONCLUSIONS: This study indicates that growth retardation in children later diagnosed with coeliac disease commonly starts at 12 months of age, and precedes clinical symptoms that usually bring the suspicion of diagnosis.