Workshop summary

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Severe asthma in adults: What are the important questions?

Pascal Chanez, MD, PhD,a Sally E. Wenzel, MD,b Gary P. Anderson, PhD,c Josep M. Anto, MD, PhD,d Elisabeth H. Bel, MD, PhD,e Louis-Philippe Boulet, MD,f Christopher E. Brightling, PhD, MRCP,g William W. Busse, MD,h Mario Castro, MD, MPH,i Babro Dahlen, MD, PhD,j Sven Erik Dahlen, MD, PhD,k Leo M. Fabbri, MD,l Stephen T. Holgate, MD, PhD,m Marc Humbert, MD, PhD,n Mina Gaga, MD,o Guy F. Joos, MD, PhD,p Bruce Levy, MD, PhD,q Klaus F. Rabe, MD, PhD,r Peter J. Sterk, MD, PhD,e Susan J. Wilson, PhD,m and Isabelle Vachier, PhDa Montpellier and Clamart, France, Pittsburgh, Pa, Melbourne, Australia, Barcelona, Spain, Amsterdam and Leiden, The Netherlands, Quebec City, Quebec, Canada, Leicester and Southampton, United Kingdom, Madison, Wis, St Louis, Mo, Stockholm, Sweden, Modena, Italy, Athens, Greece, Ghent, Belgium, and Boston, Mass
The term severe refractory asthma (SRA) in adults applies to patients who remain difcult to control despite extensive reevaluation of diagnosis and management following an
From aINSERM U454 and Clinique des Maladies Respiratoires, Montpellier; b the Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh; cthe Department of Pharmacology, University of Melbourne; dRespiratory and Environmental Health Research Unit, LInstitut Municipal dInvestigacio Me ` dica, Barcelona, Spain; ethe Department of Pulmonology, F5-259 Academic Medical Center, University of Amsterdam; fUniversite Laval, Quebec City, Quebec; gInstitute for Lung Health, University Hospitals of Leicester, h Leicester; the University of Wisconsin Medical Center, Madison; i Washington University School of Medicine, St Louis; jthe Department of Medicine, Division of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm; kthe Division of Physiology, National Institute of Environmental Medicine at Karolinska Institutet, Stockholm; lUniversita of Modena and Reggio Emilia, Modena; mthe Division of Infection, Inammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, animation Respiratoire, Southhampton; nService de Pneumologie et Re UPRES EA2705, Institut Paris-Sud sur les Cytokines, Ho pital Antoine Be cle ` re, Universite Paris-Sud, Clamart; oRespiratory Medicine Department, Sotiria Hospital, Athens University; pthe Department of Respiratory Diseases, Ghent University Hospital; qthe Department of Internal Medicine and Center for Experimental Therapeutics and Reperfusion Injury, Pulmonary and Critical Care Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston; and rthe Department of Pulmonology, Leiden University Medical Center. Supported by an unrestricted grant from Novartis France and Centocor USA. Disclosure of potential conict of interest: P. Chanez has consulting arrangements with GlaxoSmithKline, AstraZeneca, Novartis, Aimirall, Centocor, Wyeth, Altana, and UCB and has received grant support from GlaxoSmithKline, Centocor, and Novartis. S. E. Wenzel has consulting arrangements with Genentech, Critical Therapeutics, and Centacor and is on the speakers bureau for Critical Therapeutics and Genentech. L.-P. Boulet has consulting arrangements with Altana, AstraZeneca, GlaxoSmithKline, Novartis, and Merck Frost; has received grant support from 3M, Altana, Asthmatx, AstraZeneca, Boehringer-Ingelheim, Dynavas, Genentech, GlaxoSmithKline, IVAX, Merck Frost, Novartis, Pzer, Roche, Schering, and Topigen; and is on the speakers bureau for 3M, Altana, Asthmatx, AstraZeneca, Boehringer-Ingelheim, Dynavax, Genentech, GlaxoSmithKline, IVAX, Merck Frost, Novartis, Pzer, Roche, Schering, and Topigen. C. E. Brightling has consulting arrangements with AstraZeneca and Cambridge Antibody Technology; has received grant support from AstraZeneca

observational period of at least 6 months by a specialist. Factors that inuence asthma control should be recognized and adequately addressed prior to conrming the diagnosis of SRA.
and Cambridge Antibody Technology; and is on the speakers bureau for AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, and NycoMed/ Altana. W. W. Busse has consulting arrangements with Genentech/Novartis, Isis, GlaxoSmithKline, Altana, Wyeth, Pzer, Dynavax, Novartis, Merck, and AstraZeneca. M. Castro has consulting arrangements with Asthmatx and Centocor and is on the speakers bureau for Boehringer-Ingelheim, Critical Therapeutics, Genentech, and Pzer. S. E. Dahien has consulting arrangements with Centocore, L. M. Fabbri Altana, AstraZeneca, BoehringerIngelheim, Chiesi, Farmaceutici, GlaxoSmithKline, Merck Sharp and Dohme, Novartis, Roche, and Pzer and has received grant support from Altana, AstraZeneca, Boehringer-Ingelheim, Menarini, Miat, ScheringPlough, Chiesi, Farmaceutici, GlaxoSmithKline, Merck Sharp and Dohme, UCB, Pzer, the Italian Ministry of Health, and the Italian Ministry for University and Research. S .T. Holgate has consulting arrangements with MSD, Novartis, Almirall Prosdesfarma, Synairgen, Rotta Pharmaceutical, Amgen, and CAT; owns stock in Synairgen; and has consulting arrangements with Novartis, Altana, AstraZeneca, GlaxoSmithKline, Pzer, Schering-Plough, European Union GlaxoSmithKline, AstraZeneca, Novartis, BoehringerIngelheim, and Sano-Aventis. G. F. Joos has consulting arrangements with Centocore; has received grant support from Centocore; and is on the speakers bureau for Novartis. B. Levy has consulting arrangements with Critical Therapeutics. K. F. Rabe has consulting arrangements with AstraZeneca, Boehringer-Ingelheim, Chiesi Pharmaceutical, Pzer, Novartis, AltanaPharma, MSD, and GlaxoSmithKline; has received grant support from AltanaPharma, Novartis, Bayer, AstraZeneca, Pzer, MSD, Exhale Therapeutics, Boehringer-Ingelheim, Roche, and GlaxoSmithKline; and is on the speakers bureau for AstraZeneca, Boehringer-Ingelheim, Chiesi Pharmaceutical, Pzer, Novartis, AltanaPharma, MSD, and GlaxoSmithKline. G. P. Anderson has consulting arrangements with AstraZeneca and is on the speakers bureau for GlaxoSmithKline and AstraZeneca. The rest of the authors have declared that they have no conict of interest. Received for publication July 13, 2006; revised November 10, 2006; accepted for publication November 15, 2006. Available online April 13, 2007. Reprint requests: Pascal Chanez, MD, PhD, Clinique des Maladies Respiratoires, 371 av du doyen Gaston Giraud, 34295-Montpellier Cedex 05, France. E-mail: chanez@montp.inserm.fr. 0091-6749/$32.00 2007 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2006.11.702

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This report presents statements according to the literature dening SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The TH2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may inuence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies. (J Allergy Clin Immunol 2007;119:1337-48.) Key words: Epidemiology, pathophysiology, management, research perspectives, severe asthma

