At a recent summit organized by the European Academy of Allergy and Clinical Immunology (EAACI), a group of experts discussed current issues of concern and unmet needs in regard to the treatment of asthma. Most attendees presented evidence that the current guideline-driven treatment strategies fail in two vital aspects of asthma. There was a general consensus that the needs of patients with severe asthma or frequent asthma exacerbations are not being adequately covered by the current treatment guidelines and are of major health and socio-economic concern. Such patients suffer from significantly reduced quality of life and incur disproportionately higher costs on health service resources. This report summarizes the current data that indicate the need for a more rational approach to the treatment of asthma and one that takes into account the emerging evidence for pathophysiological heterogeneity of the disease, including its more severe forms.
A significant outstanding problem in the clinical management of asthma is the failure to prevent and/or efficiently treat asthma exacerbations, which are associated with significant morbidity, risk of death and high treatment cost [1-3]. Generally, an asthma exacerbation is considered to be an increase in a patient's asthma symptoms with increasingly impaired lung function that require increased medication, an unscheduled visit to a physician or hospitalization. A single asthma exacerbation requiring extra medication and possibly emergency treatment and hospitalization can increase the annual treatment costs by more than threefold . Recurrent asthma exacerbations lead to a progressive decline in lung function , and the risk of an exacerbation doubles in children who have had one or more in the previous year . A rare but distinct phenotype of asthma exacerbation is characterized by the development of sudden severe asthma symptoms in an otherwise mild or asymptomatic asthmatic subject, which may be triggered by an allergen, drug (e.g. aspirin), food, air pollutant, occupational agent, virus infection or, in many cases, an unknown (or unidentified) trigger . It has been proposed that within the group of patients with recurrent exacerbations, detailed phenotyping in terms of clinical symptoms, lung function, inflammatory and other biomarkers is warranted [7, 8]. There is a significant unmet need for identifying and characterizing the factors that increase the risk of asthma exacerbations and the therapeutic and preventive options that reduce these risks.
Patients with severe asthma have high morbidity and mortality, often require hospitalization and are expensive to treat. They have diverse clinical profiles, which probably reflect diverse disease mechanisms, and, for many of them, standard treatment is not sufficiently effective [9-11]. Severe asthma comprises a highly heterogeneous group of patients, which is defined in various ways in the published literature and in the national and international guidelines. A consensus is emerging that patients should be considered to have a ‘difficult-to-control asthma’ if they have persistent symptoms and recurrent exacerbations despite being prescribed therapy at the highest steps of the guidelines' pharmacological management . However, it is worth emphasizing that the guidelines also make clear that ‘difficult-to-control asthma’ is multifactorial, and issues such as incorrect diagnosis, comorbid conditions, nonadherence to prescribed medication, psychosocial morbidity and a number of other factors discussed later in this manuscript are major causes of ‘difficult’ asthma . Patients should be considered to have severe asthma that is resistant to currently available therapies only following a detailed analysis and appropriate management of all these background problems that are amenable to intervention. A recently published consensus statement on severe asthma broadened the concept of ‘difficult asthma’ to reflect the situation in less developed countries, where access to medications and appropriate care is a major issue, by defining three different patient groups including un(der)treated symptomatic patients, patients with low treatment adherence or unconventional therapies, and those remaining symptomatic despite high doses of anti-asthmatic therapies [13, 14].
Nonadherence to prescribed medication has been identified in a number of studies in the developed countries as the most common clinical problem amongst adults  and children  with asthma, including those with difficult-to-control asthma [15, 17]. Appropriate assessment of adherence  and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors, etc.)  has to be a priority in clinical assessment of all patients with difficult-to-control asthma, before any decision about increasing the treatment is made (including possible prescription of an expensive biological therapy) .
The clinical diversity and the underlying pathophysiology of severe treatment-resistant asthma need to be characterized, so that rational therapeutic targets can be identified and relevant biomarkers validated . In addition, there is a need for controller as well as noninterventional studies in this patient population.
Asthma exacerbations in childhood
Although inhaled corticosteroids may protect against asthma exacerbations due to allergen exposure, they are reported to be relatively ineffective in children with virus infection-induced wheezing . This suggests the existence of different types of childhood asthma with different underlying pathophysiologies [22, 23]. Recent joint modelling of longitudinal observations on wheezing from parental reports and medical records identified a novel phenotype of persistent troublesome wheeze with high rates of severe asthma exacerbations and healthcare utilization . Despite having phenotypic markers commonly considered to be indicators of good therapeutic response (atopy and eczema), these children had relatively poor response to currently available anti-inflammatory treatments .
