Lauri J. Virta

Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children

Early-life antibiotic use is associated with increased risk for metabolic and immunological diseases, and mouse studies indicate a causal role of the disrupted microbiome. However, little is known about the impacts of antibiotics on the developing microbiome of children. Here we use phylogenetics, metagenomics and individual antibiotic purchase records to show that macrolide use in 2–7 year-old Finnish children (N=142; sampled at two time points) is associated with a long-lasting shift in microbiota composition and metabolism. The shift includes depletion of Actinobacteria, increase in Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase and increase in macrolide resistance. Furthermore, macrolide use in early life is associated with increased risk of asthma and predisposes to antibiotic-associated weight gain. Overweight and asthmatic children have distinct microbiota compositions. Penicillins leave a weaker mark on the microbiota than macrolides. Our results support the idea that, without compromising clinical practice, the impact on the intestinal microbiota should be considered when prescribing antibiotics.

Antibiotic Exposure in Infancy and Risk of Being Overweight in the First 24 Months of Life

OBJECTIVE: Antibiotics have direct effects on the human intestinal microbiota, particularly in infancy. Antibacterial agents promote growth in farm animals by unknown mechanisms, but little is known about their effects on human weight gain. Our aim was to evaluate the impact of antibiotic exposure during infancy on weight and height in healthy Finnish children. METHODS: The population-based cohort comprised 6114 healthy boys and 5948 healthy girls having primary care weight and height measurements and drug purchase data from birth to 24 months. BMI and height, expressed as z-scores at the median age of 24 months (interquartile range 24 to 26 months), were compared between children exposed and unexposed to antibiotics using analysis of covariance with perinatal factors as covariates. RESULTS: Exposed children were on average heavier than unexposed children (adjusted BMI-for-age z-score difference in boys 0.13 SD [95% confidence interval 0.07 to 0.19, P < .001] and in girls 0.07 SD [0.01 to 0.13, P < .05]). The effect was most pronounced after exposure to macrolides before 6 months of age (boys 0.28 [0.11 to 0.46]; girls 0.23 [0.04 to 0.42]) or >1 exposure (boys 0.20 [0.10 to 0.30]; girls 0.13 [0.03 to 0.22]). CONCLUSIONS: Antibiotic exposure before 6 months of age, or repeatedly during infancy, was associated with increased body mass in healthy children. Such effects may play a role in the worldwide childhood obesity epidemic and highlight the importance of judicious use of antibiotics during infancy, favoring narrow-spectrum antibiotics.

Association of Repeated Exposure to Antibiotics With the Development of Pediatric Crohn’s Disease—A Nationwide, Register-based Finnish Case-Control Study

To determine whether childhood exposure to antibiotics is associated with the risk of developing inflammatory bowel disease (IBD), the authors conducted a national, register-based study comprising all children born in 1994-2008 in Finland and diagnosed with IBD by October 2010. The authors identified 595 children with IBD (233 with Crohns disease and 362 with ulcerative colitis) and 2,380 controls matched for age, gender, and place of residence. The risk of pediatric Crohns disease increased with the number of antibiotic purchases from birth to the index date and persisted when the 6 months preceding the cases diagnosis were excluded (for 7-10 purchases vs. none, odds ratio = 3.48, 95% confidence interval: 1.57, 7.34; conditional logistic regression). The association between Crohns disease and antibiotic use was stronger in boys than in girls (P = 0.01). Cephalosporins showed the strongest association with Crohns disease (for 3 purchases vs. nonuse, odds ratio = 2.82, 95% confidence interval: 1.65, 4.81). Antibiotic exposure was not associated with the development of pediatric ulcerative colitis. Repeated use of antibiotics may reflect shared susceptibility to childhood infections and pediatric Crohns disease or alternatively may trigger disease development.

Incidence and prevalence of diagnosed coeliac disease in Finland: results of effective case finding in adults.