Abbreviations used ATS: American Thoracic Society BHR: Bronchial hyperresponsiveness EGFR: Epidermal growth factor receptor FENO: Fraction of exhaled nitric oxide ICS: Inhaled corticosteroid LABA: Long-acting b2-agonist NSAID: Nonsteroidal anti-inammatory drug OCS: Oral corticosteroid SABA: Short-acting b2-agonist

Asthma diagnosis and treatment

Severe asthma in adults continues to be a challenge for doctors and scientists involved in the eld despite several international initiatives to better understand this complex condition. The current article reports a workshop held in Paris, France in February 2006, which was designed to give a comprehensive review of the current knowledge of this debilitating disease, but also to highlight the paucity of conrmed mechanisms and the poor understanding of management. By specically addressing several unanswered questions, we hope this initiative will encourage more research and improve outcomes in severe asthma.

denitions differ from the recently updated Global Initiative for Asthma guideline for asthma management and prevention in that they include medication criteria.4 According to the ATS denition, patients who need oral corticosteroids (OCSs) or high-dose ICSs to remain under control as well as patients with ongoing asthma symptoms despite appropriate maintenance therapy should be regarded as having severe asthma. All of these denitions include an assessment of disease control, exacerbating factors/comorbidities, and response to treatment, which may inuence control and treatment requirements. The diagnosis of severe asthma should be reserved for those who have refractory asthma after an extensive reevaluation and an appropriate observation period of at least 6 months.

DEFINITION OF SEVERE ASTHMA

The term severe refractory asthma applies to patients who remain difcult to control despite an extensive reevaluation of diagnosis, management, and an observational period of at least 6 months by an asthma specialist (Table I). Most patients with asthma have mild-to-moderate disease that can be well controlled with standard treatment, including the regular use of inhaled corticosteroids (ICSs) combined with short-acting inhaled b2-agonists (SABAs) or long-acting inhaled b2-agonists (LABAs). However, a subset of patients with asthma exist, in whom even high doses of these drugs fail to control the disease. Indeed, it is well recognized that some patients with asthma have more severe disease than others, and early descriptions identied a subset of patients with asthma whose disease was apparently unresponsive to corticosteroids. In the literature, these patients are labeled as having difcult-to-treat asthma, therapy-resistant asthma, steroid-dependent asthma, brittle asthma, and so on.1 In 1999, a European Respiratory Society Task Force adopted the term difcult asthma.2 In 2000, the American Thoracic Society (ATS) dened refractory asthma.3 The European Respiratory Society and ATS

Re-evaluation of diagnosis and initial investigation of severe asthma Spirometry, reversibility testing, and airway challenge tests (unless contraindicated) are mandatory in the reevaluation of the diagnosis of asthma. The diagnosis of severe asthma is predicated by a secure diagnosis of asthma. For this reason, the diagnosis of severe asthma must be conrmed by the presence of typical symptoms for asthma, together with objective evidence of variable airow limitation and/or airway hyperresponsiveness.4 In addition, alternative diagnoses need to be considered and excluded. Demonstration of reversible airways obstruction by SABAs and/or corticosteroids is valuable, but bronchial provocation testing is more sensitive and specic5 and should be performed when necessary to conrm the diagnosis of asthma. However, when airow is very low, bronchial provocation may not be helpful and/or feasible from a safety and regulatory perspective. Factors that inuence asthma control such as environmental exposures, comorbidities, adherence, and inhalation technique should be recognized and adequately addressed before conrming the diagnosis of severe asthma. Once the diagnosis of asthma is conrmed, numerous factors can contribute to refractory asthma. Managing these issues may in turn improve asthma control and therefore alter the classication of severity. It is important to recognize and, where possible, adequately manage environmental exposures, comorbidities, and adherence

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with therapy, including the inhalation technique, before conrming a diagnosis of severe asthma. The diagnosis and identication of additional factors inuencing the severity of asthma should be approached systematically. Key features in the history, examination, and later investigations are highlighted in Table I. The success of tackling many of these issues is dependent on providing sufcient education and support for the patient. Environmental exposures. Ongoing allergen exposure can induce an airway inammatory process that may increase the severity of asthma, although in recent largescale surveys, allergic responses have not been considered to be among the strongest contributing factors to asthma severity.6 The contribution of an exposure to a sensitizing agent at work should also be considered, and avoidance measures should be proposed when the relationship with the agent has been established.7 Smoking may contribute to the development and manifestations of severe asthma; smokers with asthma are more symptomatic and have more severe and frequent exacerbations and emergency care needs; have a reduced response to corticosteroid; and a more rapid decline in pulmonary function;8 However, a recent large study did not nd a relationship of smoking to severity or accelerated decline in FEV1.9 Therefore, strategies to encourage smoking cessation are an important aspect of severe asthma management. Comorbidities and other associated factors. Often comorbidities complicate severe asthma. For example, several factors have been associated with frequent exacerbations, including severe nasal and sinus disease, gastroesophageal reux, recurrent respiratory infections, psychological dysfunction, and obstructive sleep apnea.10 Upper airway conditions such as allergic and nonallergic rhinosinusitis are frequently associated with severe asthma and have been considered to inuence asthma outcomes, which seems to be particularly true when rhinosinusitis is associated with aspirin-exacerbated respiratory disease.11,12 The association between severe asthma and gastroesophageal reux disease is complex. As noted, gastroesophageal reux has been implicated as a potential factor in uncontrolled asthma, but the frequent lack of improvement with treatment suggests that its contribution to asthma severity is variable.13 Certainly signicant hyperination and drugs such as steroids and theophylline can also contribute to the development of gastroesophageal reux disease. Obesity is increasingly prevalent and has been associated with severe asthma in some studies.14 One study showed that weight reduction is associated with better asthma control and a reduction in asthma severity.15 The correlation between obesity and severe asthma seems to be more obvious in women, and hormonal inuences may be involved.16,17 Sleep apnea syndrome can be associated with asthma, although its inuence on asthma severity remains to be fully established. Premenstrual worsening of asthma symptoms has been reported in up to 40% of female patients with asthma, but severe premenstrual exacerbations are rare and characterized by an impaired response to systemic corticosteroid and inhaled b2-agonists.18

TABLE I. Assessment of patients with severe asthma Medical history History of asthma Age of onset Family history of asthma Management of disease and response to treatment Exacerbations Frequency of severe asthma exacerbations Number of hospitalizations and intensive care unit admissions Environmental exposures Exposure to allergens, occupational agents, and chemicals/pollutants Smoking history Comorbidities and cofactors Rhinosinusitis or previous surgery for nasal polyps Use of aspirin, NSAIDs, b-blockers, angiotensin-converting enzyme inhibitors, and estrogens Gastroesophageal reux disease Obstructive sleep apnea Inuence of menstruation Adherence with medications History of psychiatric disease Psychosocial circumstances Physical examination (specic points of attention) Body mass index Evidence of comorbidities such as nasal polyps Evidence of alternative diagnoses such as cardiac failure Evidence of adverse effects of treatment Assessment of severe asthma Diagnosis Spirometry (reversibility tests) Airway challenge Baseline investigations Health status and asthma control questionnaires Serum IgE and peripheral blood eosinophil count Allergy skin tests Assessment of airway inammation Assessment of lung volumes Consider additional tests for comorbidities and alternative diagnoses Outcome measures Health status and asthma control questionnaires Assessment of airway inammation Number and severity of exacerbations and use of health care Lung function

Adherence. Adherence is often suboptimal in asthma.19 In children and adolescents, poor asthma control has been associated with insufcient corticosteroid treatment adherence. Adherence is a critical issue, but how to best assess and manage poor adherence remains a signicant challenge. Additionally, poor adherence is not specic to severe asthma, with some studies suggesting adherence increases with increasing severity of disease.20 Psychological factors. Depression, anxiety, and behavioral problems may be detrimental to asthma control but also may be a consequence of it. No clear psychological prole is associated with severe asthma.21 Investigation of associated factors. Most associated factors suspected clinically can be conrmed as part of the

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routine investigation of severe asthma. However, the specic utility varies from patient to patient.

