The Journal of Allergy and Clinical Immunology
Volume 124, Issue 5 , Pages 883-890, November 2009

The irreversible component of persistent asthma

  • Rodolfo M. Pascual, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Rodolfo M. Pascual, MD, Wake Forest University School of Medicine, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157.
    • ,
  • Stephen P. Peters, MD, PhD

Center for Human Genomics and the Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC

Received 29 August 2009; received in revised form 28 September 2009; accepted 29 September 2009.

Article Outline

Irreversible airflow obstruction or limitation occurs in some patients with asthma, can develop early in life, and becomes more common as asthma becomes more severe. Efforts to understand irreversible airflow obstruction or limitation have been hampered by the lack of a standardized definition of the phenotype and by the lack of appropriate research models. Unfortunately, it appears that currently available asthma treatments do not prevent this important asthma complication. Herein, the evidence of an irreversible component of asthma, its underlying pathology, and the limitations of current asthma treatments are reviewed.

Key words: Asthma, airway remodeling, irreversible airway obstruction, irreversible airflow limitation

Abbreviations used: BHR, Bronchial hyperresponsiveness, COPD, Chronic obstructive pulmonary disease, FVC, Forced vital capacity, RBM, Reticular basement membrane

 

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Information for Category 1 CME Credit 

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: November 2009. Credit may be obtained for these courses until October 31, 2011.

Copyright Statement: Copyright © 2009-2011. All rights reserved.

Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic disease.

Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

List of Design Committee Members: Authors: Rodolfo M. Pascual, MD, and Stephen P. Peters, MD, PhD

Activity Objectives

1. To understand, define, and measure the irreversible component in asthma.

2. To discuss current evidence on irreversible airflow obstruction in patients with asthma.

3. To learn the mechanisms and pathophysiology of airway remodeling in patients with asthma.

4. To evaluate the effect of current asthma treatments on airway remodeling and irreversibility in patients with asthma.

Recognition of Commercial Support: This CME activity is supported by an educational grant from Merck & Co., Inc.

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations: R. Pascual receives research support from the

NHLBI and is on the speakers' bureau for Gilead, Actelion, and United Therapeutics.

S. P. Peters receives research support from the NIH, NHLBI, and NIAID.

Glossary

 

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AIRWAY REMODELING 

Airway remodeling is triggered by long-term, untreated airway inflammation. Over time, the airways undergo structural changes, which can be permanent if not adequately treated and severely impair lung function. These structural changes include thickening of the airway wall, increased mucus production, and increased vascularization in the airways.

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ALLERGIC SENSITIZATION 

Sometimes referred to as type 1 or IgE-mediated hypersensitivity, allergic sensitization occurs when the immune system is exposed to allergens, leading to the production of IgE antibodies. Subsequent allergen exposure cross-links the IgE antibodies, which are bound to Fcε receptors on mast cells and basophils, leading to the release of histamine and other mediators that cause allergic symptoms.

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BRONCHIAL HYPERRESPONSIVENESS 

BHR is also referred to as airway hyperreactivity and is defined as an exaggerated constriction of the bronchioles or small airways in response to physical, chemical, or pharmacologic stimuli. It is sometimes referred to as a bronchospasm, suggesting that airway smooth muscle plays an important role, and is typically assessed by using a bronchial challenge test with methacholine or histamine. BHR is a hallmark in patients with asthma and COPD.

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BRONCHODILATOR 

Bronchodilators are pharmacologic agents used to dilate the bronchi and bronchioles, thereby decreasing airway constriction and facilitating airflow. Bronchodilators are classified as either short acting or long acting based on their ability to provide quick relief from acute bronchoconstriction or control and prevent symptoms, respectively. β2-Agonists (both short and long acting), anticholinergics (short acting), and theophylline (long acting) are 3 types of commonly prescribed bronchodilators.

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CHRONIC OBSTRUCTIVE PULMONARY DISEASE 

COPD is defined as chronic obstruction of airflow in the airways that worsens over time and increases in persistence. Often, COPD is associated with chronic bronchitis or emphysema. The decreased airflow is most commonly associated with loss of lung elasticity, inflamed airways, and increased mucus production. Proper diagnosis of COPD requires pulmonary function tests.

