Published and unpublished evidence in coverage decision-making for pharmaceuticals in Europe: existing approaches and way forward.

BACKGROUND: Dissemination bias occurs when only some results emerging from clinical research reach their intended audience in the knowledge translation process. Given that coverage decisions increasingly rely on evidence, it is important to explore the types of evidence considered. This paper aimed to examine the evidence base used by regulatory institutions involved in pricing and reimbursement of pharmaceuticals in a broad range of European countries, as well as their awareness of and approach towards dissemination bias. METHODS: A mixed methods approach was adopted. Regulatory documents and published literature were identified in systematic searches and relevant documents were analysed. An online survey was carried out to verify and expand insights. RESULTS: Forty-two relevant regulatory documents and 10 publications were included. The survey had a 35% response rate, yielding valid responses for 13 countries. A fragmented impression was obtained for most countries indicating a general lack of transparency regarding both processes of decision-making and approaches towards unpublished information. Dissemination bias was rarely consistently considered. Practices for the identification and inclusion of all available evidence varied considerably, as did the influence of missing evidence on decision-making. Differences were often attributable to the regulatory context and/or institutional principles. CONCLUSIONS: Best practice is difficult to generalize given the identified variations. Individual exemplary practices support the necessity for institutional exchange at international level. Increased institutional commitment to transparency of methods and processes should be advocated.

From market access to patient access: overview of evidence-based approaches for the reimbursement and pricing of pharmaceuticals in 36 European countries.

BACKGROUND: Coverage decisions determining the benefit baskets of health systems have been increasingly relying on evidence regarding patient benefit and costs. Relevant structures, methodologies, and processes have especially been established for pharmaceuticals but approaches differ. The objective of this work was thus to identify institutions in a broad range of European countries (n = 36) in charge of determining the value of pharmaceuticals for pricing and reimbursement purposes and to map their decision-making process; to examine the different approaches and consider national and supranational possibilities for best practice. METHODS: Institutions were identified through websites of international networks, ministries, and published literature. Details on institutional practices were supplemented with information from institution websites and linked online sources. RESULTS: The type and extent of information available varied considerably across countries. Different types of public regulatory bodies are involved in pharmaceutical coverage decisions, assuming a range of responsibilities. As a rule, the assessment of scientific evidence is kept structurally separate from its appraisal. Recommendations on value are uniformly issued by specific committees within or commissioned by responsible institutions; these institutions often also act as decision-makers on reimbursement status and level or market price. While effectiveness and costs are important criteria in all countries, the latter are often considered on a case-by-case basis. In all countries, manufacturer applications, including relevant evidence, are used as one of the main sources of information for the assessment. CONCLUSION: Transparency of evidence-based coverage decisions should be enhanced. International collaboration can facilitate knowledge exchange, improve efficiency of information production, and strengthen new or developing systems.

Evidence-informed recommendations to reduce dissemination bias in clinical research: conclusions from the OPEN (Overcome failure to Publish nEgative fiNdings) project based on an international consensus meeting.

BACKGROUND: Dissemination bias in clinical research severely impedes informed decision-making not only for healthcare professionals and patients, but also for funders, research ethics committees, regulatory bodies and other stakeholder groups that make health-related decisions. Decisions based on incomplete and biased evidence cannot only harm people, but may also have huge financial implications by wasting resources on ineffective or harmful diagnostic and therapeutic measures, and unnecessary research. Owing to involvement of multiple stakeholders, it remains easy for any single group to assign responsibility for resolving the problem to others. OBJECTIVE: To develop evidence-informed general and targeted recommendations addressing the various stakeholders involved in knowledge generation and dissemination to help overcome the problem of dissemination bias on the basis of previously collated evidence. METHODS: Based on findings from systematic reviews, document analyses and surveys, we developed general and targeted draft recommendations. During a 2-day workshop in summer 2013, these draft recommendations were discussed with external experts and key stakeholders, and refined following a rigorous and transparent methodological approach. RESULTS: Four general, overarching recommendations applicable to all or most stakeholder groups were formulated, addressing (1) awareness raising, (2) implementation of targeted recommendations, (3) trial registration and results posting, and (4) systematic approaches to evidence synthesis. These general recommendations are complemented and specified by 47 targeted recommendations tailored towards funding agencies, pharmaceutical and device companies, research institutions, researchers (systematic reviewers and trialists), research ethics committees, trial registries, journal editors and publishers, regulatory agencies, benefit (health technology) assessment institutions and legislators. CONCLUSIONS: Despite various recent examples of dissemination bias and several initiatives to reduce it, the problem of dissemination bias has not been resolved. Tailored recommendations based on a comprehensive approach will hopefully help increase transparency in biomedical research by overcoming the failure to disseminate negative findings.