Outcomes to assess severe asthma The use of a range of objective outcome measures in the follow-up assessment of severe asthma is important. It is recommended that validated health status and asthma control questionnaires, lung function, assessment of airway inammation, and history of exacerbations be recorded regularly during follow-up. Traditionally, spirometric measures have been the cardinal outcomes in severe asthma. Although these measures are of value, using these measures exclusively may miss other important aspects of the disease. Therefore, it is of paramount importance that multiple objective independent outcomes are assessed that capture a spectrum of the facets of severe asthma, including health status, disease control, exacerbations, airway inammation, and lung function.22 Several composite objective health status/asthma control assessment questionnaires are now available that attempt to incorporate a range of these factors.23 Their use is encouraged. Asthma exacerbations are important outcomes in terms of their impact on the lives of patients and society. The most objective measures of exacerbations are need for OCS use, hospital admission, and episodes of life-threatening asthma. Noninvasive measures of airway inammation include assessment of sputum cell counts and supernatants, exhaled nitric oxide (FENO), and breath condensates for pH and isoprostanes. In 2 large prospective studies, therapy directed at normalizing sputum eosinophil counts markedly reduced asthma exacerbations.24,25 Both of these studies included severe asthma patients, and the greatest benet was observed in them.25 Strategies that have incorporated measures of FeNO have not led to a reduction in asthma exacerbations in adults26 or children,27 although these studies were performed in patients with milder disease. Thus, to date, sputum induction is the most robust measure of airway inammation in asthma, but simpler assessment tools are needed. In addition to basic spirometric measures, assessment of small airway function, including dynamic hyperination, and inammation may be valuable as there is increasing recognition that small airways are involved in severe asthma.28 Assessing asthma severity long term using objective lung function parameters also validates the diagnosis of severe asthma and enables an assessment of progression of disease over time. Phenotyping severe asthma Severe asthma is a heterogeneous condition, which includes several different phenotypes. Phenotyping severe asthma will improve our understanding of underlying mechanisms, natural history, and prognosis; help to guide current and possibly future treatment; and provide clues for novel therapeutic interventions. Severe asthma is not one disease but a multifaceted condition that can be subdivided into different phenotypes. They can be classied using several features of the disease,

including symptoms, health status, asthma control, airway obstruction (variable or partially xed), bronchial hyperresponsiveness (BHR), atopy, inammation, exacerbations, and response to treatment. This approach led to the recognition of several important clinical phenotypes: frequent exacerbators including near-fatal episodes, those with irreversible airway obstruction, and those with OCS dependency or resistance.1 Other features, such as date of onset of the symptoms, or triggers, such as aspirin sensitivity, may represent interesting additional phenotypes. Assessment of airway inammation led to the identication of eosinophilic, neutrophilic, and paucigranulocytic asthma.29,30 Phenotyping severe asthma can help to guide current therapy (sputum eosinophilia often predicts a favorable response to corticosteroid24,25,31), to aid in understanding pathophysiology and natural history, as well as to better link genotype to disease. It is likely that categorizing patients into dichotomous groups will not reect the true complexity of the disease. Alternatively, asthma phenotypes can be determined using complex statistical approaches such as cluster or factor analysis that use multiple parameters to describe multidimensional phenotypes.22 The advent of new technologies to better image the lungs and measure multiple inammatory markers and genetic polymorphisms enables us to use complex statistical models to better identify severe asthma phenotypes. The power to phenotype severe asthma will be further increased by establishing severe asthma networks, such as The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA)6 and the National Heart, Lung, and Blood Institute network, which allow detailed characterization of hundreds of patients.

Asthma diagnosis and treatment

Questions 1. What is the actual prevalence of severe asthma and its various phenotypes? 2. Will phenotypic markers for severe asthma, for example, biomarkers of airway inammation or tests for small airway function, allow better distinction of subgroups? 3. How well does treatment of comorbidities lessen asthma severity? 4. How can complex statistical models be used to create simpler clinical algorithms to improve our ability to phenotype severe asthma? EPIDEMIOLOGY
Severe asthma is associated with an increased risk of hospitalization and death. Severe asthma in children but not in adults is associated with increased IgE. Female gender, obesity, and smoking are associated with more severe asthma and a poor response to therapy. Few studies have attempted to quantify the prevalence of severe asthma, in large part because of variation between clinical and epidemiological denitions.30 However, it is estimated that 5% to 10% of the population with asthma has symptomatic disease despite maximum

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recommended treatment with combinations of anti-inammatory and bronchodilator drugs. This group accounts for up to 50% of the total health costs through hospital admissions, use of emergency services, and unscheduled physician visits.32 Although severe asthma is a major risk factor for hospital admissions and death, studies are needed to determine how much of this is from inadequate treatment versus refractoriness to therapy. Tobacco smoking in particular contributes to greater symptoms, increased xed airow limitation (in most but not all studies,9 with an accelerated decline over time), and resistance to corticosteroid.33 Other risk factors in adults include female gender with links to the menarche, menstrual cycle, pregnancy hormone genetics, and obesity.6 Available evidence, all based on studies before the widespread adoption of inhaled steroid therapy, suggests that severity is often determined early in life and that severity grade is not usually a progression from mild-to-severe disease over time. In children, a strong association exists among total serum IgE, atopy, and severe asthma. Childhood atopy is a risk for severe asthma in adults, but the relationship weakens possibly because of the greater proportion of patients with late-onset nonallergy asthma in this group and the increasing complexity of the disease.34

it will be important to study partial phenotypes, which are dened disease traits recognized in populations studies that are usually variable expressed in an individual patient, to advance our understanding.

Genetics Emerging evidence suggests genetic factors play a role in asthma severity. Partial phenotypes (BHR, IgE, decline in lung function) have proven useful in genetic studies of severe asthma. Genes by environment interactions are likely to be of critical importance in the development of severe asthma (extract tobacco smoke, LPS). Overwhelming evidence exists for the importance of genetic factors in a disease where heritability is reported to be as high as 70%. However, relatively little attention has been paid to identifying genetic factors that inuence disease severity or outcomes. ADAM33 is one gene for which association with asthma relates to both the severity of BHR and the decline in lung function.35,36 In addition, polymorphisms in TGF-1, IL-4, and IL-4Ra have all been independently replicated and associated with lower FEV1 and, for IL-4 and IL-4Ra, with severe exacerbations.37,38 As severe asthma is even more complex than asthma as a whole, many studies attempting to incorporate disease severity into their genetic assessments have simply been too small and underpowered. A possible way forward would be to use meta-analysis in which large numbers of smaller but well-conducted studies are pooled. As a complex disorder, most asthma susceptibility genes are likely to be strongly inuenced by environment factors, with different effects at different times during disease evolution. One good example is the inuence of parental tobacco smoking observed in genetic linkage studies and the inuence that time of exposure to LPS has in relation to polymorphisms in its receptor CD14.39 Polymorphism in the corticotrophin-releasing hormone receptor-1 and the b2-adrenoceptor gene could also contribute to severe asthma through diminishing therapeutic responsiveness.40,41 As severe refractory asthma is phenotypically heterogeneous and relatively rare,