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CORTICOSTEROIDS 

Corticosteroids are a class of hormones synthesized from cholesterol within the adrenal cortex. Glucocorticoids are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action, and a number of other mechanisms. Mineralocorticoids control electrolyte and water levels, mainly by promoting sodium retention in the kidney. Synthetic glucocorticoids are used in the treatment of inflammation in asthmatic subjects.

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CROSS-SECTIONAL STUDY 

A cross-sectional study is an epidemiologic study that measures variables within a specified population at a single point in time. These studies are used to establish the prevalence within a specified population without distinguishing between newly occurring and long-established conditions.

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FEV1 

FEV1is the volume of air that can be forced out in 1 second. FEV1 is typically measured with a spirometer during a pulmonary function test to diagnose respiratory conditions, such as asthma, cystic fibrosis, and COPD.

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FORCED VITAL CAPACITY 

FVC is the maximum volume of air that can be exhaled or inhaled by a patient with maximal effort during a pulmonary function test with a spirometer. The FEV1/FVC ratio provides a clinically useful measurement of airflow limitation and respiratory disease.

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LONGITUDINAL STUDY 

A longitudinal study is a chronologic epidemiologic study that measures variables within a specified population at repeated intervals over time. These studies are often used to establish correlations between disease onset and severity.

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MORBIDITY 

Morbidity refers to a diseased state, disability, or poor health of any cause. Rates of morbidity are of 2 types: the prevalence rate refers to the number of individuals with a specific condition at a specific time, and the incidence rate refers to the number of individuals with a particular condition over a period of time.

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PHENOTYPE 

Phenotype is defined as the physical, physiologic, and behavioral traits of an individual produced by the interaction of the genetic makeup and environmental influences.

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RETICULAR BASEMENT MEMBRANE 

RBM, also known as the lamina reticularis, is a network of type III collagen fibers and macromolecular components that varies in thickness and is connected to the basal lamina. The abnormal thickening of the RBM in patients with asthma is thought to result from the accumulation of collagen, which is referred to as subepithelial fibrosis.

The Editors wish to acknowledge Michael D. Howell, PhD, for preparing this glossary.

Asthma is a disease characterized by episodic airflow obstruction or limitation, which is at least partially reversible; lung inflammation, particularly in the airways; and bronchial (airway) hyperresponsiveness (BHR). However, asthma is a heterogeneous process in terms of its clinical presentation, natural history, and pathophysiology, and therefore it is more accurately termed a syndrome. The onset or beginning of asthma apparently has different causes, and asthma can progress or evolve differently in different patients. In terms of the natural history of asthma, astute physicians long ago observed that many of the features of asthma overlapped with bronchitis and emphysema (chronic obstructive pulmonary disease [COPD]),1 a condition characterized by a component of irreversible airflow obstruction. Clearly, some asthmatic patients experience severe and irreversible airflow obstruction, some have exacerbations with recovery to normal lung function, and others seem to have a fairly stable clinical course over many years.

The natural history of asthma,2 the mechanisms driving remodeling,3 and the clinical assessment of asthma progression4 were discussed in a recent issue of the Journal. Airway remodeling,5, 6, 7, 8 airway inflammation,9 epithelial-mesenchymal interactions,10, 11 severe asthma,12 and longitudinal changes of lung function13 have also been reviewed elsewhere. In this review evidence that an irreversible component develops as asthma evolves or progresses, potential mechanisms underlying disease progression, and limitations to existing models will be discussed. The reader is encouraged to refer to the several recent review articles mentioned above. Despite a wealth of information about airway remodeling that has been developed using various models, including longitudinal studies with repeated lung function measurements, cross-sectional studies of patients with severe asthma (a group expected to have undergone airway remodeling), investigational bronchoscopy, interventional studies using anti-inflammatory treatment, and various animal studies, many unanswered questions remain, as shown in Table I.

Table I. Unanswered questions in airway remodeling
Does the failure of an airway to undergo full bronchodilation on acute treatment with a β-agonist mean that airflow obstruction is irreversible?
Does the failure of lung function to normalize after corticosteroid treatment mean that airflow obstruction is irreversible?
Are airway injury-repair mechanisms, at least in part, distinct from inflammatory mechanisms?
Do medications that effectively treat inflammation treat abnormal injury-repair mechanisms or do medications that treat inflammation even alter the natural history of asthma?
When (during what ages) do the changes that lead to irreversible airflow obstruction occur as asthma evolves?
What clinical features, physiologic parameters, or biomarkers can predict the development of irreversible airflow obstruction?