[GRADE guidelines: 6. Rating the quality of evidence: imprecision]. / GRADE Leitlinien: 6. Einschätzung der Qualität der Evidenz - Unzureichende Präzision.

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required when clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" or OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0 and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest a RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.

High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review.

INTRODUCTION: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations. RESULTS: A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws. CONCLUSIONS: HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.

Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of soft tissue sarcomas in children and adults. SEARCH STRATEGY: We searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis. DATA COLLECTION AND ANALYSIS: Study data were recorded by two review authors independently. For studies with no comparator group, we synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: We included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 participants that received HSCT and 69 participants that received standard care. Only one study reported comparative data. In the one comparative study, OS at two years after HSCT was estimated as statistically significantly higher (62.3%) compared with participants that received standard care (23.2%). In a single-arm study, the OS two years after HSCT was reported as 20%. In a pooled analysis of the individual data of 54 participants, OS at two years was estimated as 49% (95% CI 34% to 64%). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias. AUTHORS' CONCLUSIONS: Due to a lack of comparative studies, it is unclear whether participants with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials.

CoCanCPG. Coordination of cancer clinical practice in Europe.

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, stepwise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.

How pre- and postnatal risk factors modify the effect of rapid weight gain in infancy and early childhood on subsequent fat mass development: results from the Multicenter Allergy Study 90.

BACKGROUND: It is unclear which exposures may cause or modify the adverse effect of rapid weight gain on fat mass development in term children whose birth weight is appropriate-for-gestational age (AGA). OBJECTIVE: To determine which intrauterine or postnatal exposures increase the risk of or modify the effect of rapid weight gain on body fat percentage (BF%) and body mass index (BMI) trajectories between 2 and 6 y of age. DESIGN: Term AGA singletons (n = 370) from the German Multicenter Allergy Study (MAS-90), a longitudinal birth cohort study, with repeated anthropometric measurements until 6 y, and data on breastfeeding status, exposure to smoking during pregnancy, and maternal anthropometric and socioeconomic characteristics were included in this analysis. RESULTS: A shorter gestation [multivariate-adjusted odds ratio (OR): 5.12; 95% CI: 2.22, 11.82; P = 0.0001], being firstborn (OR: 2.01; 95% CI: 1.10, 3.69; P = 0.02), and having been bottle-fed (OR: 3.02; 95% CI: 1.68, 5.43; P = 0.0002) all significantly increased a child's risk of gaining weight rapidly, whereas a larger BMI at birth was protective (OR: 0.54; 95% CI: 0.38, 0.77; P = 0.0006). Multilevel model analyses showed that rapid growers exposed to tobacco in utero subsequently gained more BF% between 2 and 6 y than did rapid growers who had not been exposed (beta +/- SE: 0.78 +/- 0.28%/y; P = 0.005). Similarly, change in BF% was greater in rapid growers with an overweight mother than in those with a normal-weight mother (1.01 +/- 0.30%/y; P = 0.0007). CONCLUSIONS: The occurrence of rapid weight gain between birth and 2 y and the magnitude of its effect on BF% development in AGA children is influenced by both intrauterine and postnatal exposures.

History of respiratory infections in the first 12 yr among children from a birth cohort.