Infections Respiratory viruses (and some bacteria) contribute to severe exacerbations of asthma and can persist in the airways for long periods after the exacerbation. However, their role in the development of severe persistent asthma remains poorly understood. Little is known about the role of respiratory viruses in the inception of persistent asthma and severe asthma in particular. Although recent prospective cohort studies have suggested rhinovirus infection is a risk factor for the development of asthma, its inuence on severity is unknown.42 What is certain is that respiratory viruses, especially the common cold viruses, are the most frequent cause of asthma exacerbations43 and represent one of the most common reasons for hospital admissions for asthma.44 Viral-induced exacerbations are usually more severe and prolonged, are associated with a neutrophilic inammation, and are relatively refractory to preventive treatment with steroids, when compared with other types of exacerbations.45,46 Why viruses play such a prominent role in severe asthma exacerbations is not clear. However, a recent in vitro study reported that asthmatic bronchial epithelium could not generate the expected primary interferon response to rhinovirus infection.47 This nding could explain why viruses continue to replicate and cause cytotoxic damage and why viral infections are poorly responsive to corticosteroid therapy. Intracellular bacteria such as Chlamydia have also been linked to chronic severe asthma.48,49 Their recognition, which requires a combination of up-to-date serum serology and PCR techniques on lung tissue samples can be helpful as some of these patients may improve with antibiotic therapy.50,51 Allergens and sensitizing agents Atopy is less frequent in severe asthma as compared with mild-to-moderate asthma. Certain allergen exposures are associated with severe asthma (cockroach, Alternaria). Occupational sensitizers can induce persistent severe asthma and are a common cause of new onset severe asthma in adults. The association of allergens and the genetic risk of IgEdependent sensitization with asthma is without dispute. However, data from ENFUMOSA and The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study suggest that severe asthma is signicantly less allergic than the asthma found in patients with milder asthma6,52 and, as compared with children and young adults, where atopy is a strong risk factor for ongoing severe disease. Interestingly, in the Childhood Asthma Management Program study, children with the most severe airow impairment had lower IgE levels and fewer allergic reactions, which suggests that allergy may have some protective effects on FEV1.53 Although patients with allergic reactions may have better lung function compared with

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those without, specic allergic reactions as recorded in the TENOR database have been associated with more exacerbation-prone disease. Interestingly, women with severe asthma seem to have better lung function, lower total IgE levels, but more specic allergic reactions than men.54 Recent studies have shown that, although allergen exposures are associated with allergic sensitization, the association with the inception and severity of asthma is weak.55 It follows that allergic avoidance will only be effective if the allergen(s) are primarily driving the disease. In contrast, studies of occupational asthma suggest that chronic ongoing antigen exposure can lead to progressive and chronic changes in asthma. In that setting, if a subject is not rapidly removed from the source of exposure, the disease can progress rapidly, sometimes to a severe phenotype, is difcult to reverse, and may continue after removal from the exposure source.56 Some of these effects may be through interactions with other environmental factors (such as air pollution, virus, and ETS).

The pathophysiology of severe asthma remains poorly understood. However, evidence exists to support the following 5 statements.

Other trigger factors Nonsteroidal anti-inammatory drugs (NSAIDs) trigger asthma exacerbations in a large subgroup of patients with severe asthma. The occurrence of NSAID-induced asthma is much higher in the adult severe asthma population than in milder patients. Although the exact cause of NSAID-induced asthma is not known, it is associated with increased urinary LTE4 excretion and genetic defects in the leukotriene synthetic and receptor pathways and is known to contribute to ongoing disease chronicity and severity.57 Although aspirin and other NSAIDs remain important triggers in this phenotype, these patients often have severe disease without any chronic exposures to these drugs. The increase in leukotrienes is believed to occur in response to decreased prostaglandin E2 levels after COX-1 inhibition.58 Of note, COX-2 inhibitors do not cause asthma exacerbations in this group of patients.59 Questions 1. What is the incidence of severe asthma, and does it develop differently in childhood as compared with adulthood? 2. Does asthma that has been mild progress to severe asthma, or does severe asthma develop very early in the course of the disease? 3. Can large data sets/bio banks, which carefully characterize severe disease, be used to better dene phenotypes and genotypes of severe asthma? 4. What role do microorganisms, such as viruses, bacteria, and fungi, play in the development of severe asthma? 5. Can long-term high-dose steroid use increase the risk of respiratory tract infections? 6. Do allergic responses have effects on chronicity, airway remodelling, and response to therapy, which differentiate allergic severe asthma from severe asthma without allergic responses? 7. What is the pathogenesis of NSAID-induced severe asthma?

Inltrating cells Inltrating inammatory cells, including mast cells, eosinophils, macrophages, neutrophils, and lymphocytes, are present in the airways of most patients with severe asthma and persist despite steroid therapy, but their relevance to the clinical manifestations of the disease remains uncertain. Despite steroid therapy, inammatory phenotypes of severe asthma are common and have been characterized by persistent eosinophilic and/or neutrophilic inltration of the airways, and in some cases by the absence of any increase in inammatory cells.30,60,61 The factors controlling both eosinophilic and neutrophilic inammation in severe asthma are not clear. Although IL-5, eotaxin, and other mediators may promote eosinophilic inammation, little data support upregulation of specic chemoattractants in a severe as opposed to a milder form of asthma. LTB4, IL8, MIP-1a, and TNF-a have been reported to be increased in severe asthma62 and can induce neutrophil chemotaxis, and upregulation of endothelial adhesion molecules. Epidermal growth factor receptor (EGFR), as a marker of epithelial stress/damage, is also increased in proportion to disease severity.63 EGFR expression in the bronchial epithelium correlates with IL-8,64 which indicates that EGFR can also contribute to a sustained neutrophilic inammation. However, no histologic criteria consistently differentiate severe from milder forms of asthma, perhaps because of confounding by the: (1) effects of therapy; (2) difculty sampling distal lung compartments; and (3) variation with time. A systematic evaluation of proximal and distal lung compartments in severe patients is needed to determine whether inammatory cells or alterations in the underlying matrix or resident cells (including nerves) contribute to the induction and the persistence of severe asthma.65 TH2 paradigm insufciency Although mild asthma is characterized by involvement of TH2-mediated inammation, with recruitment of a range of inammatory cells and enhanced mediator release, the TH2 immune process alone is often inadequate to explain the persistence of severe asthma in adults. Recurrent exacerbations in chronic asthma are often associated with infective pathogens, which suggest abnormalities in innate/adaptive immunity. In addition to TH2 cytokines or chemokines, upregulation of both innate and TH1 pathway elements in severe asthma has been observed, with small clinical studies suggesting that specic interventions in innate immune pathways (TNF-a) may improve outcomes in severe asthma.66 In contrast, clinical trials with T-cellspecic pharmacologic interventions have been disappointing. The persistence of inammation in severe asthma may also result from deciencies in endogenous homeostatic processes that promote resolution of inammation. Transcellular eicosanoid metabolism in the airway occurs during cellcell interactions that leads to generation

