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Fixed Airflow Limitation in Asthma

PCCSU Volume 25, Lesson 5

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By E. Rand Sutherland, MD, MPH, FCCP

Dr. Sutherland is Associate Professor of Medicine and Chief, Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado.

Dr. Sutherland has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:

National Institutes of Health – grant monies
Novartis, Boehringer‐Ingelheim – grant monies
GlaxoSmithKline, Dey, Schering‐Plough, TEVA, Meda – consultant fee

Objectives

  1. Review the definition of fixed airflow limitation in asthma.
  2. Identify the prevalence of fixed airflow limitation in asthma.
  3. Address the relationship between asthma phenotype and fixed airflow limitation.
  4. Discuss inflammatory pathways that lead to the development of fixed airflow limitation in asthma.
  5. Review the prognostic and therapeutic implications of fixed airflow limitation in asthma.

Key words: asthma; inflammation; physiology

Abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid; IgE = immunoglobulin E; LABA = long-acting β-agonist; TENOR = The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study

Introduction

Asthma is a clinical syndrome classically defined by pathophysiologic features that include bronchodilator-responsive expiratory airflow limitation, airway hyperresponsiveness, and chronic airway inflammation. This constellation of abnormalities leads to symptoms such as cough, shortness of breath, wheezing, and chest tightness, all of which can be persistent and recurring clinical features of asthma. Although some patients with asthma, particularly children, may have normal airflow, many will demonstrate reductions in expiratory airflow during exacerbations and in intervening periods of clinical stability. Given this, guidelines1,2 have relied heavily on the presence of airflow limitation that improves after administration of short-acting β2-agonists (eg, albuterol) as a sine qua non for the diagnosis of asthma. Conversely, the absence of bronchodilator response has been incorporated into the definition of chronic obstructive pulmonary disease (COPD), leading to uncertainty in some cases with regard to how best to classify patients with a lack of bronchodilator response who have a history that is consistent with asthma. This review will address the subset of patients with asthma who do not demonstrate improvement in airflow limitation after the administration of albuterol, focusing (1) pathways by which loss of bronchodilator response may occur; (2) what implications the loss of bronchodilator responsiveness has with regard to clinical manifestations of asthma; and (3) what, if any, alterations to therapy need to be considered by the practicing clinician.

How Is “Fixed” Airflow Limitation Defined?

Guidelines from the American Thoracic Society and European Respiratory Society3 define airflow limitation as a “disproportionate reduction of maximal airflow from the lung in relation to the maximal volume that can be displaced from the lung.” This manifests itself on simple spirometry as a reduction of the ratio of the FEV1 to the FVC to a level below the 5th percentile. In patients with airflow limitation, significant response to bronchodilators is defined using a combination of absolute changes in the volume of either FEV1 or FVC and percent change from baseline, with increases of 200 mL and 12% from baseline for either of these measurements constituting a positive response. Using these criteria, fixed, or “irreversible,” airflow limitation can then be defined as airflow limitation marked by an improvement less than these threshold values following bronchodilator administration.

Although fixed airflow limitation can be defined in the context of bronchodilator responsiveness (or lack thereof), it is also useful to consider criteria in which fixed airflow limitation is defined by the inability of the FEV1 or FEV1/FVC to exceed a certain threshold. Although there is not unanimity on the choice of threshold in this regard, the literature4,5 supports using a postbronchodilator FEV1/FVC ratio of ≤70% on at least two occasions as an alternative criterion for defining fixed airflow limitation. It is also important to note that there is intermingling of terms in the literature, with airflow limitation as described above alternately called “fixed,” “persistent,” or “irreversible.” For the purposes of this review, these terms will be used interchangeably.

What Is the Prevalence of Fixed Airflow Limitation in Asthma?

Some of the most extensive clinical data regarding fixed airflow limitation in asthma come from a secondary analysis4 of data obtained during The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, a large-scale observational cohort study of nearly 5,000 patients with severe or difficult-to-treat asthma.6 In a subset of 1,017 participants in this study, Lee and colleagues4 reported that 60% had evidence of persistent airflow limitation, defined by a postbronchodilator FEV1/FVC ratio ≤70% on two or more occasions. In the analyzed cohort, participants with persistent airflow limitation were older, with a mean age (±SD) of 54±15 years, vs 45±13 years (P <.0001) in the nonpersistent airflow limitation group. The duration of asthma was more than 10 years longer in this group, at 31±17 vs 20±14 years (P <.0001), and these patients were also more likely to be men, former smokers (although without a formal diagnosis of COPD), and of African American racial background. Interestingly, this group also had an increased prevalence of markers of atopy, including higher IgE levels and a greater likelihood of having positive skin test results. In another, smaller cohort study reported by ten Brinke and colleagues,7 patients with severe asthma defined by a constellation of symptoms, exacerbation frequency, and need for high-dose inhaled corticosteroids were enrolled. In this cohort, 48.5% of patients demonstrated evidence of persistent airflow limitation, defined as a postbronchodilator FEV1/FVC ratio <75% (rather than 70%).

In populations with asthma more mild than that of TENOR participants, the prevalence of fixed airflow limitation is lower, suggesting that fixed airflow limitation is a feature positively correlated with disease severity. In a cohort of patients with asthma with reversible airflow limitation followed for a period of 21 to 33 years by Vonk and colleagues,8 16% developed fixed airflow limitation at the end of follow up, with the development of fixed airflow limitation associated with factors including lower starting FEV1 % predicted, lesser use of corticosteroid medications at the last follow-up visit, and (somewhat paradoxically) a greater degree of airway hyperresponsiveness at baseline. Similarly, data from the Tucson Epidemiological Study of Airway Obstructive Disease indicate that approximately 26% of people with asthma who do not smoke developed persistent airflow limitation during follow-up.5

How Is Fixed Airflow Limitation Related to Asthma Phenotype?

As described above, the prevalence of fixed airflow limitation appears to increase in populations as asthma severity increases. However, severity alone is not the sole factor that has been identified as being associated with fixed airflow limitation, and a number of other relevant risk factors have been identified.9 In the cohort study of ten Brinke and colleagues,7 the authors carefully evaluated clinical and inflammatory parameters associated with persistent airflow limitation in 132 nonsmoking adults with severe asthma treated with the combination of inhaled steroids and long-acting β2-agonists (ICS/LABA). The authors made a number of interesting observations. As was observed subsequently in the TENOR study, persistent airflow association was associated with older age and longer asthma duration, although there were not differences by sex or smoking history. Physiologically, the patients with fixed airflow limitation had a greater degree of air trapping than did those without, with a ratio of the residual volume/total lung capacity of 130.2% ± 29.3% vs 101.6% ± 22.9%, respectively (P <.001). Other relevant asthma clinical parameters did not differ significantly between the two groups, including dose of inhaled corticosteroids, need for oral corticosteroids, use of rescue β2-agonists, or nocturnal symptoms, although exacerbation frequency was higher in those with fixed airflow limitation.

With regard to inflammatory and other physiologic parameters, there were no differences between those with and without persistent airflow limitation in the prevalence of atopy, total IgE, exhaled nitric oxide concentrations, or blood eosinophil counts. However, sputum eosinophil levels were significantly higher in patients with persistent airflow limitation (3.2% vs 0.5%, P = .005), with an adjusted OR (95% CI) of 7.7 [2.4 - 25.1]. There also was a greater degree of airway hyperresponsiveness to histamine, with a PC20 histamine level of ≤1.0 mg/mL having a strong association with persistent airflow limitation, as reflected by an OR of 3.9 [1.2 - 13.0]. Lastly, adult-onset asthma was also associated with persistent airflow limitation with an OR of 3.3 [1.2 - 9.0]. On the basis of these findings, the authors concluded that there is a high prevalence of fixed airflow limitation in patients with severe asthma, and that ongoing eosinophilic airway inflammation (despite ICS/LABA treatment) was associated with the development of this physiologic abnormality.7 Other studies have also suggested an association between ongoing eosinophilic inflammation in both the airway10 and the peripheral blood11 as predictors of fixed airflow limitation.

Other risk factors for the development of fixed airflow limitation have been identified, although in some cases it remains a challenge to differentiate whether these are independent predictors, per se, or whether they are simply inducers of suboptimally treated persistent airway inflammation. A number of environmental factors including cigarette smoking, occupational exposures, and recurrent lower airway infections have been associated with the development of fixed airflow limitation.9 Comorbid obesity is an important consideration as well, having been shown to be associated with reduced lung function in patients with asthma.12

What Leads to the Development of Fixed Airflow Limitation in Asthma?

It has been suggested that the persistent airway inflammation seen in asthma can lead to pathologic alterations of airway structure, a process that has been termed “airway remodeling.” Among the structural changes that have been reported in the remodeled airway are thickening of the epithelial cell layer with goblet cell hyperplasia, development of subepithelial fibrosis and collagen deposition, and increase in the mass of and disordering of the structure of the airway smooth muscle, along with angiogenesis.13 Together, these changes in structure and function of critical airway cellular components have been hypothesized to lead to obstruction of the airway lumen, narrowing of airway caliber and increases in bronchomotor tone, all of which serve to increase airflow limitation and reduce response to inhaled bronchodilators. For these reasons, fixed airflow limitation is often considered a physiologic manifestation of a remodeled airway.

Remodeling of the airway may have implications for symptoms expression in asthma, as well.14 For example, cough and sputum production in asthma could be explained in part by an increased volume of goblet cells in the airway epithelium and mucous glands in the submucosa.15 Wheezing, chest tightness, and shortness of breath are all common in asthma and may be contributed by features of airway remodeling, including accumulation of mucus, plasma exudate, and epithelial cells in the lumen. Further contributing to the elaboration of these symptoms is constriction of the airway induced by thickening of the airway wall, constriction of the smooth muscle, and even loss of lung elastic recoil in a “pseudophysiologic emphysema” pattern.16

Significant investigative efforts are underway to further elucidate the inflammatory processes that orchestrate the multiple pathologic processes that lead to airway remodeling and fixed airflow limitation. Perhaps most widely accepted is the contribution of the airway eosinophil to remodeling, with inhibition of eosinophil infiltration in the airway of IL-5 deficient mice having been shown to be associated with a significant reduction in airway remodeling.17 Eosinophils appear to mediate the development of fibrosis through elaboration of the profibrotic cytokine transforming growth factor-β.18 Other immune cells, including T helper cells and regulatory T cells, play an important role in the development of airway remodeling, as do a large number of proinflammatory, profibrotic, and proangiogenic cytokines.13

What Are the Prognostic Implications of Fixed Airflow Limitation in Asthma?

Asthma itself, independent of the presence or absence of fixed airflow limitation, is associated with an accelerated rate of lung function decline over time, as shown in multiple cohort studies. Patients with asthma who demonstrate fixed airflow limitation not only have the potential to develop an accelerated rate of lung function decline over time but also demonstrate evidence of poor prognosis in other areas, in part because reductions in postbronchodilator lung function have been associated with increased overall and asthma-specific mortality.19,20

In data reported by Lange and colleagues21 from the Copenhagen City Heart Study, the rate of lung function decline in participants with asthma was approximately double of that observed in participants without asthma, with an unadjusted decline in FEV1 of 38 mL/year in patients with asthma vs 22 mL/year in patients without asthma. Although the investigators did not independently evaluate the effect of fixed airflow limitation on the rate of decline, they were able to assess the effect of mucous hypersecretion (a feature associated with airway remodeling) on the rate of lung function decline in study participants who had asthma, reporting that mucous hypersecretion was associated with an even greater rate of decline in lung function over time. Additional data from the Melbourne Asthma Study22 have extended these observations by reporting there is also interaction between disease severity and rate of lung function decline over time, with yet other data11 suggesting that duration of disease could play a role, as well.

It is likely that the early development of airflow limitation early in life also dictates the rate of lung function decline over time, with numerous studies suggesting that lower levels of lung function over time predict greater levels of decline in the future. Frequently cited are data from the Busselton Health Study,14 which demonstrated that asthma was associated with reduced FEV1 at the age of 19 years, and that this reduced lung function in early adulthood was predictive of an increased rate of lung function decline in later adulthood. Rasmussen and colleagues23 used both cohort data from New Zealand to evaluate the relationship between childhood features of asthma and the development of fixed airflow limitation in adults aged 18-26 years. In their population, between 6% and 7% of patients with asthma manifested fixed airflow limitation when assessed either at age 18 years or age 26 years, and for those participants with low lung function at both of these assessments, an association with reduced childhood lung function was observed. Participants who had consistently low postbronchodilator FEV1/FVC ratios showed the greatest rate of decline in this ratio over the years between ages 9 and 26 years when compared with those participants who had normal lung function at the two later evaluations. The authors concluded that these data suggested that airway remodeling in asthma (defined in this case by impaired lung function) might begin in childhood and continue into adult life in many cases.

What Are the Therapeutic Implications of Fixed Airflow Limitation in Asthma?

Although the development of fixed airflow limitation appears to be associated with specific pathologic and prognostic features as described previously, current guidelines recommend that treatment for all patients with asthma be directed toward optimal asthma control rather than focusing principally on the degree of airflow limitation.1,2 However, given the association between fixed airflow limitation, severe asthma, and suboptimal control, many patients with fixed airflow limitation will require aggressive antiinflammatory and bronchodilator controller therapy. It has not yet been conclusively shown that inhaled corticosteroid therapy can significantly modify the likelihood of developing fixed airflow limitation or modify the rate of lung function decline over time, but despite this, antiinflammatory therapy with glucocorticoids remains the mainstay of controller therapy for these patients, with the ultimate goal of reducing ongoing airway inflammation that may trigger these structural changes described above.1,2

Before labeling a patient with the diagnosis of fixed airflow limitation, it is important to document that the airflow limitation is, in fact, truly “irreversible.” Careful assessment of spirometry before and after an inhaled bronchodilator (eg, albuterol) is warranted, and clinicians can also consider a brief trial of oral glucocorticoids as an adjunct to determine the maximum achievable FEV1 in these patients. While it is possible that irreversible structural changes have occurred, one must consider untreated comorbidities such as atopy, obesity, gastroesophageal reflux, or chronic rhinosinusitis as contributors to disease activity, and it is also warranted to determine the patient’s level of adherence with prescribed controller medications.

Emerging data suggest that titrating inhaled corticosteroid therapy to inflammatory biomarkers, including exhaled nitric oxide24 and sputum eosinophils, may be of value in optimizing treatment in some patients with asthma, although these approaches remain exploratory at this time. Of these studies, those which target inhaled corticosteroid therapy to sputum eosinophil percentages may be most relevant given the putative role of eosinophils in modulating airway remodeling. Green and colleagues25 reported that a treatment strategy directed at normalizing induced sputum eosinophil counts results in reduced exacerbations and hospitalizations in patients with moderate to severe asthma, on a fact that it came without requiring additional antiinflammatory therapy. In this study, the investigators titrated inhaled corticosteroid therapy to maintain a sputum eosinophil percentage of 3% or less. A subsequent study by Jayaram and colleagues26 supported these observations. In this trial, the investigators altered corticosteroid therapy to maintain sputum eosinophils at 2% or less, and in those patients in which this was achieved, the time to first exacerbation was prolonged as was the relative risk and the overall number of exacerbations requiring systemic steroids.

Overall, it is important to treat patients with asthma and fixed airflow limitation aggressively, although within the context of current recommendations in international guidelines. In general, inhaled corticosteroids are the most effective controller medications currently available for patients with fixed airflow limitation, and if adequate asthma control is not achieved with inhaled corticosteroid monotherapy, the addition of other controllers including long-acting β2-agonists, leukotriene modifiers, or other agents can be considered.1,2


References

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  2. Global Initiative for Asthma (GINA). GINA report, global strategy for asthma management and prevention (updated December 2009). http://www.ginasthma.org. Accessed August 25, 2010.
  3. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968.
  4. Lee JH, Haselkorn T, Borish L, Rasouliyan L, Chipps BE, Wenzel SE. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest. 2007;132(6):1882-1889.
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  6. Dolan CM, Fraher KE, Bleecker ER, et al. Design and baseline characteristics of the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004;92(1):32-39.
  7. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med. 2001;164(5):744-748.
  8. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax. 2003;58(4):322-327.
  9. ten Brinke A. Risk factors associated with irreversible airflow limitation in asthma. Curr Opin Allergy Clin Immunol. 2008;8(1):63-69.
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  16. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med. 2000;162(5):1778-1782.
  17. Cho JY, Miller M, Baek KJ, et al. Inhibition of airway remodeling in IL-5- deficient mice. J Clin Invest. 2004;113(4):551-560.
  18. Minshall EM, Leung DY, Martin RJ, et al. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol. 1997;17(3):326-333.
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  21. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194-1200.
  22. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964-1999. J Allergy Clin Immunol. 2002;109(2):189-194.
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  24. 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(21):2163-2173.
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  26. Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483-494.