Peter Bager

Caesarean delivery and risk of atopy and allergic disesase: meta‐analyses

Background Studies of delivery by caesarean section (c‐section) and the offsprings risk of allergic diseases are of current interest due to concerns about the increased use of c‐section in many countries. However, previous studies have reported inconsistent findings.

Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial

BACKGROUND Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease. OBJECTIVE To determine efficacy of helminth therapy for allergic rhinitis. METHODS We conducted a double-blind, placebo-controlled, parallel group trial in which 100 subjects age 18 to 65 years with grass pollen-induced allergic rhinitis were randomly assigned to ingest a total of 8 doses with 2500 live T suis ova or placebo with an interval of 21 days. The primary outcome was a change in mean daily total symptom score for runny, itchy, sneezing nose (maximum change, 9.0) or in percentage of well days during the grass pollen season. RESULTS Treatment with T suis ova (N = 49) compared with placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of participants (placebo, 2%), and increased eosinophil counts (P < .001) and T suis-specific IgE (P < .05), IgG (P < .001), IgG(4) (P < .003), and IgA (P < .001), whereas there was no significant change in symptom scores (0.0; 95% CI, -0.5 to 0.4; P = .87), well days (3%; 95% CI, -9% to 14%; P = .63), total histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction on skin prick testing with grass (P = .85) or 9 other allergens. CONCLUSION Repeated treatment with the helminth T suis induced a substantial clinical and immunologic response as evidence of infection, but had no therapeutic effect on allergic rhinitis.

Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease

Objective Enteric pathogens have been implicated in the aetiology of inflammatory bowel disease (IBD), but increased rates of stool testing of patients with unclear gastrointestinal symptoms might cause detection bias. Hence, the objective of this study was to analyse incidence rates of Crohns disease and ulcerative colitis among patients with Salmonella- or Campylobacter-positive and negative stool tests and to study the incidence of positive and negative stool tests among patients already diagnosed with IBD. Methods The Danish population was followed for 94.3 million person-years during 1992–2008 using national registers to identify persons with positive and negative stool tests and patients with IBD. Using Poisson regression, incidence rate ratios (IRRs) for IBD after positive or negative stool tests and, conversely, IRRs for positive and negative stool tests following IBD, were calculated. Results IRRs for IBD were significantly high in the first year after Salmonella- or Campylobacter-positive stool tests (IRRs 5.4–9.8), and they remained moderately increased 1–10 years later (IRRs 1.6–2.2), and less so >10 years later (IRRs 0.8–1.8). However, IRRs for IBD <1 year after a negative stool test were several-fold higher (IRRs 53.2–57.5), and a decreasing incidence pattern over time was parallel to that following positive test results. Among patients with IBD, IRRs for subsequent positive and—most notably—negative stool test results were also significantly high. Conclusion Similarities in temporal risk patterns for IBD following positive or negative stool tests indicate that the increased occurrence of Salmonella- or Campylobacter-positive results around the time of first IBD hospitalisation results from detection bias.

Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study.

Background: Intestinal bacteria have been implicated in the etiology of the common inflammatory bowel diseases (IBD) ulcerative colitis and Crohns disease. Because delivery by cesarean section disturbs the normal bacterial colonization of the newborns intestine, we determined the risk of IBD according to mode of delivery. Methods: A register‐based national cohort study of 2.1 million Danes born 1973–2008. The effect of mode of delivery on IBD incidence in the age‐span 0–35 years was estimated by means of confounder‐adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) obtained in Poisson regression analysis. Information on mode of delivery was obtained from the Danish Medical Birth Registry and cases of IBD were identified in the Danish National Patient Registry 1977–2008. Results: During 32.6 million person‐years of follow‐up, a total of 8142 persons were diagnosed with IBD before age 36 years. Cesarean section was associated with moderately, yet significantly, increased risk of IBD at age 0–14 years (IRR 1.29, 95% CI 1.11–1.49), regardless of parental disposition to IBD. Assuming causality, an estimated 3.2% of IBD cases before age 15 years were attributable to cesarean section. Conclusions: Rates of IBD with onset in childhood are moderately increased after birth by cesarean section but underlying mechanisms remain unclear. Even if the association is causal, the possible impact of increasing cesarean section practices on the overall burden of IBD in childhood is small. (Inflamm Bowel Dis 2011;)

Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: A study within the Danish National Birth Cohort