An atopy-related phenotype of children with high risk of asthma exacerbations has recently been identified by Bayesian inference in two birth cohort studies in which multiple skin and IgE tests were collected throughout childhood [25, 26]. The analysis revealed several different atopic vulnerabilities, only one of which had a much higher risk of asthma exacerbations [25, 26]. However, this group of children with a significant risk of asthma exacerbations was identified only using longitudinal data, and cross-sectional biomarkers allowing their identification in clinical practice are still lacking.
Asthma exacerbations in adults
Several attempts have been made to identify predictors of asthma exacerbations. Several comorbidities associated with recurrent asthma exacerbations have been identified in adult patients , including severe nasal sinus disease, gastro-oesophageal reflux disease, recurrent respiratory infections, psychological dysfunction and obstructive sleep apnoea. Psychological dysfunction  and treatment nonadherence are separate psychosocial factors that may significantly contribute to the risk of asthma exacerbations. A significant number of patients with high rates of asthma exacerbations, and increased airway eosinophilia, were found to have a low perception of their lung dysfunction . Asthma exacerbations are frequent in asthma patients with poor treatment adherence, and poor adherence remains one of the major challenges in the treatment of severe asthma [15, 18].
The basis of asthma treatment guidelines is the use of clinical symptoms or impaired lung function to guide treatment of airway inflammation. However, there is a strong rationale for using direct measurement of airway inflammation as an additional means to guide treatment in severe asthma. Green et al.  reported that titrating treatment to sputum eosinophil counts was more successful in reducing asthma exacerbations than treatment in accordance with guidelines. This was confirmed in a larger, multicentre study , which also reported that the frequency and severity of eosinophilic exacerbations were reduced without increasing the dose of inhaled corticosteroids (ICS) (the severity but not the frequency of noneosinophilic exacerbations was also reduced). The treatment strategy of these authors was to (i) treat patients with sputum eosinophil counts of >2% with the minimal ICS dose required to reduce sputum eosinophil counts to normal and (ii) consider other treatment options in patients with normal sputum eosinophil counts, such as treatment of airway obstruction with long-acting beta-agonists (LABAs) or a leukotriene receptor antagonist, or treatment of neutrophilic inflammation with antibiotics. Of interest, a treatment approach aimed at specifically reducing airway eosinophils using a monoclonal antibody directed against interleukin (IL)-5 reduced the risk of asthma exacerbations in patients with severe asthma and persisting airway eosinophilia [32, 33]. However, it is of note that even after using this targeted approach, approximately 50% of severe exacerbations remained unaffected by the treatment.
Attempts to identify clinical biomarkers for predicting the risk of asthma exacerbation have so far failed. However, some small studies have identified possible candidate biomarkers. For example, Gelb et al.  evaluated the use of spirometry and exhaled nitric oxide (FENO) in predicting the risk of asthma exacerbations in 44 stable, mild-to-severe patients with asthma over 18 months. Those patients with a baseline FEV1 < 76% of predicted plus an FENO >28 ppb had a probability of an asthma exacerbation in 18 months of 85%, while those with FEV1 > 76% of predicted plus a FENO <28 ppb had zero probability of an asthma exacerbation in the same period. The FENO parameter may be a robust measure of the degree of eosinophil airway inflammation [35, 36].
Asthma exacerbations and infection
Numerous epidemiological studies indicate that asthma exacerbations are associated with upper respiratory viral infections, mostly with rhinoviruses, and to a lesser degree with respiratory syncytial virus or coronavirus, with frequency estimates of 85% and 60% for childhood and adult asthma, respectively [37, 38]. This was confirmed by the GA2LEN-DARE systematic review  that reviewed data from 98 published epidemiological studies. The data for childhood asthma are more extensive than that for adult asthma and reveal the absence of geographical influence.
The same review indicated that high rates of respiratory bacterial infections are also associated with asthma exacerbations, but the data are inconsistent. However, Bisgaard et al.  provided evidence that bacterial infection and viral infection were independently associated with wheezing episodes in infants (<3 years old), with odds ratios of 2.9 and 2.8, respectively.
Although confirmatory studies need to be performed, current data strongly suggest that respiratory infections are the major cause of asthma exacerbations. Case–control studies have revealed a synergism between viral infection and allergen exposure in increasing the risk of asthma exacerbation requiring hospitalization in children  and in adults .
Airway infection and impaired innate immunity
Atopic asthmatic patients have more severe and prolonged lower respiratory tract symptoms during rhinovirus infections than nonatopic healthy controls . This may be explained by impaired innate and acquired immunity of the airways in asthma, as indicated from the studies of experimental and clinical viral infection [37, 44]. Such impairments in airway immunity correlate with the in vivo severity of the infections and with the viral load [45, 46]. Consequently, specific and nonspecific antiviral strategies may have great potential as therapeutic and preventative strategies for asthma exacerbations, a hypothesis that is supported by preliminary clinical studies . Patients with asthma also have deficient interleukin-12 and type III interferon responses to bacterial stimuli, suggesting that inadequate host defence mechanisms and mechanisms specific to the infectious agents are the underlying factors for increased susceptibility [45, 46]. Rhinovirus and enterovirus infections are more likely to cause an asthma exacerbation than most other viruses in patients of any age, with the exception of RSV in infants , while virus load and virus co-infection rates correlate with symptom severity .
Case–control studies indicate that asthma subjects are at greater risk of invasive pneumococcal infections than patients without asthma, with reported ORs ranging from 2.5 to 12.0 [48-50]. For example, the population-based case–control study by Klemets and colleagues  assessed the risk of invasive pneumococcal (Streptococcus pneumoniae) infection (IPI) amongst adult patients with asthma. Using a national population-based laboratory surveillance, 1,282 cases of IPI were selected in patients aged 18–49 years (thus largely excluding COPD patients) along with 10 noninfected controls per IPI case, matched for age, sex and health district. Asthma cases were categorized as high (≥1 hospitalization within the previous 12 months) and low risk (with prescription drug entitlement and no hospitalization within the previous 12 months). Overall, 7.1% of cases had asthma (6.0 and 2.4% with high- and low-risk asthma, respectively) vs 2.5% of controls (1.0 and 1.1% with high- and low-risk asthma, respectively), indicating that adults of working age with asthma are at substantially increased risk of IPI.
Impaired immune responses may be associated with exacerbations in asthmatic children with reduced lung function, but not in those with normal lung function . Specifically, at the time of an asthma exacerbation, a lower expression of Th1 response genes was observed in children with reduced lung function than in children with normal lung function. Other studies have shown that genetic factors such as vitamin D  or particulate matter (PM10)  can modify the effect of environmental exposure on exacerbation frequency. The advent of genomewide association studies in populations with severe asthma  and asthma exacerbations  may aid in better prediction of exacerbation phenotypes and the subclassification of patients into subphenotypes that may reflect the differing aetiopathogenesis and response to treatment and so allowing better targeting of treatment.
Attempts to characterize severe asthma in childhood
In childhood asthma, guidelines that outline stepwise treatment escalation with increased disease severity or impaired symptom control fail to adequately deal with nonresponders [56-58]. In particular, the stepwise treatment appears not always to be appropriate for children younger than 4 years, particularly those with mainly virus-driven asthma, who often do not respond to inhaled corticosteroids .
Severe asthma in children is complex, with the asthma phenotype changing during development and requiring continual reassessment [56, 58, 59]. This makes cross-sectional analyses of childhood asthma less useful, as any apparent phenotypic stability within a population will obscure the significant individual instability of disease expression. One of the characteristics of severe treatment-resistant asthma in childhood is the large size of skin test wheal to inhalant and food allergens . Furthermore, in this patient group, the results of skin tests and IgE measurements for individual allergens are not always concordant; as a consequence, both tests should be carried out and quantified . Similar quantitative relationship between skin tests (and sIgE levels) has also been reported in relation to severity of airway hyper-reactivity in adults .
Rhinovirus infection in infants induces wheeze and, in a longitudinal study, was shown to be significantly associated with the development of childhood asthma . In another 11-year prospective study, teenage asthma was strongly associated with infant wheezing requiring hospitalization . This study identified eczema and allergen-specific IgE as early asthma-predictive factors and the risk of developing teenage asthma to be increased fivefold after respiratory syncytial virus-induced wheezing in infants and >10-fold after rhinovirus-induced wheezing. Rhinoviruses are frequently found in the lower airways in infants with recurrent respiratory symptoms, with the majority of these rhinovirus-infected infants exhibiting increased airway resistance . In infants with wheezing requiring hospitalization, sole rhinovirus infection, but not sole infection with any other common airway viruses, was associated with atopy . A recent study has demonstrated that a cardinal feature of bronchial epithelial cells from children with severe treatment-resistant asthma is impaired interferon-β and IFN-λ induction by rhinovirus . Although this patient group was highly atopic, no relationship was observed between atopy, allergy or Th2-mediated inflammation with impaired interferon .
A longitudinal study of an unselected birth cohort, which monitored lung function from the age of 3–26 years , reported that persistent wheezing, starting early in life, was associated with a decline in lung function in adult life and increased risk of exacerbations. A decline in lung function has also been associated with severe asthma exacerbations in adult asthma . A German birth cohort of more than 900 children showed that the risk of development of persistent asthma at age 13 years was significantly increased by early allergen sensitization in combination with exposure to high levels of perennial allergens early in life . In a recent study, predictors of subsequent troublesome symptoms amongst 3-year-old children with wheezing were large skin test responses to allergens and history of previous exacerbations and eczema .
Attempts to characterize severe asthma in adults
Attempts to identify phenotypes of adult asthma include the use of unsupervised cluster analyses [70, 71] aiming to group patients who share key features of asthma and airway inflammatory disease. Haldar and colleagues  grouped patients according to clinical symptoms and evidence of airway inflammation (based on sputum eosinophil count) and found that symptom-led treatment of airway inflammation was appropriate in patients with mild and moderate asthma, but failed in more severe forms. They identified two discordant groups of patients who were refractory to standard treatment approaches and represented about 25% of all patients. One discordant group of patients were characterized as an obese, symptom-predominant, noneosinophilic phenotype, while the other group had few asthma symptoms, but a high degree of airway inflammation. Using symptom-driven asthma treatment in these two discordant groups would lead to overtreatment of the former and undertreatment of the latter group.
One difficulty with attempts to use clustering techniques to define disease mechanisms is defining cause and effect. In other words, ‘are the pathophysiological features a consequence or an underlying cause of the disease?’ A further confounding factor is the influence of treatment or lack of it (nonadherence). Defining groups of patients with chronic diseases according to different personality traits  has identified personality traits that govern treatment adherence.
There was a significant overlap between the phenotypes identified by Haldar et al.  and those identified by Moore et al. . Other similar initiatives included the EU-sponsored Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium that has published a consensus-based systematic algorithm approach to differentiate between ‘problematic’, ‘difficult’ and ‘severe refractory’ asthma in the evaluation of patients with chronic severe asthma symptoms for use in clinical research and specialized care . The published PRACTAL consensus report on ‘endotypes’  attempts to assign patients with asthma to groups sharing specific pathophysiological features, with the aim of identifying a basis for rational treatment of heterogeneous groups. Patients with severe asthma are found in each of these groups. Three recognizable clinical phenotypes of severe asthma emerge from these various analytical studies (see Table 1): (i) a severe atopic form, (ii) severe ‘intrinsic’ asthma (the most malignant severe asthma phenotype ) and (iii) severe asthma with obesity. However, it has to be emphasized that distinct pathophysiological mechanisms underpinning these different clinical phenotypes of severe asthma have not as yet been identified.
Table 1. Four distinct clinical phenotypes of severe asthma and their characteristics
|Severe atopic form||High serum IgE levels|
|Detectable allergen-specific IgEs|
|Frequently presenting with fungal sensitivity (predominantly to Aspergillus).|
|Severe ‘intrinsic’ asthma||High eosinophil counts in bronchoalveolar lavage fluid|
|Severe asthma with obesity||Several comorbidities|
|Gastro-oeosophageal reflux disease|
|Low eosinophil counts|
|Sudden asthma attacks||Recurrent in otherwise mild asthmatics|
|More frequent in women|
|Triggered by allergens, drugs, food, chemicals|
|Often unrecognized cause|
One potential problem of the cross-sectional approach to unbiased clustering is that the analysis does not include the important dimension of time, which may be essential to take into account potentially crucial longitudinal changes. Furthermore, while unsupervised learning may be a useful tool to generate new hypotheses, using these techniques to find an association with predefined outcomes such as severe asthma can be misleading if asthma severity is derived using the same variables that are used for clustering.
There is mounting evidence to demonstrate a close association between sensitisation to fungi and asthma severity , and the term ‘severe asthma with fungal sensitization’ (SAFS) has been proposed for patients with persistent severe asthma and fungal sensitization . Proof-of-concept pilot studies have suggested an improvement in asthma after antifungal treatment in this patient group .
Treatment approaches to severe asthma and prevention of asthma exacerbations
Several studies have shown that the standard guideline treatment of persistent asthma with ICS provides a variable response, with 25–35% of asthmatic subjects showing little improvement in FEV1 and/or bronchial hyper-responsiveness [9-11]. In the Gaining Optimal Asthma Control (‘GOAL’) study , Bateman and colleagues used 1 year of increasing doses of combined ICS and LABA treatment in patients with persistent asthma and reported that about 30% of patients, with varying degrees of disease severity, did not achieve ‘well-controlled asthma’. Asthma exacerbation risk may be further reduced using the same medication (i.e. an inhaled combination of a rapid-acting beta-2 agonist and corticosteroid ) as a controller and as a reliever of the disease. The PRICE trial  aimed to identify predictors of short-term (6 weeks) response to ICS. Although several baseline biomarkers and asthma symptoms correlated with short-term improvements, only greater bronchodilator (short-acting β2-agonist) reversibility showed a strong (P < 0.001) correlation. Differentiating between responders (>5% FEV1 improvement) and nonresponders (<5% FEV1 improvement) revealed that asthma control in responders was maintained only with continued ICS, while, in nonresponders, no improvement was observed with or without ICS. Interestingly, tiotropium, a long-acting antimuscarinic agent, still approved only for COPD, has been recently shown to further improve lung function in patients with severe uncontrolled asthma .
Of the four clinical phenotypes of severe asthma described in Table 1, the severe atopic form partially responds to standard treatment. Table 2 indicates possible treatment approaches in the two groups of patients with severe asthma, which were described by Haldar et al. , that are less responsive to standard treatment. These treatment options for patients with severe asthma who remain symptomatic despite adhering to standard medical care include novel anti-inflammatory drugs that have been shown in preliminary studies to be effective in treating airway inflammation in asthma and so warrant further investigation [32, 83-86], and other novel approaches such as bronchial thermoplasty . It is important to note that, for a more effective use of these novel treatment options, a better understanding of the pathophysiology and of the inflammatory mechanisms of the severe asthma subtypes are required in order that studies can delineate specific response patterns. As previously noted, antifungal treatments may be of benefit in patients with severe asthma with fungal sensitization [78, 88], but large studies are needed to support these initial findings.
Table 2. Possible treatment approaches in treatment-resistant severe asthma
|Severe asthma with obesity||Focus on comorbidities|
|Reduction in body weight|
|Cessation of smoking|
|Direct treatment of airway smooth muscle|
|Treating impaired airway defences|
|Targeting neutrophil-driven inflammation of the lower airways|
|Treatment of rhinosinusitis|
|Severe ‘intrinsic’ asthma||Focus on nasal polyps|
|Reducing air trapping using ICS|
|Novel anti-inflammatory drugs shown to be effective in airway inflammation|
|Omalizimab  (an anti-IgE monoclonal antibody for treatment of eosiniphilic inflammation) is effective in improving asthma control, reducing asthma exacerbations  and reducing seasonal peaks in exacerbations (especially in patients with increased (>2%) FENO) .|
|Mepolizamab (anti-interleukin-5 monoclonal antibody) reduces asthma exacerbations and airway inflammation in patients selected for eosinophilic airway inflammation [32, 33].|
|Sudden asthma attacks||Focus on education of the patient to avoid trigger|
|Focus on education of the patient to treat attacks|
|High dose inhaled rapid-acting bronchodilators|
|High dose oral steroids|
|Intramuscular adrenaline if required|
|Prompt referral to the emergency room|
Current treatment of asthma exacerbations is inadequate, and new approaches to treatment are needed. These may include interferon-based treatments, treatments that aim to boost deficient antiviral immune responses and/or specific antiviral treatments. There may be patients with severe asthma who could benefit from treatments that target neutrophilic inflammation without further suppressing anti-infective immunity. Another question that needs to be addressed is the possible benefit in asthma exacerbations of antibacterial treatments that are widely used , despite not being recommended in guidelines.
The advances in molecular biology and immunology are being used to develop novel biological drugs for asthma treatment. These include therapeutic antibodies, soluble receptors, cytokines, small molecules and combinations thereof that target different effector molecules that influence the underlying immune and inflammatory processes. Some biological drugs are currently in clinical trials in asthma . However, there are major difficulties in developing novel drugs to treat asthma. These include (i) the complexity of the disease (in terms of the different disease phenotypes and the underlying molecular mechanisms), (ii) the limited number of biomarkers that have been identified for disease classification, (iii) the effectiveness of the current standard treatment approaches (combined inhaled steroid and beta-adrenergic agonist is not only effective but cheap) makes any comparative improvement difficult to identify in multicentre clinical trials, (iv) low patient adherence, which is characteristic of treatments of chronic disease, and (v) preclinical animal models may be poorly predictive of clinical efficacy .
Importantly, future clinical trials will need to identify the patient groups that respond to novel treatment to provide evidence for the stratified, personalized approach to asthma management.
Severe asthma in primary care
In primary care, recognition of the clinical heterogeneity of asthma and the existence of different forms of severe asthma is obscured by a number of general deficiencies, including limited available time and clinical resources and lack of capacity and clinical capability. Nonguideline treatment of asthma is high, and provision of treatment to patients with asthma varies greatly, for example, in the use of ICS across European countries . The influence of comorbidities and of asthma exacerbations on asthma symptoms, in both children and adults, are not sufficiently recognized [92, 93]. Most patients with asthma in primary care have been found to have uncontrolled disease . Furthermore, it is becoming increasingly clear that many patients diagnosed as asthmatic, even after full evaluation at tertiary centres, do not have asthma, but various other diagnoses [95, 96], which indicate a fundamental need to establish improved diagnosis as a basis of appropriate management . The resources needed to review patients frequently until disease control is achieved vary between healthcare systems. The Finnish National Asthma programme , predicated on a systematic approach to disease management and underpinned by educational and skills training in primary care, demonstrates that investment in the structure of the health system that delivers asthma care reduces morbidity significantly and at a lower overall cost.
The above discussion aims to highlight the prominent issues and the attempts to acquire a better understanding of asthma exacerbations and severe asthma. However, there are several additional clinical and pathophysiological issues of importance for improving our understanding of asthma as a complex disease. These have not been highlighted here partly because there is no scientific consensus of their exact relevance. However, two examples are briefly reviewed here.
Airway remodelling is associated with poor clinical outcomes amongst asthmatic patients, but the pathophysiological relevance of, and the effect of treatment on, airway remodelling is unclear . Airway remodelling is a feature of adult asthma and is found to a similar extent, and quite early, in children with difficult-to-treat asthma . Using epithelial reticular basement membrane thickening as a marker for airway remodelling, no association between airway remodelling and age, symptom duration, lung function and concurrent eosinophilic airway inflammation was found , albeit in a small number of patients. Inflammatory and structural changes typical of asthma, such as airway eosinophilia and angiogenesis, have been observed not only in children with asthma but also in atopic children without asthma, raising the possibility that some of these pathological lesions may be associated with atopy even in the absence of asthmatic symptoms. Reticular membrane thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in the wheezing infants with reversible airflow obstruction, even in the presence of atopy [101, 102]. It was proposed that this lack of RBM thickening in wheezy infants was due to the apparent paucity of eosinophilic inflammation , which may have a role in driving allergic airway remodelling .
Based on the data from many population studies, it is generally considered that the environment has an important influence on the development of asthma and other allergic diseases. However, the proposed mechanisms, particularly the role of atopy, that underlie the effects of environment on asthma aetiology need to be revised in the light of recent findings , such as the evident increase in prevalence of severe asthma in developing countries and its parallel decline in several developed countries . The interaction of environment and asthma disease mechanisms is complex, and genetic variants that are protective in one environment may be associated with increased risk in another environment .
Conflicts of interest
A. Custovic serves as a consultant for Circassia. He received speaker fees from Glaxo Smith Kline, Thermo Fisher Scientific, Airsonet, Novartis, MSD and ALK. He received research grants from the UK Medical Research Council, Moulton Charitable foundation National Institute of Health Research.
In the past five years S. L. Johnston has had research grants from Astra Zeneca, Centocor, GlaxoSmithKline, MedImmune, Sanofi-Pasteur and Synairgen. S. L. Johnston holds share options in Synairgen. S. L. Johnston does some consultancy work for AstraZeneca, Centocor, GlaxoSmithKline, MedImmune, Sanofi-Pasteur and Synairgen.
In the last five years, I. D. Pavord has received speaker's honoraria for speaking at sponsored meetings from Astra Zeneca, Boehringer Inglehiem, Aerocrine and GSK. He has received honoraria for attending advisory panels with Almirall, Astra Zeneca, Boehringer Ingelheim, GSK, MSD, Schering-Plough, Novartis, Dey and Napp. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, Astra Zeneca and Napp.
M. Gaga received research grants from Novartis, BI, Cephalon, Teva and GSK.
L. M. Fabbri has received consultancy fees from: Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Nycomed, Pearl Therapeutics, Sterna, Peer Voice Europe, OM Pharma Sa, Kyorin Pharmaceutical, Boston Scientific and Bayer. Readings, advisory board or reimbursement of expenses: AstraZeneca, Novartis, Sigma-Tau, Roche, Deutsches Zentrum für Luft und Raumfahrt, German Aerospace Center, Mundipharma Int., Genetech Inc., Elevation Pharmaceutical, Ferrer Group, Nycomed, Dynamicon and Laboratori Guidotti.
E. Bel has received consultancy fees from Novartis, GSK and Sanofi-Regeneron, and fees for speaking from GSK.
P. Le Souëf has received speaker fees from Glaxo Smith Kline and AstraZeneca and has received research funding from AstraZeneca and Pharmanet AG. He has received research grants from the National Health and Medical Research Council of Australia and the Australian Research Council.
J. Lötvall has over the last five years been a consultant and/or given lectures for GSK, AstraZeneca, Aerovant, Novartis, UCB, Oriel and Merck, for which he has received honoraria. He has also received research grants and participated in clinical trials for Novartis, GSK, AstraZeneca and Actelion under the full organization of the University of Gothenburg.
P. Demoly is a consultant and a speaker for Stallergenes, ALK, Circassia and Chiesi and is a speaker for Merck, AstraZeneca, Menarini and GlaxoSmithKline.
C. Akdis serves in the scientific advisory boards of Novartis, Actellion, Circassia, Allergopharma and Stallergenes. He received research grants from Novartis, Swiss National Science Foundation, Swiss-Polish Research Grant.
D. Ryan has been supported to attend conferences, provide consultancy services to or lectured on behalf of AZ, Novartis, Chiesi, Mundipharma, MSD and Aerocrine.
Mika Mäkelä has received speaker fees from Berlin-Chemie Menarini, GlaxoSmithKline, MSD and Orion Pharma. He serves as a consultant for Orion Pharma. He received research grant from Sigrid Juselius Foundation and Helsinki University Hospital Research Grant.
F. D. Martinez served as a consultant to MedImmune in 2010. He received speaker fees from Merck in 2011 and from Abbott in 2011 and 2012. He receives grant funds from the National Institutes of Health.
P. O'Byrne serves in the scientific advisory boards of Abbott, AstraZeneca, Asmacure, Boehringer Ingelheim, GlaxoSmithKline and Medimmune Merck. He received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Nycomed, and also he received grants from AIM, Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Novartis and ONO.
A. Papi has been on scientific advisory boards and received speaker fees from AstraZeneca, Chiesi, GlaxoSmithKline, Teva, Mundipharma, Novartis, BI, Almirall and Menarini. He received research grants from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, BI and the University of Ferrara.
A. Magnan serves as a consultant for Novartis, Takeda Mundipharma and Boehringer. He received speaker fees from Glaxo Smith Kline, Chiesi, Novartis, MSD and Mundipharma. He received research grants from MSD.
E. Hamelmann serves as a consultant for Boehringer Ingelheim, HAL Allergy, ALK and Novartis. He received speaker fees from Stallergenes, Symbiopharm, Novartis and ALK. He received research grants from the German National Research Foundation (DFG), the German Ministry for Education and Research (BMBF), and the Ministry for Education and Research of Nordrhein-Westfalen.
N. G. Papadopoulos has received payment for consultancy from AbbVie, Novartis, Menarini, MEDA for lectures from Novartis, URIACH, GSK, ALLERGOPHARMA, Stallergens for development of educational presentations from URIACH, MEDA and grants from Nestle, MSD and GSK.
The other authors of the paper declare no conflicts of interest.