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Defining an irreversible component in asthma 

The concept of irreversibility of airflow obstruction implies that a change in the structure-function relationship of the airway has occurred that reduces expiratory airflow, that this change would not normally revert to the prior state, and that no endogenous mechanism or treatment would be capable of causing reversion to the prior state. Hence no cross-sectional study can demonstrate irreversibility, and even longitudinal studies that do not use a process to try to reverse what appears to be a change in airflow obstruction cannot prove irreversibility. What does exist is much indirect evidence that progressive airflow obstruction develops (longitudinal studies), that severe or progressive airflow obstruction seemingly occurs in some patients despite ongoing anti-inflammatory (glucocorticoid) or bronchodilator treatment, and that when severe airflow obstruction does develop in a patient, the obstruction typically cannot be completely reversed with conventional treatments (severe asthma studies).

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Measuring an irreversible component 

One important issue is that asthma itself is clinically defined by the presence of reversible airflow obstruction. Hence some patients (or study participants) whose lungs and airways exhibit the inflammatory features of asthma, who are not cigarette smokers, and who have reduced lung function but who are not responsive to β-agonists on a given day might not be given a diagnosis of asthma but rather a diagnosis of COPD. Interestingly, on a different day, such potential subjects could exhibit bronchodilator reversibility; however, although that subject would usually exhibit BHR, airway challenge testing is underused and might be avoided if severe nonreversible obstruction were present.

This phenomenon has also been observed for COPD, wherein various degrees of bronchodilator reversibility might be exhibited within a given subject over time. Some practitioners falsely believe that the airflow obstruction is completely reversible in the asthmatic subject and, conversely, not at all reversible in the patient with COPD. However, even a cursory examination of the typical prebronchodilator and postbronchodilator FEV1 measurements in most asthma studies show that the average postbronchodilator FEV1 measurements are often less than 100% of predicted value, which is what would be expected if the airways were restored to a normal state. In a group of subjects who do not reach 100% of predicted FEV1 in the face of aggressive bronchodilator treatment, one would postulate that airflow obstruction is not reversible. However, this does not necessarily mean that it is permanently irreversible, just not completely responsive to that single treatment episode. Unfortunately, most of the data from severe asthma studies, although showing substantial reductions in average FEV1 and typically reversal that is far short of complete, are cross-sectional and do not definitively show irreversibility, as we have defined it.

Similarly, several important longitudinal studies that will be discussed show that airflow obstruction worsens at an accelerated rate in asthmatic patients when compared with that seen in control patients, but there is often no specific attempt to reverse this loss, and hence irreversibility cannot really be confirmed in this case either. Longitudinal study data are suggestive of the concept that as obstruction worsens for most asthmatic patients, there will not be spontaneous reversion back to normal. If one assumes that severe asthma usually evolves from mild asthma and hence results in progressive airflow obstruction and one also assumes that bronchodilator reversibility is often not complete, one can infer that irreversible changes in structure-function relationships have occurred. This is most easily demonstrated with more severe airflow obstruction, although more mild changes might also be irreversible. Therefore, practically speaking, data that show an incomplete reversibility of obstruction on bronchodilator challenge or progressive loss of lung function in subjects despite their being treated can be considered to suggest an irreversible component in persistent asthma. In summary, the argument that irreversible airflow obstruction occurs in patients with severe asthma cannot be proved using existing models, but there are several lines of evidence strongly suggestive of its occurrence.

From a practical standpoint, irreversibility of airflow obstruction is usually defined by persistently low FEV1 measurements over time or failure of low FEV1 or FEV1/forced vital capacity (FVC) values to improve to within normal limits or above a defined threshold with treatment. Across studies, there is significant variability in the stated criteria used to define the irreversibility of airflow obstruction; hence it is difficult to compare results from one study with those from another.