Respiratory infections are the most frequent health problem in childhood. There is little precise information on how many respiratory illness episodes can be expected in a normal child. This study was designed to create reference values for the frequency of respiratory infections as recordable by history. Respiratory illnesses were recorded in a prospective birth cohort of 1314 German children born in 1990 and tracked until age 12 yr (760 children). Parents recorded the child's illnesses in a diary and answered structured questions yearly up to age 12. Age of study subjects was categorized into infancy (0-2 yr), pre-school age (3-5 yr), and school age (6-12 yr). The mean cumulative number of respiratory infection episodes up to age 12 yr was 21.9 (s.d. 9.0) episodes. In infancy, the mean annual number was 3.4 (3.7) episodes; at pre-school age, 2.3 (2.6) episodes; and at school, age 1.1 (1.2) episodes. The mean cumulative time of episodes up to age 7 yr was 20.1 (15.2) wk. Forty-five percent of the infants in the upper episode incidence tertile continued to be in the upper tertile at school age. Based on a twofold standard deviation of the mean number, up to 11 respiratory infection episodes per year in infancy, 8 episodes per year at pre-school age, and 4 episodes per year at school age could be regarded as normal. Episodes within these reference values per se should not cause unwarranted concern or intervention because of suspected immunodeficiency.

Regional variation in medication following coronary events in Germany.

BACKGROUND: Mortality rates from ischaemic heart disease have consistently been higher in East compared to West Germany both prior to and since reunification. Coronary care is inversely related to mortality from ischaemic heart disease. The objective of the present study was, therefore, to compare cardiovascular medication in East and West German patients following cardiac rehabilitation. METHODS: East German (n = 530) and West German (n = 1638) patients were included at admission to one of 18 rehabilitation centres. Inclusion criteria were myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The follow-up period was 12 months. RESULTS: At admission, East and West German patients differed with regard to sociodemographic variables, risk factors and medical conditions. At 12 months, a higher percentage of West compared to East German patients were prescribed beta-blockers (71% vs. 65%, P = 0.04) and lipid-lowering agents (64% vs. 55%, P = 0.002). Angiotensin converting enzyme (ACE) inhibitors, on the other hand, were prescribed more frequently in the East compared to the West (60% vs. 48%, P < 0.001). In multivariable analyses, region of residence remained a significant predictor for the prescription of lipid-lowering agents (East vs. West: OR 0.61, 95% CI 0.46-0.81) and ACE inhibitors (East vs. West: OR 1.78, 95% CI 1.33-2.39). CONCLUSION: There is a considerable variation in the prescription of cardiovascular medication in secondary prevention within Germany. Some, but not all, of this variation can be explained by differences in patient characteristics.

Gastro esophageal reflux disease is associated with absence from work: results from a prospective cohort study.

AIM: To study the association of gastro-esophageal reflux disease (GERD) with the absence from work and to estimate the extent of loss in gross domestic product due to inability to work. METHODS: Analysis was based on the prospectively gathered data of a large European cohort study involving 6 215 symptomatic GERD patients (ProGERD). Among these patients, 2 871 were initially employed. The calculation of the loss of gross domestic product was based on the assumption that the prevalence of GERD was about 15% in Germany. According to the German Federal Statistical Office, the mean gross wage of employees was 150 EUR/d in 2002. RESULTS: The data of 2 078 employed patients who were prospectively followed up for over 2 years were analyzed. At study entry, the patients reported a mean of 1.8 d per year of inability to work. During the prospective follow-up under routine clinical care, the proportion of patients reporting days with inability to work decreased from 14% to 6% and the mean number of days per year with inability to work decreased to 0.9 d. Assuming a prevalence of troublesome GERD of 15% in the employed German population, the loss of gross domestic product amounted to 668 million EUR/year in Germany. CONCLUSION: GERD causes a relevant impairment on the national economics by absence from work. The presented data demonstrate the importance of GERD, not only for patients and health insurance companies, but also for the community at large.

European survey on circadian variation of angina pectoris (ESCVA) in treated patients.