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of bioactive lipid mediators known as lipoxins, which can regulate inammation and functional responses. A lower biosynthetic capacity for these potentially anti-inammatory mediators has been linked to severe asthma.67,68 Development of small-molecule mimetics of these pro-resolving mediators will enable further investigation of the impact of these compounds to severe asthma.69 In addition, alveolar macrophages from patients with severe asthma produce lower levels of another potentially protective mediator, prostaglandin E2, in association with defective apoptotic inammatory cell uptake, which could also limit anti-inammatory responses.70 An increased oxidative metabolism has been described in asthma.71 However, the mechanisms responsible for these changes and its specicity for severe asthma are not yet resolved. Similar to decreases in anti-inammatory mediators, low plasma concentrations of specic antioxidants have been observed in more severe asthma, which suggests either that a defect in their production occurs or that long-term oxidative burden exhausts their levels.72 Additional trials of antioxidants are likely.73,74 Translational research to better understand the contributions of innate effector cells, dendritic cells, adaptive immune processes (both TH1 and TH2) and the loss of antiinammatory responses to severe asthma is important. Animal models that resemble severe human asthma have been developed and should allow for specic pathway evaluation and the role of cellular imprinting (epigenetic changes associated with chromatin remodelling) to be explored the future.75

which may be perhaps restored by future therapies that increase the expression of histone deacetylase.80,81

Poor corticosteroid response Complete absence of response to corticosteroid in severe asthma is very rare. Rather, reduced responsiveness, often described as corticosteroid-dependent asthma,76 is more common, where large doses of ICS and even OCS are needed to control asthma77,78 Poor responsiveness to corticosteroid is likely to be multifactorial, varying by phenotype, changing over time and duration of disease, with environmental conditions and within different cell types. However, treatment of eosinophilic severe asthma with a large dose of OCS can lead to a clinically meaningful response.31 On the other hand, neutrophilic moderate-to-severe asthma seems to be poorly responsive to high-dose ICS.29 Additionally, the necessity for OCS in many acute and chronic situations supports the concept that severe asthma involves more than just the proximal airways and may, in fact, be a systemic disease. In severe asthma, the use of high doses of ICS and OCS leads to numerous clinically signicant side effects, which are often inevitable because of the limited therapies available to these patients. More information is needed on the mechanisms for corticosteroid unresponsiveness in severe asthma. As different forms of glucocorticoid receptors have recently been described,79 examination of expression and potential genetic and epigenetic determinants is of potential interest to explain corticosteroid unresponsiveness. However, epigenetic causes of corticosteroid refractoriness are likely to occur in asthma,

Epithelial and smooth-muscle cells Epithelial cell and smooth-muscle abnormalities are observed in most patients with fatal and/or severe asthma and likely contribute to airway narrowing. Interest in the mechanisms involved in differentiation and repair of the airway epithelium, especially as it applies to severe asthma, has increased. Although no difference exists in the expression of the proliferation marker, PCNA, in the bronchial epithelium of healthy controls and patients with asthma with mild and severe disease,82 increased expression of the cyclin-dependent kinase inhibitor p21waf has been reported that could, in part, explain the failure of the epithelium to repair. TGF-b2, produced by the epithelium (and submucosal cells), is increased in asthma83 and can increase mucin expression in the bronchial epithelium in vitro.84 Although a thickened lamina reticularis is a hallmark of asthma,85 whether it is further increased in severe as compared with mild asthma is controversial. Increased airway smooth muscle has been found in the bronchi of individuals who died of status asthmaticus and has been reported in endobronchial biopsies from patients living with severe asthma.86 Whether this increase is from hyperplastic or hypertrophic changes or both remains uncertain. Increased proliferation of bronchial smooth-muscle cells may lead to increased muscle mass in the airways of patients with asthma, and a cell-typespecic absence of C/EBP-a may be responsible for the enhanced proliferation of bronchial smooth muscle and may explain the failure to inhibit proliferation in vitro. The relevance to severe asthma should be investigated.87 The mechanisms driving the increase in smooth muscle in severe asthma remain to be elucidated. Although it may be secondary to inammatory responses, it is also possible that the impaired physiologic stretch of the airways contributes to changes in structure, stiffness, length, and thereby the dynamics of smooth muscle.88,89 A current ATS Task Force entitled Airway smooth muscle dynamics is specically addressing this issue.90 Recent interventional studies targeting the ablation of airway smooth muscle will help determine whether severe asthma can be explained by smooth-muscle abnormalities alone.91,92 Advances in tomography should make it feasible to assess airway structure in longitudinal studies. Inammatory cells are selectively localized to airway structural cells, and cross-talk between cells is likely to be important in the development of some features of severe asthma. Most notably, mast cells are increased in number in the airway smoothmuscle bundle93 with increased degranulation94 and neutrophils, and mast cells localize to glands and are associated with increased mucus plugging in fatal asthma.95 Structural changes Large and small airway wall thickening is observed in many patients with severe asthma, but emerging evidence suggests that parenchymal abnormalities may also inuence airow limitation in severe disease.

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The functional consequences of the structural changes have been difcult to ascertain. Recent physiologic and pathologic studies have suggested that damage may be occurring in the region of alveolar attachments associated with decreased elastic ber content in the adventitial layer of small airways and peribronchial alveoli, which leads to airway collapse and loss of elastic recoil.96,97 Unfortunately, tissue studies of the lung parenchyma/airway attachments are rare in patients living with asthma because of difculties in safely obtaining distal lung biopsies. In addition, imaging techniques are not yet of sufcient sensitivity to noninvasively evaluate this region. In all cases, linking structural changes to functional (physiologic and clinical) impact has been difcult, even though recent results in chronic obstruction pulmonary disease are very promising.98

Questions 1. Can the pattern of inltrating cells and/or molecular markers predict the severity and persistence of asthma? 2. Does enhanced TH2 immunity contribute to severe asthma development, either alone or in combination with other factors? 3. Does a defect in the resolution of inammation contribute to the development of severe asthma? 4. What are the most important mechanisms for corticosteroid hyperresponsiveness in severe asthma? 5. What are the contributions of structural cells to the pathogenesis of severe asthma? 6. How do structural changes predict functional abnormalities? 7. Is impaired smooth-muscle dynamics a critical feature of severe asthma? MANAGEMENT OF SEVERE ASTHMA
ICSs and bronchodilators are the mainstay of treatment for severe persistent asthma. Although corticosteroids are extremely powerful antiinammatory medications, they are relatively less effective in the treatment of severe persistent asthma. In severe asthma, high doses are frequently prescribed without pharmacologic evidence for their utility but with increasing side effects. Few studies have examined doses >2000 mg day. In a study published by Reddel et al,99 a starting dose of 3200 mg/day of budesonide led to better improvements in BHR than a starting dose of 1600 mg, but these patients with moderate-to-severe asthma remained equally well controlled when tapered to the same dose (1600 mg). Two studies that titrated corticosteroid treatment aimed at normalizing sputum eosinophil counts have observed a marked reduction in asthma exacerbations without an excess in increased doses of corticosteroid.24,25 Both studies included patients with severe disease, and in one analysis, it was undertaken with patients stratied by severity, which revealed that the greatest benet was in those subjects with severe disease.24 It was recently shown that parenteral triamcinolone can reduce sputum eosinophils and

