Tari Haahtela

Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children). Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.

Environmental biodiversity, human microbiota, and allergy are interrelated

Rapidly declining biodiversity may be a contributing factor to another global megatrend—the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations worldwide. According to the “biodiversity hypothesis,” reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity. Analyzing atopic sensitization (i.e., allergic disposition) in a random sample of adolescents living in a heterogeneous region of 100 × 150 km, we show that environmental biodiversity in the surroundings of the study subjects’ homes influenced the composition of the bacterial classes on their skin. Compared with healthy individuals, atopic individuals had lower environmental biodiversity in the surroundings of their homes and significantly lower generic diversity of gammaproteobacteria on their skin. The functional role of the Gram-negative gammaproteobacteria is supported by in vitro measurements of expression of IL-10, a key anti-inflammatory cytokine in immunologic tolerance, in peripheral blood mononuclear cells. In healthy, but not in atopic, individuals, IL-10 expression was positively correlated with the abundance of the gammaproteobacterial genus Acinetobacter on the skin. These results raise fundamental questions about the consequences of biodiversity loss for both allergic conditions and public health in general.

A 10 year asthma programme in Finland: major change for the better

Background: A National Asthma Programme was undertaken in Finland from 1994 to 2004 to improve asthma care and prevent an increase in costs. The main goal was to lessen the burden of asthma to individuals and society. Methods: The action programme focused on implementation of new knowledge, especially for primary care. The main premise underpinning the campaign was that asthma is an inflammatory disease and requires anti-inflammatory treatment from the outset. The key for implementation was an effective network of asthma-responsible professionals and development of a post hoc evaluation strategy. In 1997 Finnish pharmacies were included in the Pharmacy Programme and in 2002 a Childhood Asthma mini-Programme was launched. Results: The incidence of asthma is still increasing, but the burden of asthma has decreased considerably. The number of hospital days has fallen by 54% from 110 000 in 1993 to 51 000 in 2003, 69% in relation to the number of asthmatics (nu200a=u200a135 363 and 207 757, respectively), with the trend still downwards. In 1993, 7212 patients of working age (9% of 80 133 asthmatics) received a disability pension from the Social Insurance Institution compared with 1741 in 2003 (1.5% of 116 067 asthmatics). The absolute decrease was 76%, and 83% in relation to the number of asthmatics. The increase in the cost of asthma (compensation for disability, drugs, hospital care, and outpatient doctor visits) ended: in 1993 the costs were €218 million which had fallen to €213.5 million in 2003. Costs per patient per year have decreased 36% (from €1611 to €1031). Conclusion: It is possible to reduce the morbidity of asthma and its impact on individuals as well as on society. Improvements would have taken place without the programme, but not of this magnitude.

Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (Pu200a=u200a2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P Stage1+Stage2u200a=u200a1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P Stage1+Stage2u200a=u200a1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.

Probiotic effects on faecal inflammatory markers and on faecal IgA in food allergic atopic eczema/dermatitis syndrome infants.

Probiotic bacteria are proposed to alleviate intestinal inflammation in infants with atopic eczema/dermatitis syndrome (AEDS) and food allergy. In such infants we investigated effects of probiotic bacteria on faecal IgA, and on the intestinal inflammation markers tumour necrosis factor‐α (TNF‐α), α1‐antitrypsin (AT), and eosinophil cationic protein (ECP). A total of 230 infants with AEDS and suspected cows milk allergy (CMA) received in a randomized double‐blinded manner, concomitant with elimination diet, Lactobacillus GG (LGG), a mixture of four probiotic strains (MIX), or placebo for 4u2003wk. Four weeks after treatment, CMA was diagnosed with a double‐blind placebo‐controlled milk challenge. Faecal samples of 102 infants, randomly chosen for analysis, were collected before treatment, after 4‐wk treatment, and on the first day of milk challenge. After treatment, IgA levels tended to be higher in probiotic groups than in the placebo group (LGG vs. placebo, pu2003=u20030.064; MIX vs. placebo, pu2003=u20030.064), and AT decreased in the LGG group, but not in other treatment groups. After challenge in IgE‐associated CMA infants, faecal IgA was higher for LGG than for placebo (pu2003=u20030.014), and TNF‐α was lower for LGG than for placebo, but non‐significantly (pu2003=u20030.111). In conclusion, 4‐wk treatment with LGG may alleviate intestinal inflammation in infants with AEDS and CMA.