Objective. The majority of patients with coeliac disease remain undetected world-wide. Finland has aimed at a high detection rate by training health personnel, and has advocated serologic screening for known coeliac disease risk groups. The purpose here was to assess whether this approach has been effective in clinical practice. Material and methods. The study was based on a prospective database of new coeliac patients aged 16 years or more, to whom the Social Insurance Institution had paid monthly compensation for the additional cost of maintaining a gluten-free diet since 2002. To obtain this compensation the diagnostic criteria for coeliac disease, including biopsy findings, had to be attested in a statement from a physician. The incidence and prevalence rates were calculated until the end of 2006. The total population aged 16 years or more was 4.31 million. Results. In 2004–06, a total of 5020 persons (64% female) receiving a new dietary grant were identified through the database. The mean annual incidence of proven coeliac disease was thus 39 per 100,000 individuals. Altogether, 23,553 persons received the dietary grant. This gives a nation-wide point prevalence of adult coeliac disease of 0.55% (0.70% F, 0.38% M). There was a regional variation from 33 to 49 per 100,000 in the annual incidence and from 0.41% to 0.72% in the prevalence of coeliac disease. Conclusions. To the best of our knowledge, these figures for proven coeliac disease are the highest reported. Increased alertness to the condition and active case finding has made this efficient diagnostics possible.

Diagnosis of celiac disease in clinical practice: physician's alertness to the condition essential.

Goals We have for several years been training health personnel to recognize celiac disease, and have advocated serologic screening in risk groups. The aim was to establish whether this approach would offer an alternative to population screening, which has yielded a prevalence of 1% in Finland. Background The number of detected celiac disease cases is much lower than that obtained in serologic screening studies. Study Nationwide recommendations for the detection of celiac disease were published in 1998, and training of health personnel took place in 2001 to 2002. The prevalence of celiac disease was calculated from the national registry of patients receiving reimbursement for dietary costs, attested by physicians statement. In 1 of the 10 statements the diagnostic criteria and clinical manifestations were scrutinized. Results The nationwide prevalence of celiac disease was 0.45%; 0.7% in the highest to 0.3% in the lowest area. The annual number of new patients increased from 5/100,000 in the early 1980s to 20/100,000 today. The percentage of patients found in risk groups (relatives of celiac disease patients, patients with extraintestinal symptoms or concomitant autoimmune disorders) was currently 16.3% in the high and 6.6% in the low prevalence area. Seventeen percent of patients had dermatitis herpetiformis, and its incidence was declining. Conclusions A maximal prevalence of 0.7% of celiac disease was ascertained; educating primary health care staff regarding the protean manifestations of the disease seemed to be the key issue. The increase in incidence implies that a prevalence of 1.0% is possible, rendering population screening unnecessary.

Prenatal and post‐natal exposure to antibiotics and risk of asthma in childhood

Evidence on the association between post‐natal exposure to antibiotics and the development of asthma is extensive, but inconsistent and even less is known about prenatal exposure.

Mother's and Offspring's Use of Antibiotics and Infant Allergy to Cow's Milk

Background: Evidence on the association between antibiotics and the risk of food allergies is limited. We explored the associations between mother’s and offspring’s use of antibiotics and the risk of cow’s milk allergy in infancy. Methods: We used a national registry to identify all children who were born in 1996–2004 in Finland and diagnosed with cow’s milk allergy after 1 month of age by November 2005 (n = 15,672). For each case, we selected one control matched for birth date, sex, and hospital district. Information on antibiotic purchases and putative confounders was obtained from registries. The associations were analyzed using conditional logistic regression. Results: Maternal use of antibiotics before and during pregnancy was associated with an increased risk of cow’s milk allergy in the offspring (odds ratio = 1.26 [95% confidence interval = 1.20–1.33] and 1.21 [1.14–1.28], respectively, adjusting for putative confounders). The risk of cow’s milk allergy increased with increasing number of child’s antibiotics used from birth to diagnosis (test for trend P < 0.001). Conclusions: Both maternal and child’s use of antibiotics were associated with an increased risk of cow’s milk allergy. Future studies are needed to confirm these novel findings and to explore the potential biologic mechanisms behind the association.