improve lung function in patients with severe asthma over a short period of time in a placebo-controlled study.31 Parenteral dosing can also address issues of lack of efcacy because of poor compliance/adherence or a need for a sustained systemic effect. Of note, corticosteroid does not affect LTD4 responsiveness, which indicates that the leukotriene pathway is clearly steroid insensitive.100 Although LABAs are the most effective add-on therapy in asthma, the optimal add-on therapy or combination of therapy for the treatment of severe asthma is still being dened. SABAs form a fundamental part of asthma treatment regardless of asthma severity, and their use is a good measure of disease control. Excessive reliance on these agents is not advisable because it is known that: (1) regular use of high-dose SABA may cause a partial loss of effectiveness; and (2) high doses of SABA may be detrimental to the control of asthma, perhaps by interfering with corticosteroid action.33 Recent studies have demonstrated that the argininearginine mutation on the 16th amino acid of the b2-adrenoceptor (B16 Arg/Arg) is associated with a greater degree of bronchodilator desensitization and worse asthma outcomes compared with the wild-type b2-adrenoceptor.101,102 The role of this polymorphism in the evolution of severe asthma should be evaluated. Despite intensive multidrug treatment (with high-dose ICS 1 OCS, LABA) and other controller medications, many patients with severe asthma remain uncontrolled and an urgent need exists for new, more effective medications. Antileukotrienes are currently included in multiple guidelines as add-on therapy for the treatment of severe asthma.103,104 As the biosynthesis of leukotriene is corticosteroid independent and increased urinary leukotriene levels exist in many patients with severe asthma,105 antileukotriene therapy may be benecial in some patients, with evidence to support their use as add-on therapy in aspirin-sensitive asthma.106 Patients requiring high doses of ICSs demonstrated signicant improvement in symptoms, lung function, and b2-agonist use with high-dose zarlukast.107 In general, these drugs, when added on to multiple drugs in patients with severe asthma, are without denite evidence of benet.106 Anecdotally leukotriene modiers have been reported to be more effective in this population, especially those with NSAID sensitivity.108 Prospective controlled studies comparing receptor antagonists and 5 lipoxygenase inhibitors as add-on therapy in severe asthma with and without aspirin sensitivity should be performed. A Cochrane review concludes that no evidence exists to support anticholinergics as part of add-on treatment for severe uncontrolled patients.109 Whether the long-acting anticholinergic tiotropium has a role in severe asthma therapy remains to be investigated. Methylxanthines can also be used as add-on treatment to ICS, although LABAs are more effective in reducing symptoms and improving lung function.109 Similar to antileukotrienes and LABAs, studies on the use of xanthines in combination with ICS (with or without LABAs) in severe asthma are lacking. Other corticosteroid sparing drugs (cyclosporine, tacrolimus, methotrexate, gold, and gammaglobulins) have shown

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marginal efcacy, and their side effects are so notable that corticosteroids remain the anti-inammatory cornerstone of severe asthma treatment. Omalizumab, a humanized monoclonal antibody directed against IgE, has been approved for treatment of patients with moderate-tosevere asthma. In general, administration of omalizumab has proven safe, and reports indicate its effectiveness in some patients with severe asthma, particularly in regard to asthma exacerbations, and to a lesser degree on lung function.110-112 Anti-IgE requires approximately 3 months to achieve maximal efcacy, at which point corticosteroid tapering should be attempted. Studies in patients with uncontrolled severe asthma have been less impressive.85,113 No specic characteristics have been identied that predict response to anti-IgE. AntiTNF-a therapies are also being evaluated. An open-label study of the soluble TNF-areceptor etanercept in 17 patients with severe asthma demonstrated improvements in lung function, symptoms, and airway responsiveness.62 A double-blind placebo-controlled trial of soluble TNF-areceptor in 10 patients with severe asthma also demonstrated signicant improvements in lung function, BHR, and quality of life.66 Large-scale trials are underway to evaluate the efcacy and safety of these potential harmful drugs.114 Lastly, chronic infections may contribute to severe asthma. Infection with Chlamydia pneumoniae has been associated with a lower FEV1 for a given duration of asthma.49 In patients with mild asthma with serologic or PCR evidence of Mycoplasma infection, treatment with macrolide improved FEV1, reduced inammatory cytokine levels,48 and reduced BHR.115 For all pharmacologic approaches to severe asthma, the role of education should be highlighted. Cote et al116 showed that a structured educational program greatly helps compliance: Less than 20% of patients who get a prescription comply with instructions, whereas around 70% of patients who receive a structured education plan in addition comply with treatment, even after 6 months. A good dialogue between patients and care providers is encouraged. Moreover, patients may have different ideas from doctors regarding symptoms and control as well as strong lay beliefs about medications and their side effects, which should be addressed. However, physicians should be aware that with high-dose systemic steroids, a balance between asthma efcacy and overall quality of life should be established. Providing education, environmental control, adherence with treatment and proper use of inhalers, and using an adequate asthma control assessment represent key factors to help to reduce the severity of asthma.117

In conclusion, networks should be encouraged to standardize the diagnosis and assessment of severe asthma using a common panel of outcome measures, such as those proposed in Table I. This approach may also give insight into the real prevalence of severe asthma, in turn perhaps warranting orphan disease status for severe asthma. Eventually both cross-sectional and longitudinal assessments can be uniformly analyzed to provide a better opportunity to unravel the complex heterogeneity of severe asthma and improve outcomes. Longitudinal sampling of airways in relation to genotype/phenotype is encouraged to better understand the natural history of inammatory and remodeling processes. Tissue sampling of the distal lung for evaluation of the outer airway wall, small airways, and the surrounding parenchyma in association with static and dynamic imaging studies is required to better link structure to functional changes, particularly loss of elastic recoil and small airway collapse. Improved animal models, which better represent the severe asthma phenotypes, are also needed. Performing clinical trials in well-phenotyped and well-genotyped patients in whom adequate therapy is optimized and comorbidities are addressed should be encouraged by independent investigators from specialized centers. A systemic corticosteroid intervention trial is recommended to better understand the pathologic and genetic reasons for the poor responsiveness observed in patients with severe asthma. The use of biologically targeted therapies in human subjects will also help evaluate the contribution of select cellular pathways and mediators to severe asthma pathophysiology. Outcomes in these studies should include patientrelated outcomes (symptom control, quality of life, and/ or prevention of exacerbations) in addition to traditional measures (lung function, BHR, and/or inammatory markers). For most treatment goals, especially asthma control and exacerbations, the duration of the study should be at least 6 months.

REFERENCES 1. Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med 2004;10: 44-50. 2. Chung K, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, et al. Difcult/therapy resistant asthma: the need for an integrated approach to dene clinical phenotypes, evaluate risk factors, understand pathophysiology and nd novel therapies. ERS Task Force on Difcult/ Therapy-Resistant Asthma. Eur Respir J 1999;13:1198-208. 3. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000;162:2341-51. 4. National Institutes of Health NH, Lung, and Blood Institute. Global strategy for asthma management and prevention. Global initiative for asthma 1995.

Questions 1. When the addition of LABAs is not sufcient to control asthma, what is the optimal add-on therapy for severe asthma or its phenotypes? 2. Will use of noninvasive inammatory measures improve the titration of inhaled and systemic corticosteroid therapy?

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3. Will identication of certain subgroups (clinical, physiologic, inammatory phenotypes, or genotypes) enable the prediction of response to specic therapies? 4. Does maximized adherence with therapy in the severe asthma patient improve outcomes?