BACKGROUND High pre-pregnancy body mass index (BMI) and excessive gestational weight gain (GWG) are suggested to influence risk of asthma and atopic disease in offspring. OBJECTIVE We examined the effect of BMI and GWG on risk of asthma, wheezing, atopic eczema (AE), and hay fever in children during the first 7 years of life. METHODS This was a cohort study of 38,874 mother-child pairs from the Danish National Birth Cohort (enrollment 1996-2002) with information from the 16th week of pregnancy and at age 6 months, 18 months, and 7 years of the child. Odds ratios (ORs) with 95% CIs were calculated by logistic regression with adjustment for potential confounders. RESULTS During the first 7 years of life, 10.4% of children developed doctor-diagnosed asthma, 25.8% AE, and 4.6% hay fever. Maternal BMI and to a lesser extent GWG were associated with doctor-diagnosed asthma ever. In particular, BMI≥35 (adjusted OR, 1.87; 95% CI, 0.95-3.68) and GWG≥25 kg (adjusted OR, 1.97; 95% CI, 1.38-2.83) were associated with current severe asthma at age 7 years. Maternal BMI was also associated with wheezing in offspring, with the strongest association observed between BMI≥35 and late-onset wheezing (adjusted OR, 1.87; 95% CI, 1.28-2.73). Maternal BMI and GWG were not associated with AE or hay fever. CONCLUSIONS Maternal obesity during pregnancy was associated with increased risk of asthma and wheezing in offspring but not with AE and hay fever, suggesting that pathways may be nonallergic.

Symptoms after Ingestion of Pig Whipworm Trichuris suis Eggs in a Randomized Placebo-Controlled Double- Blind Clinical Trial

Symptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3rd dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation. Trial registration University hospital Medical Information Network trial registry Reg. no. R000001298, Trial ID UMIN000001070.

Age at childhood infections and risk of atopy.

Background: It has been proposed that early age at exposure to common childhood infections is associated with a decreased risk of allergy. Previous studies on the possible association between allergy and infection with measles, mumps, rubella, and varicella have not been conclusive as most did not include information on exact age at exposure. The objective of our study was to investigate whether early age at exposure to these infections was associated with a decreased risk of atopy using information on exact age at infection. Methods: The study population consisted of 889 pregnant women who participated in a national birth cohort study in Denmark and for whom detailed information on history of measles, rubella, varicella, and mumps before school entry (age 7 years) was available from school health records from Copenhagen. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during pregnancy. Results: Measles in the first year of life was associated with a higher risk of atopy than no measles before age 7 years (OR 3.36, 95% CI 1.47 to 7.68). There was no association between atopy and mumps, rubella, or varicella in the first 7 years of life or with measles acquired after the first year of life. The risk of atopy increased significantly with increasing number of childhood infections in the first 2 years of life (ptrend=0.01). Conclusions: These findings do not support the suggestion that childhood exposure to measles, rubella, varicella, or mumps protects against atopy, even if acquired very early in life.

Age at bacille Calmette–Guérin vaccination and risk of allergy and asthma

Background It has been proposed that early age at bacille Calmette–Guérin (BCG) vaccination protects against the development of allergy.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect

Background: An observational study has suggested that relapsing–remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. Objective: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. Methods: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24–55) years, disease duration 9 (4–34) years, Expanded Disability Status Scale score 2.5 (1–5.0), and number of relapses within the last two years 3 (2–5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Results: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. Conclusions: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.

Helminth Infection Does Not Reduce Risk for Chronic Inflammatory Disease in a Population-Based Cohort Study

BACKGROUND & AIMS Parasitic helminth infections can suppress symptoms of allergy, type 1 diabetes, arthritis, and inflammatory bowel disease in animal models. We analyzed data from a large, population-based cohort study to determine whether common childhood enterobiasis protects against these diseases. METHODS We collected information on individual prescriptions filled for the drug mebendazole against Enterobius vermicularis for all children born in Denmark 1995-2008 from the National Register of Medicinal Product Statistics (n = 924,749; age 0-14 years); 132,383 of these children (14%) filled a prescription for mebendazole, 102,482 of the children (11%) had a household peer who was registered with a filled mebendazole prescription, and the remaining 689,884 children (75%) comprised the reference group. Children diagnosed with asthma, type 1 diabetes, juvenile arthritis, ulcerative colitis, or Crohns disease were identified from the National Patient Registry. We used Poisson regression to estimate confounder-adjusted incidence rate ratios for first in- or outpatient hospital diagnosis of chronic inflammatory disease according to history of mebendazole treatment prescribed to children in the study. RESULTS Chronic inflammatory disease was diagnosed in 10,352 children during 6.4 million person-years of follow-up. The incidence rate ratios was 1.07 for asthma (95% confidence interval [CI]: 1.00-1.13), 1.05 for type 1 diabetes (95% CI: 0.79-1.12), 1.13 for juvenile arthritis (95% CI: 0.94-1.37), 0.77 for ulcerative colitis (95% CI: 0.41-1.46), and 1.44 for Crohns disease (95% CI: 0.82-2.53). Results were not modified by number of treatments or age at treatment. CONCLUSIONS Based on a population-based analysis, enterobiasis does not reduce risk for asthma, type 1 diabetes, arthritis, or inflammatory bowel disease.