Long-Term Persistence with Statin Therapy: A Nationwide Register Study in Finland

BACKGROUND Preventive statin therapy is often recommended as lifelong treatment. OBJECTIVE The aim of this study was to analyze persistence with statin therapy over a decade of use and to identify factors associated with its discontinuation. METHODS Persistence with therapy among new users of statins in 1995 was followed up until December 31, 2005, in Finland using the nationwide drug reimbursement register. Cumulative persistence was analyzed using Kaplan-Meier analysis. A Cox regression model was applied to analyze associations of various baseline covariates with discontinuation. We further modeled the association of time-specific covariates by stratifying the duration of therapy in years and using a logistic regression in which those continuing therapy until the end of follow-up (persistent users) formed the reference group. Adherence, defined as the proportion of days covered by statins, stratified by the timing of discontinuation, was computed for the respective groups. RESULTS Of the 18,072 new statin users, 73.3% (n =13,254) were aged >54 years and 54.8% (n =9908) were men. Of this cohort, 43.9% (n = 7926) were using statins throughout and at the end of the tenth year. Sex was not associated with persistence at any point. In the Cox model, persons aged 45 to 74 years at initiation were more likely to continue statin use than younger or older age groups. Among those who still used statins after the fifth year of observation, the age difference was not observed in the logistic regression model. The use of 1, 2, 3, or > or =4 cardiovascular drugs before the initiation predicted continuation relative to no cardiovascular drug use (hazard ratio for discontinuation significantly <1.00 in all comparisons). Adherence was best (median 93.9%) among the persistent users. CONCLUSIONS The 10-year persistence with statin use in this general population was approximately 44%. Persons aged 45 to 74 years at initiation and those with at least 1 prescription for another cardiovascular medication were the most likely to continue statin therapy up to the fifth year.

The decline in joint replacement surgery in rheumatoid arthritis is associated with a concomitant increase in the intensity of anti-rheumatic therapy: a nationwide register-based study from 1995 through 2010.

Background and purpose Drug-based treatment of rheumatoid arthritis (RA) has evolved markedly over the past 2 decades. Using nationwide register data, we studied how this has affected the rates of hip, knee, shoulder, and elbow replacement from 1995 to 2010. Methods The number of primary joint replacements was obtained from the Finnish Arthroplasty Register. To test the hypothesis that improvements in medical treatment of RA reduce the need for joint replacements, we also collected data about purchases of different disease-modifying anti-rheumatic agents (DMARDs) and biological drugs from the nationwide drug registers. Results The annual incidence of primary joint replacements for RA declined from 19 per 105 in 1995 to 11 per 105 in 2010. The decline was greater for upper-limb operations than for lower-limb operations. At the same time, the numbers of individuals using methotrexate, hydroxychloroquine, and sulfasalazine (the most commonly used DMARDs) increased 2- to 4-fold. Interpretation Our results are in accordance with observations from other countries, and indicate that the use of joint replacements in RA has decreased dramatically. Our data suggest that effective medical therapy is the most likely explanation for this favorable development.

Increasing incidence of inflammatory bowel diseases between 2000 and 2007: A nationwide register study in Finland

Background: The incidence of inflammatory bowel disease (IBD) is high in Western countries, but during the last decade the figures have stabilized, or only slightly increased; at the same time, an increasing incidence rate has been observed in Eastern Europe and Asia. The purpose of this study was to estimate the incidence of IBD in Finland between 2000 and 2007. Methods: New IBD cases between 2000–2007 were retrieved from the national database of special reimbursements for drugs costs. The register includes virtually all Finnish IBD patients since 1986. The incidence rates were calculated per 100,000 persons assuming a Poisson distribution. Results: In total, 14,214 IBD patients were identified; 10,352 had ulcerative colitis (UC) and 3,862 had Crohns disease (CD). During the whole study period the mean annual incidence of IBD per 100,000 was 34.0: in CD 9.2 and in UC 24.8. The incidence of UC was notably higher in males (27.8) than in females (21.9). In CD the incidence rates did not differ significantly between genders. The incidence of UC increased from 22.1 in 2000–2001 to 27.4 in 2006–2007. The incidence of CD increased only slightly. Conclusion: In Finland, the incidence of IBD is high, and UC is almost three times more common than CD. During the new millennium the incidence rate of UC has increased, while the incidence rate of CD has remained fairly stable. To the best of our knowledge, the incidence of UC in this nationwide register study is one of the highest reported to date. (Inflamm Bowel Dis 2012;)