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5. Hunter CJ, Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;121:1051-7. 6. ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003;22:470-7. 7. Malo JL. Asthma may be more severe if it is work-related. Am J Respir Crit Care Med 2005;172:406-7. 8. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J 2004;24:822-33. 9. de Marco R, Marcon A, Jarvis D, Accordini S, Almar E, Bugiani M, et al. Prognostic factors of asthma severity: a 9-year international prospective cohort study. J Allergy Clin Immunol 2006;117:1249-56. 10. ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT, Zwinderman AH, et al. Risk factors of frequent exacerbations in difcult-totreat asthma. Eur Respir J 2005;26:812-8. 11. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difcult-to-treat asthma. J Allergy Clin Immunol 2005;116:970-5. 12. Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev 2004:CD001108. 13. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reux treatment for asthma in adults and children. Cochrane Database Syst Rev 2003:CD001496. 14. Weiss ST, Shore S. Obesity and asthma: directions for research. Am J Respir Crit Care Med 2004;169:963-8. 15. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol 2005;115:897-909; quiz 10. 16. Hancox RJ, Milne BJ, Poulton R, Taylor DR, Greene JM, McLachlan CR, et al. Sex differences in the relation between body mass index and asthma and atopy in a birth cohort. Am J Respir Crit Care Med 2005; 171:440-5. 17. Saint-Pierre P, Bourdin A, Chanez P, Daures JP, Godard P. Are overweight asthmatics more difcult to control? Allergy 2006;61:79-84. 18. Tan KS. Premenstrual asthma: epidemiology, pathogenesis and treatment. Drugs 2001;61:2079-86. 19. Lacasse Y, Archibald H, Ernst P, Boulet LP. Patterns and determinants of compliance with inhaled steroids in adults with asthma. Can Respir J 2005;12:211-7. 20. Moser M, Cushman W, Handler J. Resistant or difcult-to-treat hypertension. J Clin Hypertens (Greenwich) 2006;8:434-40. 21. ten Brinke A, Ouwerkerk ME, Bel EH, Spinhoven P. Similar psychological characteristics in mild and severe asthma. J Psychosom Res 2001;50:7-10. 22. Schatz M, Mosen D, Apter AJ, Zeiger RS, Vollmer WM, Stibolt TB, et al. Relationships among quality of life, severity, and control measures in asthma: an evaluation using factor analysis. J Allergy Clin Immunol 2005;115:1049-55. 23. Juniper EF, OByrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7. 24. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715-21. 25. Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006;27:483-94. 26. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-73. 27. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005;172:831-6. 28. van Veen IH, Sterk PJ, Schot R, Gauw SA, Rabe KF, Bel EH. Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma. Eur Respir J 2006;27:951-6. 29. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identication of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875-9.

30. Wenzel S. Severe asthma: epidemiology, pathophysiology and treatment. Mt Sinai J Med 2003;70:185-90. 31. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Refractory eosinophilic airway inammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004;170:601-5. 32. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J 2002;19:61-7. 33. Adcock IM, Ito K, Barnes PJ. Glucocorticoids: effects on gene transcription. Proc Am Thorac Soc 2004;1:247-54. 34. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inammation. J Allergy Clin Immunol 2004;113:101-8. 35. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, Koppelman GH, et al. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 2004;34:757-60. 36. Lee JY, Park SW, Chang HK, Kim HY, Rhim T, Lee JH, et al. A disintegrin and metalloproteinase 33 protein in patients with asthma: relevance to airow limitation. Am J Respir Crit Care Med 2006;173:729-35. 37. Pulleyn LJ, Newton R, Adcock IM, Barnes PJ. TGFbeta1 allele association with asthma severity. Hum Genet 2001;109:623-7. 38. Sandford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000;106:135-40. 39. Lodrup Carlsen KC, Lovik M, Granum B, Mowinckel P, Carlsen KH. Soluble CD14 at 2 yr of age: gender-related effects of tobacco smoke exposure, recurrent infections and atopic diseases. Pediatr Allergy Immunol 2006;17:304-12. 40. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 2004;13:1353-9. 41. Weiss ST, Lake SL, Silverman ES, Silverman EK, Richter B, Drazen JM, et al. Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses. Proc Am Thorac Soc 2004;1:364-7. 42. Everard ML. The relationship between respiratory syncytial virus infections and the development of wheezing and asthma in children. Curr Opin Allergy Clin Immunol 2006;6:56-61. 43. Murray CS, Simpson A, Custovic A. Allergens, viruses, and asthma exacerbations. Proc Am Thorac Soc 2004;1:99-104. 44. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston SL, et al. Study of modiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006;61:376-82. 45. Grissell TV, Powell H, Shafren DR, Boyle MJ, Hensley MJ, Jones PD, et al. Interleukin-10 gene expression in acute virus-induced asthma. Am J Respir Crit Care Med 2005;172:433-9. 46. Wark PA, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002;19:68-75. 47. Chen Y, Hamati E, Lee PK, Lee WM, Wachi S, Schnurr D, et al. Rhinovirus induces airway epithelial gene expression through doublestranded RNA and IFN-dependent pathways. Am J Respir Cell Mol Biol 2006;34:192-203. 48. Kraft M, Cassell G, Pak J, Martin R. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002;121:1782-8. 49. ten Brinke A, van Dissel J, Sterk P, Zwinderman A, Rabe K, Bel E. Persistent airow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 2001;107:449-54. 50. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol 2006;117:1233-6. 51. Kraft M. The role of bacterial infections in asthma. Clin Chest Med 2000;21:301-13. 52. Miller MK, Johnson C, Miller DP, Deniz Y, Bleecker ER, Wenzel SE. Severity assessment in asthma: an evolving concept. J Allergy Clin Immunol 2005;116:990-5. 53. Borish L, Chipps B, Deniz Y, Gujrathi S, Zheng B, Dolan CM. Total serum IgE levels in a large cohort of patients with severe or difcultto-treat asthma. Ann Allergy Asthma Immunol 2005;95:247-53.

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Chanez et al 1347

54. Lee JH, Haselkorn T, Chipps BE, Miller DP, Wenzel SE. Group. TS. Gender differences in IgE-mediated allergic asthma in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. J Asthma 2006;43:179-84. 55. Lemanske RF Jr, Busse WW. 6. Asthma: factors underlying inception, exacerbation, and disease progression. J Allergy Clin Immunol 2006; 117:S456-61. 56. Lemiere C, Cartier A, Malo JL, Lehrer SB. Persistent specic bronchial reactivity to occupational agents in workers with normal nonspecic bronchial reactivity. Am J Respir Crit Care Med 2000;162:976-80. 57. Sayers I, Barton S, Rorke S, Beghe B, Hayward B, Van Eerdewegh P, et al. Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma. Thorax 2003;58:417-24. 58. Szczeklik W, Sanak M, Szczeklik A. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. J Allergy Clin Immunol 2004;114:248-53. 59. Gyllfors P, Bochenek G, Overholt J, Drupka D, Kumlin M, Sheller J, et al. Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib. J Allergy Clin Immunol 2003;111:1116-21. 60. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inammation in persistent asthma: evidence of neutrophilic inammation and increased sputum interleukin-8. Chest 2001;119:1329-36. 61. Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am J Respir Crit Care Med 2005;172:559-65. 62. Howarth P, Babu K, Arshad H, Lau L, Buckley M, McConnell W, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005;60:1012-8. 63. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000;14:1362-74. 64. Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I, Dearman RJ, et al. The role of the epidermal growth factor receptor in sustaining neutrophil inammation in severe asthma. Clin Exp Allergy 2003;33:233-40. 65. Joos GF, Germonpre PR, Pauwels RA. Role of tachykinins in asthma. Allergy 2000;55:321-37. 66. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006;354:697-708. 67. Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E. Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med 2005;172:824-30. 68. Vachier I, Bonnans C, Chavis C, Farce M, Godard P, Bousquet J, et al. Severe asthma is associated with a loss of LX4, an endogenous antiinammatory compound. J Allergy Clin Immunol 2005;115:55-60. 69. Petasis NA, Akritopoulou-Zanze I, Fokin VV, Bernasconi G, Keledjian R, Yang R, et al. Design, synthesis and bioactions of novel stable mimetics of lipoxins and aspirin-triggered lipoxins. Prostaglandins Leukot Essent Fatty Acids 2005;73:301-21. 70. Huynh ML, Malcolm KC, Kotaru C, Tilstra JA, Westcott JY, Fadok VA, et al. Defective apoptotic cell phagocytosis attenuates prostaglandin E2 and 15-hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages. Am J Respir Crit Care Med 2005;172:972-9. 71. Henricks PA, Nijkamp FP. Reactive oxygen species as mediators in asthma. Pulm Pharmacol Ther 2001;14:409-20. 72. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther 2006;111:476-94. 73. Misso NL, Brooks-Wildhaber J, Ray S, Vally H, Thompson PJ. Plasma concentrations of dietary and nondietary antioxidants are low in severe asthma. Eur Respir J 2005;26:257-64. 74. Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax 2003;58:175-82. 75. Beavitt SJ, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, et al. Lyn-decient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity. J Immunol 2005;175: 1867-75. 76. Bonnans C, Chanez P, Meziane H, Godard P, Bousquet J, Vachier I. Glucocorticoid receptor-binding characteristics in severe asthma. Eur Respir J 2003;21:985-8.

77. Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc 2004;1:264-8. 78. Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006;117:522-43. 79. Rhen T, Cidlowski JA. Antiinammatory action of glucocorticoids new mechanisms for old drugs. N Engl J Med 2005;353:1711-23. 80. Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med 2004;170:141-7. 81. Ito K, Yamamura S, Essile-Quaye S, Cosio B, Ito M, Barnes PJ, et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med 2006;203:7-13. 82. Puddicombe SM, Torres-Lozano C, Richter A, Bucchieri F, Lordan JL, Howarth PH, et al. Increased expression of p21(waf) cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium. Am J Respir Cell Mol Biol 2003;28:61-8. 83. Balzar S, Chu HW, Silkoff P, Cundall M, Trudeau JB, Strand M, et al. Increased TGF-beta2 in severe asthma with eosinophilia. J Allergy Clin Immunol 2005;115:110-7. 84. Chu HW, Balzar S, Seedorf GJ, Westcott JY, Trudeau JB, Silkoff P, et al. Transforming growth factor-beta2 induces bronchial epithelial mucin expression in asthma. Am J Pathol 2004;165:1097-106. 85. Holgate S, Chuchalin A, Hebert J, Lotvall J, Persson G, Chung K, et al. Efcacy and safety of a recombinant anti-immunoglobin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004;34:632-8. 86. Pepe C, Foley S, Shannon J, Lemiere C, Olivenstein R, Ernst P, et al. Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol 2005;116:544-9. 87. Roth M, Johnson PR, Borger P, Bihl MP, Rudiger JJ, King GG, et al. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med 2004; 351:560-74. 88. Liu JQ, Yang D, Folz RJ. A novel bronchial ring bioassay for the evaluation of small airway smooth muscle function in mice. Am J Physiol Lung Cell Mol Physiol 2006;291:L281-8. 89. Maksym GN, Deng L, Fairbank NJ, Lall CA, Connolly SC. Benecial and harmful effects of oscillatory mechanical strain on airway smooth muscle. Can J Physiol Pharmacol 2005;83:913-22. 90. Fredberg JJ. Bronchospasm and its biophysical basis in airway smooth muscle. Respir Res 2004;5:2. 91. Bel EH. Hot stuff: bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:941-2. 92. Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965-9. 93. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell inltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699-705. 94. Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002; 19:879-85. 95. Carroll NG, Mutavdzic S, James AL. Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax 2002;57:677-82. 96. Gelb AF, Schein A, Nussbaum E, Shinar CM, Aelony Y, Aharonian H, et al. Risk factors for near-fatal asthma. Chest 2004;126:1138-46. 97. Mauad T, Silva LF, Santos MA, Grinberg L, Bernardi FD, Martins MA, et al. Abnormal alveolar attachments with decreased elastic ber content in distal lung in fatal asthma. Am J Respir Crit Care Med 2004; 170:857-62. 98. Hasegawa M, Nasuhara Y, Onodera Y, Makita H, Nagai K, Fuke S, et al. Airow limitation and airway dimensions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:1309-15. 99. Reddel H, CR J, Marks G, Ware S, Xuan W, Salome C, et al. Optimal asthma control, starting with high doses of inhaled budesonide. Eur Respir J 2000;16:226-35. 100. Gyllfors P, Dahlen SE, Kumlin M, Larsson K, Dahlen B. Bronchial responsiveness to leukotriene D(4) is resistant to inhaled uticasone propionate. J Allergy Clin Immunol 2006;118:78-83. 101. Israel E, Chinchilli V, Ford JG, Boushey HA, Cherniak R, Craig TJ, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratied, randomized, placebo-controlled cross-over trial. Lancet 2004;364:1505-12.

Asthma diagnosis and treatment

1348 Chanez et al

J ALLERGY CLIN IMMUNOL JUNE 2007

102. Wechsler M, Lehman E, Lazarus S, Lemanske JR, Boushey H, Deykin A, et al. b-adrenergic Receptor Polymorphisms and Response to Salmeterol. Am J Respir Crit Care Med 2006;173:519-26. 103. British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national guideline. 2005. 104. National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. National Institutes of Health, National Heart, Lung, and Blood Institute, 1997. 105. Vachier I, Kumlin M, Dahlen SE, Bousquet J, Godard P, Chanez P. High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma. Respir Med 2003;97:1225-9. 106. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001;357:2007-11. 107. Virchow J, Prasse A, Naya I, Summerton L, Harris A, and the Zarlukast Study Group. Zarlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85. 108. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:9-14. 109. Westby M, Benson M, Gibson P. Anticholinergic Agents for chronic asthma in adults. The Cochrane Database Syst Rev 2004: CD003269. 110. Busse W, Corren J, Lanier B, McAlary M, Fowler-Taylor A, Cioppa G, et al. Omalizumab, anti-IgE recombinant humanized monoclonal

111.

112.

113.

114.

115.

116.

117.

antibody, for the treatment of severe allergic asthma. J Allerg Clin Immunol 2001;108:184-90. Corren J, Casale T, Deniz Y, Ashby M. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allerg Clin Immunol 2003;111:87-90. Soler M, Matz J, Townley R, Buhl R, OBrien J, Fox H, et al. The antiIgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18:254-61. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benets of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309-16. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275-85. Kostadima E, Tsiodras S, Alexopoulos E, Kaditis A, Mavrou I, Georgatou N, et al. Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma. Eur Respir J 2004;23:714-7. Co te J, Bowie D, Robichaud P, Parent J-G, Battisti L, Boulet L-P. Evaluation of two different educational interventions for adult patients consulting with an acute asthma exacerbation. Am J Resp Crit Care Med 2001;163:1415-9. Wenzel S, Szeer SJ. Managing severe asthma. J Allergy Clin Immunol 2006;117:508-11.

Asthma diagnosis and treatment