The biodiversity hypothesis and allergic disease: world allergy organization position statement

Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.

Determinants of respiratory system input impedance and bronchodilator response in healthy Finnish preschool children.

In order to study the determinants of respiratory system impedance and bronchodilator response in preschool children, a sample (n=109) of healthy children (age 2·1–7·0u2003years) attending kindergarten was measured by using the impulse oscillometry. Their selection was based on a standardized questionnaire, negative skin prick test results and clinical examination, and sufficient cooperation. Triple measurements of respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, 15 and 20u2003Hz, total respiratory impedance (Zrs), the resonance frequency (Fr) and the frequency dependence of resistance (dRrs/df) were performed, to determine individual mean values. Measurements were repeated after inhalation of 300u2003μg salbutamol (n=89) or placebo (n=19). At the baseline, Zrs and Rrs5‐20 showed negative, and Xrs5‐20, Fr and dRrs/df positive correlations with age, height and weight. However, logarithmic transformed height was the best independent variable for the regression equations of all the oscillometric variables. After inhalation of placebo, none of the oscillometric variables changed significantly. In the salbutamol group, the mean (SD) change in Rrs5 was −0·187 (0·124) kPau2003l–1u2003s–1 and –19·2 (10·2)%, corresponding to a lower reference limit of –36·9%. Both the within‐test and between‐test repeatabilities for the measurement of respiratory resistance were acceptable, for Rrs5 the coefficients of variation being 6·2 and 6·1%, respectively. As the overall success rate in our sample was high (89%), the forced oscillation technique seems to be a useful method in assessing respiratory function and bronchial lability in preschool children.

Meteorological conditions, climate change, new emerging factors, and asthma and related allergic disorders. A statement of the World Allergy Organization

The prevalence of allergic airway diseases such as asthma and rhinitis has increased dramatically to epidemic proportions worldwide. Besides air pollution from industry derived emissions and motor vehicles, the rising trend can only be explained by gross changes in the environments where we live. The world economy has been transformed over the last 25 years with developing countries being at the core of these changes. Around the planet, in both developed and developing countries, environments are undergoing profound changes. Many of these changes are considered to have negative effects on respiratory health and to enhance the frequency and severity of respiratory diseases such as asthma in the general population.Increased concentrations of greenhouse gases, and especially carbon dioxide (CO2), in the atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, variability in temperature, increased air pollution, forest fires, droughts, and floods – all of which can put the respiratory health of the public at risk. These changes in climate and air quality have a measurable impact not only on the morbidity but also the mortality of patients with asthma and other respiratory diseases. The massive increase in emissions of air pollutants due to economic and industrial growth in the last century has made air quality an environmental problem of the first order in a large number of regions of the world. A body of evidence suggests that major changes to our world are occurring and involve the atmosphere and its associated climate. These changes, including global warming induced by human activity, have an impact on the biosphere, biodiversity, and the human environment. Mitigating this huge health impact and reversing the effects of these changes are major challenges.This statement of the World Allergy Organization (WAO) raises the importance of this health hazard and highlights the facts on climate-related health impacts, including: deaths and acute morbidity due to heat waves and extreme meteorological events; increased frequency of acute cardio-respiratory events due to higher concentrations of ground level ozone; changes in the frequency of respiratory diseases due to trans-boundary particle pollution; altered spatial and temporal distribution of allergens (pollens, molds, and mites); and some infectious disease vectors. According to this report, these impacts will not only affect those with current asthma but also increase the incidence and prevalence of allergic respiratory conditions and of asthma. The effects of climate change on respiratory allergy are still not well defined, and more studies addressing this topic are needed. Global warming is expected to affect the start, duration, and intensity of the pollen season on the one hand, and the rate of asthma exacerbations due to air pollution, respiratory infections, and/or cold air inhalation, and other conditions on the other hand.

High intestinal IgA associates with reduced risk of IgE-associated allergic diseases

Kukkonen K, Kuitunen M, Haahtela T, Korpela R, Poussa T, Savilahti E. High intestinal IgA associates with reduced risk of IgE‐associated allergic diseases.u2028Pediatr Allergy Immunol 2010: 21: 67–73.u2028© 2009 John Wiley & Sons A/S

Clinical Use of Probiotics in Pediatric Allergy (cuppa): A World Allergy Organization Position Paper

BackgroundProbiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness.ObjectiveA World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy.MethodsA qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications.ResultsDespite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications.ConclusionsProbiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful.