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The aim of the present study was to investigate whether repeated peak exposure (gassings) to sulphur dioxide (SO2) and other irritant gases increases the risk of new-onset asthma. A questionnaire was sent to 4,112 sulphite workers, of whom 1,919 completed the questionnaire and 396 completed the short-form questionnaire, which was sent out as a last reminder. A sample of 130 nonrespondents completed a telephone interview using the short-form questionnaire. The incidence of adult-onset, physician-diagnosed asthma during employment duration was analysed in relation to exposure to SO2 and gassings giving rise to respiratory symptoms. Incidence rates, as well as incidence rate ratios with 95% confidence interval (CI), were calculated. Further Cox regression models were used allowing assessment of hazard ratios (HR) stratified for sex and adjusted for atopy, smoking habits and age. The incidence rate for asthma among sulphite mill workers reporting gassings of SO2 was 6.2 out of 1,000 person-yrs, compared with 1.9 out of 1,000 person-yrs among subjects unexposed to SO2 and any gassings (HR (95% CI) 4.0 (2.1-7.7)). Among males reporting gassings to SO2, the HR (95% CI) for asthma was 5.8 (2.6-13) compared with unexposed males. In conclusion, repeated peak exposure to sulphur dioxide increased the incidence of asthma during work in sulphite pulp mills, which supports the hypothesis of irritant-induced asthma.

Background: There are now many biological therapies to treat severe asthma. To assess which work best for which patient, we need to develop definitions of response. This narrative review aims to capture severe asthma patients' perceptions about non-response and response to biological therapy., Methods: Four bibliographic databases were searched from inception to September 2021. Grey literature was searched with the involvement of patient representatives. A thematic approach was used for synthesis. No qualitative studies specifically explore patients' perspectives on response to biological therapy for severe asthma. Three papers and one published asthma patient interview were included. Relevant grey literature was included from online discussion forums, blogs and social media websites., Results: Adult patients framed positive response to biological therapy in terms of reduced burden of disease and treatment. Both were multifaceted. Some patients experienced reduced benefit from biological therapy over time. There was a group of patients who described a limited response or non-response to biological therapy. This was framed within the context of continuing hospitalisation and oral corticosteroid treatment. The speed of onset of benefit was felt to be important by some., Conclusions: Definitions of non-response and response need to be patient-centred, yet there is a complete lack of qualitative research focused on this topic. By combining relevant published and grey literature we have provided a description of adult patients' perceptions of response to biological therapy in severe asthma. We now need to understand the views of children and adolescents with severe asthma and their carers, and diverse patient experiences in real-world settings., Competing Interests: Conflict of interest: All authors report that funding was received to support this work by the European Lung Foundation (ELF) from European Commission's Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 831434 (3TR). C. Coleman and C. Williams are employees of the ELF. There are no further disclosures., (Copyright ©The authors 2023.)

Background: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children., Methods: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach., Results: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework., Conclusion: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future., Competing Interests: Conflict of interest: E.A. Gaillard reports consultancy work for Boehringer Ingelheim with money paid to the University of Leicester; investigator led research grants from Circassia, Gilead and Chiesi Ltd; research collaboration with Medimmune. Conflict of interest: C.E. Kuehni has nothing to disclose. Conflict of interest: S. Turner has nothing to disclose. Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: K.A. Holden has nothing to disclose. Conflict of interest: C.C.M. de Jong has nothing to disclose. Conflict of interest: C. Lex reports other (lecture fee paid to institution) from Novartis, outside the submitted work. Conflict of interest: D.K.H. Lo has nothing to disclose. Conflict of interest: J.S. Lucas reports grants and non-financial support (provision of equipment) from Circassia, outside the submitted work. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: R. Mozun has nothing to disclose. Conflict of interest: G. Piacentini has nothing to disclose. Conflict of interest: D. Rigau acts as ERS methodologist. Conflict of interest: B. Rottier has nothing to disclose. Conflict of interest: M. Thomas reports personal fees from GSK, Boehringer Ingelheim and Chiesi, outside the submitted work. Conflict of interest: T. Tonia acts as ERS Methodologist. Conflict of interest: J. Usemann reports personal fees from Vertex, outside the submitted work. Conflict of interest: O. Yilmaz reports non-financial support for meeting attendance from Abdi Ibrahim, other (lecture fees) from Novartis, outside the submitted work. Conflict of interest: A. Zacharasiewicz has nothing to disclose. Conflict of interest: A. Moeller has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Artificial intelligence (AI) when coupled with large amounts of well characterised data can yield models that are expected to facilitate clinical practice and contribute to the delivery of better care, especially in chronic diseases such as asthma.The purpose of this paper is to review the utilisation of AI techniques in all aspects of asthma research, i.e. from asthma screening and diagnosis, to patient classification and the overall asthma management and treatment, in order to identify trends, draw conclusions and discover potential gaps in the literature.We conducted a systematic review of the literature using PubMed and DBLP from 1988 up to 2019, yielding 425 articles; after removing duplicate and irrelevant articles, 98 were further selected for detailed review.The resulting articles were organised in four categories, and subsequently compared based on a set of qualitative and quantitative factors. Overall, we observed an increasing adoption of AI techniques for asthma research, especially within the last decade.AI is a scientific field that is in the spotlight, especially the last decade. In asthma there are already numerous studies; however, there are certain unmet needs that need to be further elucidated., Competing Interests: Conflict of interest: K.P. Exarchos has nothing to disclose. Conflict of interest: M. Beltsiou has nothing to disclose. Conflict of interest: C-A. Votti has nothing to disclose. Conflict of interest: K. Kostikas reports grants, personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini and Novartis, grants from NuvoAir, personal fees from Sanofi, outside the submitted work; and was an employee and shareholder of Novartis Pharma AG until October 2018., (Copyright ©ERS 2020.)

The US Food and Drug Administration's procedure for scale validation requires a documented stepwise process of qualitative and quantitative data. The aim of this paper is to provide final quantitative validating data for the Severe Asthma Questionnaire (SAQ).The SAQ, Asthma Control Test, Mini Asthma Quality of Life Questionnaire and EQ-5D-5L were completed by 160 patients attending a severe asthma clinic; 51 patients completed the SAQ on two occasions for test-retest reliability analysis. The SAQ produces two scores, a SAQ score based on the average of 16 items and a SAQ-global score from a single 100-point global quality of life scale.Construct validity was demonstrated by factor analysis of the 16 items, convergent validity by correlations of >0.6 between the SAQ, SAQ-global and other questionnaires, and discriminant validity by the ability of the SAQ and SAQ-global to distinguish between different treatment levels. Test-retest reliability (intra-class correlation) was 0.93 for the SAQ and 0.93 for the SAQ-global, and the alpha coefficient for the SAQ was 0.93.The SAQ was developed using recommended qualitative and quantitative procedures for scale development, and can be used to gain insight into patients' perceptions of how severe asthma and its treatment affects their lives., Competing Interests: Conflict of interest: M.E. Hyland reports an unrestricted medical educational grant from Novartis and non-promotional grant from AstraZeneca during the conduct of the study, and speaker fees from Novartis and GlaxoSmithKline outside the submitted work. R.C. Jones reports an unrestricted medical educational grant from Novartis and non-promotional grant from AstraZeneca, during the conduct of the study; and personal fees from GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Chiesi, Cipla, Novartis and Pfizer outside the submitted work. Conflict of interest: J.W. Lanario reports an unrestricted medical educational grant from Novartis and non-promotional grant from AstraZeneca during the conduct of the study and speaker fees from Novartis outside the submitted work. Conflict of interest: M. Masoli reports unrestricted non-promotional grants from Novartis and AstraZeneca, who supported the initial study of patient interviews and questionnaire development. The SAQ validation study has been supported through Plymouth Hospitals NHS Trust research fund. M. Masoli has received speaker fees from Novartis and Astra Zeneca outside the submitted work., (Copyright ©ERS 2018.)

On February 21, 2017, a European Respiratory Society research seminar held in Barcelona discussed how to best apply precision medicine to chronic airway diseases such as asthma and chronic obstructive pulmonary disease. It is now clear that both are complex and heterogeneous diseases, that often overlap and that both require individualised assessment and treatment. This paper summarises the presentations and discussions that took place during the seminar. Specifically, we discussed the need for a new taxonomy of human diseases, the role of different players in this scenario (exposome, genes, endotypes, phenotypes, biomarkers and treatable traits) and a number of unanswered key questions in the field. We also addressed how to deploy airway precision medicine in clinical practice today, both in primary and specialised care. Finally, we debated the type of research needed to move the field forward., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

We analysed the influence of rhinovirus (RV) in nasopharyngeal fluid (NPF) on type I and III interferon (IFN) responses (e.g. IFN-α and IFN -: λ) and their signal transduction, at baseline and during disease exacerbation, in cohorts of pre-school children with and without asthma.At the time of recruitment into the Europe-wide study PreDicta, and during symptoms, NPF was collected and the local RV colonisation was analysed. Peripheral blood mononuclear cells (PBMCs) were challenged in vitro with RV or not. RNA was analysed by quantitative real-time PCR and gene arrays. Serum was analysed with ELISA for IFNs and C-reactive protein.We found that PBMCs from asthmatic children infected in vitro with the RV1b serotype upregulated MYD88, IRF1, STAT1 and STAT2 mRNA, whereas MYD88, IRF1, STAT1 and IRF9 were predominantly induced in control children. Moreover, during symptomatic visits because of disease exacerbation associated with RV detection in NPF, IFN-α production was found increased, while IFN-λ secretion was already induced by RV in asthmatic children at baseline.During asthma exacerbations associated with RV, asthmatic children can induce IFN-α secretion, indicating a hyperactive immune response to repeated respiratory virus infection., (Copyright ©ERS 2017.)

Asthma is a highly prevalent chronic condition worldwide, and is particularly common in younger people compared to other chronic conditions. Asthma can result in a number of symptoms that are detrimental to the quality of life of sufferers. The aim of the present systematic literature review was to analyse the existing literature on the relationship between asthma and fatal and nonfatal suicidal behaviours. Articles were retrieved from Scopus, PubMed, ProQuest and Web of Knowledge. We searched for the terms (suicid* OR self-harm) AND (asthma* OR "bronchial hyperreactivity") published in English-language peer-reviewed journals between 1990 and December 2014. Original research papers providing empirical evidence about the potential link between asthma and suicidal behaviours were included. The initial search identified 746 articles. Specific limiting criteria reduced the number of articles to the 19 articles that were finally included in the systematic review. The review found a potential link between asthma and suicide mortality, ideation and attempts across the age groups. Limitations of the review include the restriction to English-language papers published within the chosen time period, the limited number of papers involving suicide mortality, and the fact that the majority of papers originated from the USA., (Copyright ©ERS 2015.)

Clinical trials do not report sputum eosinophil data in a consistent method and this makes it difficult to compare across studies and to evaluate the sample sizes estimated in these studies. The objectives of the paper are: 1) to systematically review reporting of effect size and sample calculations in randomised controlled trials using sputum eosinophil count as a primary outcome and 2) to illustrate sample size estimation under different methods of data representation using data from an effective anti-eosinophil treatment strategy (mepolizumab). Randomised controlled trials in adults (excluding allergen provocation models) of treatment of asthma and chronic obstructive pulmonary disease for the past 10 years were searched in Ovid MEDLINE and 20 studies were identified that met all the inclusion criteria. Only nine studies discussed sample size calculation. Change from baseline was used as an outcome in 11 studies and was expressed as change in absolute percentage count, percentage change from baseline or as fold changes. Assuming a minimal clinically important reduction of 15% in absolute terms, 18 subjects in each arm will be required to achieve 80% power using an ANCOVA analysis, which we recommend, to detect significance with an alpha error of 0.05.

This systematic review and meta-analysis sought to investigate whether asthma exacerbations, oral corticosteroid use or asthma severity are associated with prematurity and intrauterine growth restriction. Cohort studies published between 1975 and March 11, 2012 were considered for inclusion. 138 publications were identified for possible inclusion, and nine papers met the inclusion criteria, by reporting perinatal outcomes of interest (low birth weight, <2500 g), pre-term birth (<37 weeks gestation unless otherwise stated) and small for gestational age (<10th percentile for gestational age and sex) in groups of asthmatic patients stratified by history of exacerbations, oral corticosteroid use or asthma severity. Maternal asthma exacerbations and oral corticosteroid use had a significant effect on outcomes, including low birth weight (RR 3.02, 95% CI 1.87-4.89 and RR 1.41, 95% CI 1.04-1.93, respectively) and pre-term delivery (RR 1.54, 95% CI 0.89-2.69 and RR 1.51, 95% CI 1.15-1.98, respectively). Moderate-to-severe asthma during pregnancy was associated with an increased risk of small for gestational age (RR 1.24, 95% CI 1.15-1.35) and low birth weight (RR 1.15, 95% CI 1.05-1.26) infants. These data suggest that asthma exacerbations, oral corticosteroid use or asthma severity defined as moderate-to-severe may be associated with pre-term delivery, low birth weight, and small for gestational age infants. Further studies on the effect of maternal asthma control on perinatal outcomes are warranted.

We reviewed the main epidemiological studies that evaluate the respiratory effects of indoor air pollutants quantitatively in industrialised countries. Consistent results support short-term (aggravation) and, although more rarely, long-term (prevalence augmentation) effects on asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD) in indoor settings with poor air quality. Environmental tobacco smoke is one of the most important risks for respiratory symptoms and diseases worldwide. The evidence is also reliable for indoor nitrogen dioxide and particulate matter, which have been associated with asthma, bronchitis and COPD. Whereas formaldehyde and volatile organic compounds seem to be the main pollutants in indoor settings, relevant papers on their respiratory effects are still scarce, and limited to asthma and bronchitis. Moulds have been associated with an increased risk of asthma and COPD. Contradictory results have been found between endotoxins and asthma. The role of phthalates, persistent organic pollutants and flame retardants in respiratory diseases remains to be established. Results from rural areas of industrialised countries indicate that exposure to some indoor bio-contaminants might be protective in early life, while it is associated with adverse respiratory adverse effects in adulthood. Studies focusing on indoor air pollutants should be developed to better understand their involvement in the inception and aggravation of respiratory diseases.

Our aim was to systematically review and meta-analyse longitudinal studies on antibiotic use and subsequent development of wheeze and/or asthma with regards to study quality, outcome measurement, reverse causation (RC; wheezing/asthma symptoms have caused prescription of antibiotics) and confounding by indication (CbI; respiratory tract infections leading to antibiotic use may be the underlying cause triggering asthma symptom development). English-language papers and studies published before November 1, 2010 with longitudinal observational design were included. Study quality was assessed using the Newcastle-Ottawa scale. We identified 21 longitudinal studies. The effect of antibiotic use on wheeze/asthma risk varied between studies. 18 studies were eligible for meta-analysis showing pooled OR 1.27 (95% CI 1.12-1.43) for wheeze/asthma. When we eliminated studies with possible RC and CbI, the pooled risk estimate in the nine remaining studies was attenuated to OR 1.12 (95% CI 0.98-1.26). Definition of wheeze/asthma and age at follow-up differed between studies. Three studies focused on wheeze/asthma beyond 5-6 yrs of age with the presence of active symptoms and/or medication (pooled OR 1.08, 95% CI 0.93-1.23; dominated by one study). RC and CbI lead to overestimation of the association between antibiotic use and subsequent development of wheeze/asthma. Association was weak when fully adjusted for these types of bias. Heterogeneity of disease definition between studies could affect the results.

There is abundant literature on how to select and statistically deal with predictors in prediction models. Less attention has been paid to the choice of the outcome. We assessed the impact of different asthma definitions on prevalence estimates and on the prediction model's performances. We searched PubMed and extracted data of definitions used to diagnose childhood asthma (between 6 and 18 yrs) in cohort studies. Next, using data from an ongoing cohort study (n = 186), we constructed and compared four prediction models which all predict asthma at age 6 yrs, using a fixed set of predictors and four different definitions in turn. We defined an area of clinical indecision (posterior probability between 25% and 60%) and calculated the number of children who remained inside this area. 122 papers yielded 60 different definitions. Prevalence estimates varied between 15.1% and 51.1% depending on the asthma definition used. The percentage of children whose posterior asthma probability was in the area of clinical indecision varied from 14.9% to 65.3%. Variation in definitions and its effect on the performance of prediction models may be another source of otherwise inexplicable variation in daily clinical decision making. More uniformity of operational asthma definitions seems needed.

Cross-shift measurements of peak expiratory flow (PEF) are commonly employed in the diagnosis of occupational asthma, although evidence for this approach is lacking. The current paper presents an evaluation of the technique. Mean changes in PEF across morning/day shifts were compared between workers with occupational asthma, confirmed using specific challenge testing, and non-working asthmatics. Individuals were divided into a development set, used to identify the optimum cross-shift change for diagnosing occupational asthma, and an evaluation set, used to test the sensitivity and specificity of this value. Comparative analysis of serial PEF records was performed using the Oasys-2 computerised system. A cross-shift decrease in PEF of 5 L.min(-1) achieved acceptable specificity in the development set. Applied to the evaluation set, this cut-off had a specificity of 90.9% and a sensitivity of 50%. Sensitivity could not be improved without unacceptable compromise to specificity. Analysis of serial PEF records using linear discriminant analysis identified occupational asthma with a sensitivity of 83.3% and a specificity of 90.9%. Serial analysis using mean work/rest day PEF comparison had a sensitivity of 66.7% and a specificity of 100%. Cross-shift changes in PEF in morning/day-shift workers have poor sensitivity in diagnosing occupational asthma, and are inferior to serial techniques.

Asthma is a highly prevalent condition across Europe and numerous guidelines have been developed to optimise management. However, asthma can be neither cured nor prevented, treatment choices are limited and many patients have poorly controlled or uncontrolled asthma. The Brussels Declaration on Asthma, sponsored by The Asthma, Allergy and Inflammation Research Charity, was developed to call attention to the shortfalls in asthma management and to urge European policy makers to recognise that asthma is a public health problem that should be a political priority. The Declaration urges recognition and action on the following points: the systemic inflammatory component of asthma should be better understood and considered in assessments of treatment efficacy; current research must be communicated and responded to quickly; the European Medicines Agency guidance note on asthma should be updated; "real world" studies should be funded and results used to inform guidelines; variations in care across Europe should be addressed; people with asthma should participate in their own care; the impact of environmental factors should be understood; and targets should be set for improvement. The present paper reviews the evidence supporting the need for change in asthma management and summarises the ten key points contained in the Brussels Declaration.

Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure. Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level. The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.

Smoking is the leading cause of preventable death worldwide. Hundreds of millions of individuals still smoke, affecting their health as well as that of their peers, family and offspring. Smoking is a well-established prime risk factor for chronic obstructive pulmonary disease and hampers the response to treatment in asthma and chronic obstructive pulmonary disease. In the present paper, new concepts are discussed with respect to pathology, treatment, smoking cessation and tobacco control. Recommendations for future directions are given.

The effects of rhinosinusitis treatment upon asthma are disputed. The first randomised prospective study of surgical compared with medical therapy of chronic rhinosinusitis in 90 patients with and without nasal polyps was previously reported. Asthma symptoms, control, forced expiratory volume in one second (FEV1), peak flow, exhaled nitric oxide, medication use and hospitalisation at 6 and 12 months from the start of the study were also monitored. This paper reports these results in 43 of those patients with concomitant asthma. Both medical and surgical treatment of chronic rhinosinusitis were associated with subjective and objective improvements in asthma. Overall asthma control improved significantly following both treatment modalities, but was better maintained after medical therapy, where improvement could also be demonstrated in the subgroup with nasal polyps. Medicine was superior to surgery with respect to a decrease in exhaled nitric oxide and increase in FEV1 in the polyp patients. Two patients noted worsening of asthma post-operatively. Improvement in upper airway symptoms, as assessed using a visual analogue scale, correlated with improvement in asthma symptoms and control. Treatment of chronic rhinosinusitis, medical or surgical, benefits concomitant asthma; that associated with nasal polyposis benefits more from medical therapy.

There is current evidence to demonstrate a close association between fungal sensitisation and asthma severity. Whether such an association is causal remains to be confirmed, but this is explored by means of a detailed literature review. There is evidence from two randomised controlled trials that, in the example of allergic bronchopulmonary aspergillosis (ABPA), treatment with systemic antifungal therapy can offer a therapeutic benefit to approximately 60% of patients. ABPA is only diagnosed if a combination of clinical and immunological criteria is achieved. It is not known whether such cases are a discrete clinical entity or part of a spectrum of the pulmonary allergic response to fungi or fungal products. This paper describes the epidemiological evidence that associates severity of asthma with fungi and discusses possible pathogenetic mechanisms. Many airborne fungi are involved, including species of Alternaria, Aspergillus, Cladosporium and Penicillium, and exposure may be indoors, outdoors or both. The potential for a therapeutic role of antifungal agents for patients with severe asthma and fungal sensitisation is also explored. Not only are many patients with severe asthma desperately disabled by their disease, but, in the UK alone, asthma accounts for 1,500 deaths per yr. The healthcare costs of these patients are enormous and any treatment option merits close scrutiny. Within this report, the case for the consideration of a new term related to this association is put forward. The current authors propose the term "severe asthma with fungal sensitisation". However, it is recognised that enhanced and precise definition of fungal sensitisation will require improvements in diagnostic testing.

Since severe asthma is a poorly understood, major health problem, 12 clinical specialist centres in nine European countries formed a European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA). In a cross-sectional observational study, a total of 163 subjects with severe asthma were compared with 158 subjects whose asthma was controlled by low doses of inhaled corticosteroids (median dose of beclomethasone equivalents 666 microg). Despite being treated with higher doses of inhaled corticosteroids (median dose 1773 microg) and for a third of the severe asthmatics also being treated with regular, oral-steroid therapy (median daily dose 19 mg), the subjects with severe asthma met the inclusion criteria. The criteria required subjects to have undergone at least one asthma exacerbation in the past year requiring oral steroid treatment. Females dominated the severe asthma group (female/male ratio 4.4:1 versus 1.6:1 in the controlled asthmatics), and compared with controlled asthmatics, they had a predominantly neutrophilic inflammation (sputum neutrophils, 36 versus 28%) and evidence of ongoing mediator release but less atopy. From these findings and other physiological and clinical data reported in this paper, it is suggested that severe asthma might be a different form of asthma rather than an increase in asthma symptoms. The findings prompt for longitudinal studies and interventions to define the mechanisms in severe asthma.

The European Community Respiratory Health Survey (ECRHS) II will determine the incidence of and risk factors for the development of allergic disease, atopy and rapid loss of lung function in middle-aged adults living in Europe. From 1991-1993, >18,000 individuals took part in ECRHS I and provided information on symptoms and exposure to known or suspected risk factors for asthma. Blood samples for assessment of specific immunoglobulin E to environmental allergen were taken and lung function and bronchial responsiveness to methacholine were assessed. From 1999-2001, study participants were re-contacted to determine symptom status and exposure to a variety of factors, including tobacco smoke, animals, occupational agents and air pollutants (including particulate matter). In a subsample of responders, exposure to house dust-mite allergen was assessed by analysis of dust samples taken from participants' mattresses. In addition, blood samples suitable for deoxyribonucleic acid extraction were collected and stored. Currently, European Community Respiratory Health Survey II is being conducted in 29 centres in 14 countries. At the time of writing this paper, 27 centres had begun the study and approximately 12,000 participants had completed a short postal questionnaire, approximately 9,000 had completed a more detailed health assessment and 3,500 participants had provided dust samples. Historical air-pollution data have been collated and the programme of monitoring particles with a 50% cut-off aerodynamic diameter of 2.5 microm has been completed in 21 centres in 10 countries.

Inhaled corticosteroids have been established as the most effective treatment for childhood asthma. However, concerns persist regarding their potential effects on growth and, most importantly, final height. To assess their effects on growth, inhaled corticosteroids can be compared with placebo (type 1 study), nonsteroidal anti-asthma therapy (type 2 study), another inhaled corticosteroid (type 3 study) or "real-life" anti-asthma therapy (type 4 study). Owing to the difficulties in obtaining final height data, several different surrogate measures have often been used: short-term lower leg growth, longer-term statural height growth velocity, childhood height and predicted final height. This paper discusses the choice of end point, key trial design issues (including selection and number of subjects in the active and control populations) duration of assessments and methods for measuring height and data analysis, in the context of the different study types. Specific study design recommendations have been developed after consideration of these factors, and these principles will be used to guide the interpretation of previously published growth studies.

The Darlington and Northallerton long-term asthma study observes outcome in asthmatics in the light of potential explanatory variables recorded prospectively. This paper reports changes in mortality during the study, and assesses the relevant risk factors. All asthmatics attending secondary care were recruited at 5-yr intervals from 1983 and reviewed 5 yrs later. Demographic and functional variables, including a formal estimate of best function were recorded prospectively. The dynamic cohort comprised 1,148 asthmatics with 95% follow-up, enabling 612 observations in the period 1983/1988, 774 in 1988/93 and 823 in 1993/98, with 101, 111 and 100 deaths respectively. Principal risk factors for mortality were lower social class and best forced vital capacity. Mortality relative to 1983 halved by 1993/98 and was reduced against the Darlington population, despite an entry forced expiratory volume in one second of 84.7%. There was no change in predictive value of risk factors during the study period, or with date of entry. This study demonstrates a consistent reduction in mortality, which was not entirely a survivor effect, but may be associated with changes in management. By 1993/98 mortality approximated to that of the local reference population despite a lower than predicted forced expiratory volume in one second.

Health status (or Health-Related Quality of Life) measurement is an established method for assessing the overall efficacy of treatments for asthma and chronic obstructive pulmonary disease (COPD). Such measurements can indicate the potential clinical significance of a treatment's effect. This paper is concerned with methods of estimating the threshold of clinical significance for three widely used health status questionnaires for asthma and COPD: the Asthma Quality of Life Questionnaire, Chronic Respiratory Questionnaire and St George's Respiratory Questionnaire. It discusses the methodology used to obtain such estimates and shows that the estimates appear to be fairly reliable; ie. for a given questionnaire, similar estimates may be obtained in different studies. These empirically derived thresholds are all mean estimates with confidence intervals around them. The presence of these confidence intervals affects the way in which the thresholds may be used to draw inferences concerning the clinical relevance of clinical trial results. A new system of judging the magnitude of clinically significant results is proposed. Finally, an attempt is made to translate these thresholds into scenarios that illustrate what a clinically significant change with treatment may mean to an individual patient.

Sulphur dioxide (SO2) is an important air pollutant and causes bronchoconstriction in normal and asthmatic adults. This paper has explored the autonomic consequences of SO2 exposure using the spectral analysis of heart rate variability. Electrocardiogram recordings were made in 12 normal and 12 asthmatic adults undergoing pollutant exposures. Exposures were of a 1 h duration, double blind, in random order, > or = 2 weeks apart and included air and 200 parts per billion SO2. Spectral analysis of R-R intervals was performed. SO2 exposure was associated with an increase in total power (TP) and high (HF) and low frequency (LF) power in the normal subjects, and a reduction in these indices in the subjects with asthma. The difference in TP with SO2 exposure compared to air was +1730 ms2 in the normal group and -1021 ms2 asthmatic group (p<0.003). For HF the respective values were +964 ms2 and -539 ms2 (p=0.02) and for LF, +43 7 ms2 and -57 2 ms2 (p=0.01). No change in lung function or symptoms was observed in either group. This suggests that SO2 exposure at concentrations which are frequently encountered during air pollution episodes can influence the autonomic nervous system. This may be important in understanding the mechanisms involved in SO2 induced bronchoconstriction, and of the cardiovascular effects of air pollution.

The class label warning in the United States for inhaled corticosteroids (ICS's) states that these drugs may reduce growth velocity in children. In this paper, the evidence for this warning is reviewed from a clinical point of view. Children with asthma tend to grow slower than their healthy peers during the prepubertal years because they go into puberty at a later age. However, asthmatic children do achieve a (near) normal adult height. In randomized controlled clinical trials, the use of inhaled beclomethasone, budesonide and fluticasone is associated with a reduced growth during the first months of therapy, in the order of magnitude of approximately 0.5-1.5 cm x yr(-1). It is, however, unlikely that such an effect continues or persists because accumulating evidence shows that asthmatic children, even when they have been treated with ICS for years, attain normal adult height. Individual rare cases have been reported, however, where ICS use was associated with clinically relevant growth suppression. Inhaled corticosteroids are the most effective therapy available for maintenance treatment of childhood asthma. Fear of reduced growth velocity is based on exceptional cases and not on group data. It should, therefore, not be a reason to withhold or withdraw such highly effective treatment in children with asthma.

It has been suggested that, in epidemiological studies, asthma should be defined as symptomatic bronchial hyperresponsiveness (BHR). This paper critically examines the validity of this and alternative methods of defining asthma by reviewing population-based studies validating BHR and symptom questionnaires against asthma defined on the basis of a clinical assessment. It is emphasized that a single definition of asthma will not be applicable to all studies. When the aim of a study is to compare differences in prevalence of asthma between populations, Youden's Index (sensitivity + specificity - 1) is the best single measure of validity. BHR has similar or better specificity, but much worse sensitivity, and therefore a worse Youden's Index, than symptom questionnaires. When the aim is to estimate relative risks, the validity of the definition of asthma depends more on its positive predictive value. Therefore, more specific methods of detecting asthmatics, such as severe symptoms, diagnoses of asthma, or symptomatic BHR may be most useful in cohort and case-control studies. In contrast, conversely, the method of choice for the first phase of prevalence comparisons is standardized written or video symptom questionnaires. In order to explore reasons for the differences in asthma prevalence, and to estimate possible differential symptom reporting, questionnaires can be supplemented with bronchial hyperresponsiveness and other testing in subsamples of the symptomatic and nonsymptomatic subjects. However, symptoms and bronchial hyperresponsiveness should usually be analysed separately rather than combined due to the poor agreement between bronchial hyperresponsiveness and clinical asthma.

The purpose of this study was to estimate the risk of adult asthma in relation to certain occupational exposures. The study was designed as a case-control study in Göteborg, including 321 subjects with asthma, born between 1926 and 1970. Controls (n=1,459) were randomly selected from the same area from registers of the 1986 population. Questionnaire information was collected in 1996, and included occupational exposures and smoking habits. Odds ratios were calculated for exposure before asthma onset, stratified by sex and age-class. The highest risks for asthma were associated with exposure to grain dust (odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-10.7) and flour dust (OR 2.8, 95% CI 1.1-7.2). Among males, significantly increased risks were observed after exposure to flour dust, welding fumes, man-made mineral fibres, and solvents. Among females, increased risks for asthma were associated with exposures to paper dust and textile dust. In logistic regression models controlling for age, smoking, sex and interacting exposures, increased risks were seen for welding fumes (OR 2.0, 95% CI 15-3.4), man-made mineral fibres (OR 2.6, 95% CI 1.4-7.3) and solvents (OR 2.2, 95% CI 1.2-3.2). The fraction of asthma attributed to occupational exposures after adjusting for sex, smoking and age was 11% (95% CI 7-14%). In conclusion, exposure to welding fumes, man-made mineral fibres, solvents and textile dust is associated with increased risk for asthma.

This paper examines the clinical expression of asthma in a group of patients displaying rhinitis according to age, sex, associated symptoms, smoking, familial history of asthma, atopy, type of sensitization to aeroallergens (pollens and/or indoor allergens), total serum immunoglobulin E (IgE), and blood eosinophils. A total of 117 adults with rhinitis were analysed on the basis of symptoms. Among them, 51 also displayed asthma, defined as a history of recurrent episodes of dyspnoea with a reversible airflow obstruction or a positive methacholine challenge. The logistic regression analysis carried out in a stepwise approach, combining several factors, showed that various parameters affected the risk of having asthma associated with rhinitis. A further analysis was made in 74 rhinitis patients comparing 42 subjects without nonallergic airway hyperresponsiveness (NAAH) to 32 patients with asthma and NAAH. Atopy, high total serum IgE levels, elevated blood eosinophil count and maternal asthma were associated with asthma. Furthermore, in atopic patients, pollen sensitization was more closely related to rhinitis alone, whereas sensitization to indoor allergens was a major determinant for the association of asthma with the symptoms of rhinitis. The same risk factors as those found in the clinical part of the study discriminated the patients with rhinitis without NAAH from those with rhinitis, asthma and NAAH. In conclusion, this study gives new insights into the relationships between asthma and rhinitis.

Electronic spirometers offer the prospect of paperless home monitoring, but data quality is not automatically better than from conventional monitoring. The aim of this study was to determine the extent to which the quality and processing of self-recorded spirometric data from patients with asthma complied with international guidelines for spirometry. Data were from 33 subjects with poorly controlled asthma who had completed the first 9 weeks of a clinical budesonide trial. MicroMedical DiaryCard electronic spirometers were used to record three spirometric manoeuvres in twice-daily sessions. Confounding events were recorded in a paper diary. Within-session reproducibility was calculated for forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF) during the first week of run-in and week 9 of budesonide treatment. Geometric means of within-session reproducibility (mean difference between highest and second-highest value from each session over a one-week period) for FEV1, FVC and PEF were 76 mL, 116 mL and 18 L x min(-1), respectively, during run-in. Times of spirometric sessions varied widely, with some overlap between morning and evening session times. Manoeuvre-induced falls in PEF and FEV1 occurred only as often as expected by chance. Nonasthma events including equipment faults and painful conditions caused changes in spirometric results. Home spirometric monitoring can be carried out with excellent reproducibility in patients with asthma. However, quality-control issues are complex and an accompanying paper diary remains essential.

Asthma and allergic disease in children is increasing in many Western countries but such trend has not been well-defined in Chinese populations. This paper aims to determine the prevalence of asthma and allergic disease in Hong Kong schoolchildren and compare it with previous data to identify a changing trend. We studied 4,665 schoolchildren aged 13-14 yrs using the International Study of Asthma and Allergy in Childhood (ISAAC) protocol to determine prevalence rates for asthma, wheeze, respiratory symptoms, rhinitis and eczema in 1994-1995. Additional questions on education levels of the parents and smoking status were also asked. Concordance between responses to the written and video questionnaires was good (76% for wheeze ever, 80% for current wheeze). Prevalence rates for asthma ever, wheeze ever, and current wheeze were 11, 20 and 12%, respectively, and were greater in boys (p < 0.05). Rhinitis affected slightly over half of the subjects (52%), and eczema was reported by a sixth (15%), whilst current rhinitis and current eczema were present in 44% and 3.6% of children, respectively. In multiple logistic regression: odds ratio male sex (OR) 1.47; (95% confidence interval (95% CI) 1.15-1.86); current rhinitis (OR 3.00; 95% CI 2.36-3.81); current eczema (OR 2.34; 95% CI 1.40-3.93); and active smoking (OR 2.00; 95% CI 1.38-2.89) were associated with current wheeze; whilst severe wheezing attack was associated with: current rhinitis (OR 2.72; 95% CI 1.47-5.02); current eczema (OR 6.13; 95% CI 2.82-13.33); and active smoking (OR 4.62; 95% CI 2.43-8.76). Age, parental education and passive smoking were not important factors. When compared to previous epidemiological data obtained in 1992, the prevalence rates for asthma ever and wheeze ever had increased by 71 and 255%, respectively, in Hong Kong schoolchildren. The severity of asthma and respiratory symptoms showed a similar increasing trend. Further studies should aim to identify the role of the environment in the pathogenesis of asthma.

During recent years, new auxological techniques have been introduced for assessment of the risk of growth suppression in asthmatic children treated with exogeneous glucocorticosteroids. Assessment of lower leg growth rates with the knemometer has made short-term studies of growth processes under strictly controlled conditions possible. However, short-term lower leg growth rates cannot be used for estimations of intermediate-term height growth rates or long-term evaluations of final height. Consequently, the distinctions between the various types of growth studies in asthmatic children treated with inhaled glucocorticosteroids have become important and need to be discussed. The present paper presents a review of the long-, intermediate- and short-term growth studies available. The bulk of evidence from intermediate- and short-term evaluations indicates that growth rate is not affected when standard paediatric doses of inhaled glucocorticosteroids are used. However, further focus needs to be placed on differences between specific glucocorticosteroids, doses and delivery systems. Intermediate- and short-term growth data should be evaluated in the long-term perspective.

Asthma is a common chronic disorder which may be increasing in prevalence. However, little is known of its distribution and determinants. The European Community Respiratory Health Survey (ECRHS) is a multicentre survey of the prevalence, determinants and management of asthma. This paper presents a descriptive account of the variation in self-reported attacks of asthma and asthma symptoms across Europe, and in part fulfils the first aim of the study. A screening questionnaire, including seven questions relating to the 12 month prevalence of symptoms of asthma, was distributed to representative samples of 20-44 year old men and women in 48 centers, predominantly in Western Europe. The median response rate to the questionnaire was 75% but, after removing from the denominator those who were the wrong age, were known to have moved out of the area, or had died, it was 78% (range 54-100). The prevalence of all symptoms varied widely. Although these were generally lower in northern, central and southern Europe and higher in the British Isles, New Zealand, Australia and the United States, there were wide variations even within some countries. Centres with a high prevalence of self-reported attacks of asthma also reported high prevalences of nasal allergies and of waking at night with breathlessness. The use of asthma medication was more common where wheeze and asthma attacks were more frequent. In most centres in The Netherlands, Sweden, New Zealand and the United Kingdom over 80% of those with a diagnosis of asthma were currently using asthma medication. In Italy, France and Spain the rate was generally less than 70%. These data are the best evidence to date that geographical differences in asthma prevalence exist, are substantial and are not an artefact of the use of noncomparable methods.

At present, asthma represents a substantial burden on health care resources in all countries so far studied. The costs of asthma are largely due to uncontrolled disease, and are likely to rise as its prevalence and severity increase. Costs could be significantly reduced if disease control is improved. A large proportion of the total cost of illness is derived from treating the consequences of poor asthma control-direct costs, such as emergency room use and hospitalizations. Indirect costs, which include time off work or school and early retirement, are incurred when the disease is not fully controlled and becomes severe enough to have an effect on daily life. In addition, quality of life assessments show that asthma has a significant socioeconomic impact, not only on the patients themselves, but on the whole family. Underuse of prescribed therapy, which includes poor compliance, significantly contributes towards the poor control of asthma. The consequences of poor compliance in asthma include increased morbidity and sometimes mortality, and increased health care expenditure. To improve asthma management, international guidelines have been introduced which recommend an increase in the use of prophylactic therapy. The resulting improvements in the control of asthma will reduce the number of hospitalizations associated with asthma, and may ultimately produce a shift within direct costs, with subsequent reductions in indirect costs. In addition, costs may be reduced by improving therapeutic interventions and through effective patient education programmes. This paper reviews current literature on the costs of asthma to assess how effectively money is spent and, by estimating the proportion of the cost attributable to uncontrolled disease, will identify where financial savings might be made.

Snoring was described in literature even before medicine. Common definitions do not consider acoustic measurements of snoring. In this paper we discuss the main pathophysiological aspects of snoring and the snoring-sleep relationship as the generating mechanisms. Snoring can be analysed and measured by the following methods: 1) Leq-Equivalent Continuous Sound Level, which only quantifies noisiness, annoyance, and damage to the partner's and snorer's hearing; 2) Power Spectrum, with frequency values, formantic structure data and typical shape, which can help to distinguish simple snoring from heavy snoring with obstructive sleep apnoea syndrome (OSAS); 3) Linear Prediction Code (LPC) method, which can define the cross-sectional area (CSA) of the upper airways and which locates sites of obstruction. Simulated snoring analysis with LPC and with simultaneous fluoroscopy permits the definition of CSA and the identification of three snoring patterns: nasal, oral and oronasal. Snoring is an important sign of sleep-related breathing disorders (SRBD), of the upper airway resistance syndrome (UARS), and of the OSAS. Snoring is a symptom of nasal obstruction and is associated with cardiovascular diseases and nocturnal asthma as a trigger or causative factor; however, its acoustic features in these disorders are not well-defined. Home monitoring of snoring is very useful for epidemiology and is mandatory, together with heart rate and arterial oxygen saturation (Sa,O2), to screen SRBD.

We have previously demonstrated that the adult outcome of childhood asthma differs from that of wheeze occurring only in the presence of infection. This paper examines the role of atopy in relation to outcome. We investigated the atopic status, current symptoms and bronchial reactivity to methacholine of 235 subjects aged 34-40 yrs, originally classified at age 10-15 yrs as having asthma (asthma group), wheeze only in the presence of infection (wheezy group), or no respiratory symptoms (comparison group). Subjects from the original asthma group were more likely to be atopic as defined by skin test reactivity, total serum immunoglobulin E (IgE) measurement or specific IgE radio allergosorbent test (RAST) measurement than those from the wheezy group. The wheezy group differed significantly from the reference group only in RAST results, when other variables were taken into account. In a logistic regression model, the important independent predictors for adult wheezing symptoms were original group, atopy and current smoking. Methacholine responsiveness was independently associated with original group (the asthma group were more likely to respond positively), atopy and female gender. The results suggest that atopy is an important predictor for wheeze and bronchial hyperreactivity in middle age. However, the difference in outcome for children who had asthma compared to those who had wheeze only in the presence of infection cannot be explained by atopy alone.

This paper focuses on the prevention of asthma caused by exposure to sensitizing agents in the workplace. Control of exposure (primary prevention) is the most direct method of reducing the number of incident cases. Screening programmes are also necessary as a "safety net", and have value as secondary prevention, because early detection may improve long-term prognosis. It is recommended that regulatory or advisory bodies with responsibility for occupational asthma publish a guidance document on occupational asthma explaining their current concepts. Surveillance activities provide information on how common asthma is relative to other occupational lung diseases, and on the relative frequency of occurrence of asthma caused by different agents. Publication of a list of sensitizing agents would aid those with responsibility for control of exposure in the workplace. Epidemiological research on exposure-response relations is is necessary as a background to prevention. This paper recommends such studies. Immunotoxicological research also has a role in testing hypotheses that cannot be tested in human subjects. Some standardization of screening programmes in industry is desirable. A short symptoms questionnaire is economical and acceptable to workers, but there are other approaches. Finally, evaluative research on prevention measures gives information on their effectiveness and efficiency.

Inhaled nedocromil sodium, an anti-inflammatory agent for the maintenance treatment of asthma, has been the subject of many clinical trials but only a proportion have been published. This paper provides an overview analysis of all known placebo-controlled, double-blind, randomized therapeutic trials. Both single centre and multicentre trials are included. A comparison has been made between the treatment effects of nedocromil sodium and placebo, using six efficacy variables (day and night asthma, cough, mean daily peak expiratory flow rate, inhaled bronchodilator use, clinic lung function (forced expiratory volume in one second) and global opinion of treatment efficacy. One hundred and twenty seven trial centres, involving 4,723 patients, have been included. The results demonstrate the efficacy of inhaled nedocromil sodium in a variety of patients with asthma. Optimal effects are evident in patients with moderate asthma, currently receiving treatment with inhaled and oral bronchodilators.

Glucocorticosteroid (GCS) therapy is one of the corner-stones in the treatment of asthma. Its value in acute severe asthma is still open for debate. Many of the papers published on the topic are subject to methodological problems. In 8 of 13 placebo-controlled studies, GCS therapy proved to be superior to placebo, evaluated either as result of pulmonary function, blood gas tension, or hospital admission rate. The most important point for GCS therapy in acute severe asthma seems to be frequent dosage, typically 4 times daily. Oral and intravenous administration seem to have equal efficacy. Only 2 of 10 studies were able to prove a dose-response relationship. Both studies included very low doses of GCS. Doses of 100-200 mg of methylprednisolone for 24 h seem as effective as high doses. A protective effect against relapses within a certain time after the GCS therapy has been demonstrated only for periods not exceeding 4 weeks, and only in children. So far, no study has been able to depict the categories of patients who may or may not benefit by the addition of GCS therapy to the symptomatic treatment of acute severe asthma.

In 1961 the hypothesis (later referred to as the Dutch Hypothesis (DH)) was put forward that asthma, chronic bronchitis and emphysema should be considered as different expressions of one disease entity, in which both endogenous (host) and exogenous (environmental) factors play a role in the pathogenesis. A hereditary predisposition to develop allergy and bronchial hyperreactivity were considered to be important denominators of disease susceptibility. Complications and complicating diseases would also contribute to the ultimate phenotype of the patient. In the present paper we discuss the relevance of this hypothesis in 1990. Until now it has not been refuted; circumstantial evidence in its favour has accumulated, but formal proof is still lacking. Further research should pay more attention to the genetic aspects of the disease. Arguments are presented against the use of the terms asthma, chronic bronchitis, and emphysema as indicators of disease entities, and in favour of the use of an umbrella-term, e.g. chronic non-specific lung disease (CNSLD), provided that, in addition, every patient is characterized using so-called defining criteria.

The International Union against Tuberculosis and Lung Disease (IUATLD) Bronchial Symptoms Questionnaire (1984) was developed for use in studies of asthma and its reliability measured in an earlier survey in England. The association of the symptoms elicited by this questionnaire to bronchial response to histamine has also been described. This paper presents the results of studies of the questionnaire in four clinical centres in Europe. The reliability of the questionnaire and its ability to predict the bronchial response to histamine were compared for English, Finnish, French and German translations of the questionnaire in samples of diagnosed asthmatics and controls in Nottingham, Berlin, Helsinki and Paris. The answers to questions showed good repeatability, especially in Finland and Germany, particularly those questions on asthma and wheeze. The most sensitive symptom for predicting hyperresponsiveness was the question on wheeze, the most specific questions were those on waking at night with shortness of breath (Paris and Nottingham) and morning tightness (Helsinki and Berlin). This study shows that the IUATLD (1984) questionnaire may provide useful, valid and comparable data even in translation but these studies will need to be repeated in representative samples before such a possibility is accepted as fully demonstrated.