BACKGROUND AND PURPOSE: Previous reports of a circadian variation of angina pectoris were based primarily on selected patients of clinical studies. The present ESCVA Study (European Survey on Circadian Variation of Angina Pectoris) was designed to determine the timing of angina pectoris attacks in outpatients, the association of wake time and possible external triggers with angina attacks, and the influence of cardiac medication on the circadian pattern. PATIENTS AND METHODS: Inclusion criteria were stable angina pectoris for at least 3 months, average frequency of two or more attacks per week, and treatment with on-demand nitrates. Standardized self-administered questionnaires were provided to all participating physicians to obtain medical information and to their patients to obtain prospective recordings of angina attacks during the 7 subsequent days. RESULTS: From January 1998 to March 1999, 1,333 patients (60% male, 65 +/- 10 years, 40% female, 68 +/- 10 years) were enrolled in 243 centers of six European countries and reported a total of 4,293 angina pectoris attacks (range 0-48 per patient). The occurrence of angina pectoris demonstrated a significant circadian variation (p < 0.001) with a primary morning peak from 09:00 to 12:00 o'clock (relative risk 2.9, 95% confidence interval 2.6-3.2, compared to other times of day) and a secondary afternoon peak from 15:00 to 18:00 o'clock (relative risk 1.5, 95% confidence interval 1.3-1.7). Of all angina attacks 50% occurred within the initial 6 h after awakening, and 74% were associated with possible external triggers such as physical activity or anger. CONCLUSION: The study demonstrated a marked wake time-related circadian variation in the occurrence of angina pectoris attacks. To improve preventive strategies, type, dosage and particularly timing of cardiac medication appear of importance, as may be behavior modification.

Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD study initiative.

OBJECTIVES: Gastroesophageal reflux disease can be divided into three categories: nonerosive GERD (NERD), erosive GERD (ERD), and Barrett's esophagus. A shift among these categories rarely occurs. The aim of the present study was to elucidate potential patient-associated risk factors associated with ERD. METHODS: A total of 6,215 patients with troublesome heartburn were recruited to a large, prospective, multicenter open cohort study comprising an initial treatment phase and a 5-yr follow-up phase. Each center planned to recruit an equal number of patients with NERD and ERD. All patients underwent an interview based on standardized questionnaires, a physical examination, and endoscopy with biopsies. Data were analyzed by multiple logistic regression analysis. RESULTS: Risk factor analysis was performed on 5,289 patients (NERD: n = 2,834; ERD: n = 2,455), which was the intent-to-treat population excluding patients with suspected/proven complicated reflux disease. Stepwise regression analysis identified the following independent predictors of ERD: male gender, overweight, regular use of alcohol, a history of GERD >1 yr, and smoker or ex-smoker. A higher level of education and a positive Helicobacter pylori (H. pylori) status were associated with a lower risk of ERD. CONCLUSIONS: Some patient-associated factors increase the risk of erosive esophagitis as opposed to nonerosive reflux disease. However, no single factor or combination of factors is capable of predicting mucosal damage with clinically sufficient certainty. Thus, endoscopy is still required in all GERD patients if valid information on the state of the esophageal mucosa is needed.

Regional trends in cerebrovascular mortality in Germany after unification (1990-1999).

BACKGROUND AND PURPOSE: After the unification in 1990 two different health and political systems merged in Germany. Our aim was to analyze trends in mortality from cerebrovascular diseases in the formerly divided western and eastern parts of Germany since the unification. METHODS: Trends in mortality were determined by analyzing age-adjusted vital statistics data obtained from the Federal Statistics Office. ICD-9 was used from 1990 to 1997 and ICD-10 in 1998 and 1999. RESULTS: Cerebrovascular mortality declined in Germany between 1991 and 1999 from 104.4 to 72.3 per 100000 men and from 82.2 to 55.5 per 100000 women. Mortality rates from cerebrovascular diseases in East Germany were continuously above West German rates: in 1991 the overall rate ratio in East compared to West Germany was 1.6 and in 1999 it was 1.5 in both men and women. This regional variation is mainly due to a higher rate of cerebrovascular diseases being defined as 'Other' (ICD-9 437, now ICD-10 I67) in East compared to West Germany. CONCLUSION: Nearly 10 years after the unification, cerebrovascular mortality is still markedly higher in East compared to the West Germany. Further investigation is needed to determine the causes for the regional variation in cerebrovascular mortality and to improve preventive strategies.

Comparing methodological quality and consistency of international guidelines for the management of patients with chronic heart failure.

BACKGROUND: Guidelines (GLs) for the management of heart failure (HF) are of great importance in order to define and disseminate therapeutic recommendations based on scientific evidence. The aim was to analyse and to compare the methodological quality of HF GLs as well as to evaluate the consistency of therapeutic recommendations. METHODS: Eleven international GLs for the management of chronic HF were identified by search of the internet, electronic databases and references of published literature. Their methodological quality was assessed by two different appraisal instruments: (1) according to the US National Guideline Clearinghouse (NGC) on a scale from 0 to 17 points, (2) according to the German Guideline Clearinghouse (Agency for Quality in Medicine, AQUMED) on a scale from 0 to 44 points. Clinical criteria for assessment of the consistency of the recommendations included diagnostic testing, pharmacological and non-pharmacological treatment. RESULTS: The quality scores of the GLs varied substantially with a range of 1.5-15.5 points (NGC) and 8-30 points (AQUMED). The greatest variation was found in the dimensions "development" and "evidence". Only 3 of the 11 GLs (approximately 30%) were rated as methodologically well prepared. The recommendations on diagnostic procedures and medical management were rather consistent among the different GLs. CONCLUSIONS: Published international GL recommendations on medical management of patients with chronic HF are broadly consistent. The methodological quality of the GLs, however, varies to a great extent. Improvement is needed in most methodological aspects, especially in the dimensions "evidence" and "applicability".

[Return to work after cardiologic rehabilitation]. / Berufliche Wiedereingliederung nach kardiologischer Rehabilitation.

OBJECTIVES: The objectives of the present study were to determine prospectively return to work and its predictors in patients after cardiac rehabilitation. METHODS: Patients were enrolled at admission to inpatient cardiac rehabilitation centres (n = 18). Primary indications for admission were myocardial infarction, coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. RESULTS: We included 2441 consecutive patients (1907 men, mean age: 60 +/- 10 years; 534 women, mean age: 65 +/- 10 years). A total of 43% of all patients had been actively employed before the event. Of these patients, 65% had returned to work six months and 67% 12 months after cardiac rehabilitation. Successful return to work after 12 months was significantly predicted by younger age, non-manual work, self-employment, a higher physical and mental quality of life, and a better exercise ECG result. CONCLUSION: Return to work is predicted by sociodemographic factors, quality of life, and the exercise ECG at the rehabilitation centre. The determination of early predictors for return to work may aid to identify patients particularly at risk for failure to return to work.

How should a birth cohort study be organised? Experience from the German MAS cohort study.

Birth cohort studies offer the opportunity to study average risks, rates and occurrence times of disease longitudinally from birth. The effect of genetic and environmental factors and their interactions can be studied. Furthermore, quantity and duration of exposure to environmental agents can be evaluated prospectively. However, prospective birth cohort studies are expensive, labour intensive and take many years to complete. Loss of subjects over time as well as recall bias complicate the interpretation of observations. This paper summarises the potential pitfalls of such studies and discusses the experience of the German Multicentre Allergy Study (MAS), which began in 1990 in five German cities and included 1314 newborns for the study of the natural course of atopic diseases.

The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS).

Epidemiological surveys have indicated that there has been a notable increase in the prevalence of both asthma and other allergic symptoms in children and young adults. Since it seems unlikely that genetic factors would contribute to the rising trend, environmental factors might play a major part in the development of childhood asthma. In a prospective birth-cohort study, we assessed the relevance of different exposures such as mite and cat allergen exposure, environmental tobacco smoke (ETS) exposure, early infectious diseases and vaccinations for the development of childhood asthma up to the age of 10 years. Data up to 7 years of age have been evaluated. Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children (72%). Assessments included repeated measurements of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months and 3 years of age and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial responsiveness was determined in 645 children. At age 7, the prevalence of wheezing in the past 12 months was 10% (94 out of 938), and 6.1% (57 out of 939) parents reported a doctor's diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness. However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. During the first 3 years of life, intra-uterine tobacco and consistent ETS exposure have an adjuvant effect on allergic sensitisation that is transient and restricted to children with a genetic predisposition for allergy. Children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88). Children with repeated episodes (> or =2) of runny nose before the age of 1 year were less likely to develop asthma by the age of 7 years (OR = 0.52; 95% CI = 0.29-0.92). Our data do not support the hypothesis that exposure to environmental allergens directly causes asthma in childhood but that induction of specific IgE responses and the development of childhood asthma are determined by independent factors. Indoor allergen avoidance is recommended as first line treatment in secondary and tertiary prevention; however, conclusions should be drawn with caution about the possible effect of primary preventative measures. Since allergic asthma seems to be a Th2-disease, immunomodulating factors such as early childhood infections, LPS-exposure or other factors influencing gene-environment interaction and individual susceptibility seem to be relevant for the development of childhood asthma.