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Longitudinal studies 

As shown in Table II,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 a number of longitudinal studies have been performed in an attempt to elucidate the natural history of asthma. Other studies were designed to determine risk factors for the onset of asthma, especially in children. Important observations from these studies include the fact that lung function defined by FEV1 or FEV1/FVC ratio tends to decrease more rapidly over time in patients with asthma. Cigarette smoking further accelerates loss of lung function or the worsening of airflow obstruction. Perhaps not surprisingly because BHR also tracks with more severe disease, a greater degree of BHR in childhood has been associated with the development of irreversible or persistent airflow obstruction in adulthood.14, 15, 16 However, this is not a consistent finding in all populations.17 Importantly, seminal studies show that, on average, loss of lung function can occur at a very early age.14, 18 Some data suggest that a subset of patients lose significant lung function early in life as the lung is maturing and growing, with little further loss in percent predicted FEV1 over the ensuing years.19

Table II. Selected longitudinal asthma studies
Childhood Asthma Management Program (CAMP)18, 23, 24RCT with average follow-up of 4.3 years and mean age of 9 years. All groups experienced reduction of FEV1/FVC ratio. A subgroup (25.7% of subjects) experienced >1% loss of FEV1 percent predicted per year; this was not modified by treatment.
Coronary Artery Risk Development in Young Adults (CARDIA) study25Lung function followed in young adults for 10 years. Asthmatic subjects had lower baseline FEV1 and experienced a higher rate of loss of lung function than nonasthmatic subjects. Smoking accelerated the loss of lung function.
University Hospital of Groningen, The Netherlands26, 27Cohort of asthmatic children followed for 30 years. A small increase in FEV1 percent predicted was seen over time, although FEV1/FVC ratio seemed to decrease.
Beatrixoord Hospital, Haren, The Netherlands17, 28, 29Cohort of 281 adult asthma patients including smokers followed for 26 years. Increased BHR was paradoxically associated with less risk of irreversible airflow obstruction. Exacerbations were associated with accelerated loss of lung function.
Copenhagen City Heart Study30, 31Large, community-based study; asthma was self-reported in 778 adult subjects. Asthma prevalence increased over time. Patients with asthma experienced accelerated loss of lung function made worse by cigarette smoking.
Dunedin, New Zealand15Population-based birth cohort evaluated over 17 years. BHR or bronchodilator reversibility in childhood was associated with relapsed or persistent asthma in adulthood.
Manchester, United Kingdom20, 21Study performed in young children showed that increased airway resistance (sRaw) at age 3 years predicted increased sRaw and was associated with persistent wheezing at age 5 years, suggesting that loss of lung function occurs early in life.
German Multicenter Allergy Study22, 32Population-based birth cohort. Children with allergic sensitization (especially to perennial allergens) exhibited greater reductions in FEV1 and postbronchodilator FEV1/FVC ratio than nonsensitized children.
Melbourne Asthma Study19, 33, 34, 35, 36Population-based cohort of children followed for 42 years. Loss of lung function (reduced FEV1 percent predicted) was most profound in the severe asthma group. The loss occurred early in life (by age 10 years) but did not worsen over time in any group.
Tucson Children's Respiratory Study14, 16, 37, 38, 39Population-based birth cohort of 1,246 infants followed for 22 years. Persistent asthma at age 22 years was associated with low lung function, BHR, and persistent wheezing at age 6 years.
Copenhagen, Denmark40Clinic-based cohort of 92 nonsmoking patients followed for 10 years. On re-examination, nonreversible airflow obstruction was associated with increasing bronchodilator reversibility at enrollment and long-term use of oral corticosteroids.

RCT, Randomized controlled trial.

Other childhood studies show that wheezing is very common with lower respiratory tract infections but that asthma tends to develop in those wheezers who also had early allergic sensitization.14, 20, 21, 22 Interestingly, reductions in FEV1/FVC ratio can occur as asthma develops, whereas FEV1 itself might change less, suggesting that lung elastic recoil might be lost and the growth of lung volume might be more preserved. Importantly, although inhaled corticosteroids improve quality of life and reduce exacerbations, they do not seem to be effective in preserving lung function in asthmatic subjects in many instances. This suggests that glucocorticoids might have less effect on remodeling mechanisms than they do on inflammatory mechanisms.

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Studies of severe asthma 

As shown in Table III,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 a number of studies examining patients with severe asthma have been carried out in an attempt to determine risk factors and characteristics that differentiate severe asthma from nonsevere asthma. As discussed before, the cross-sectional nature of most studies precludes conclusions about reversibility. However, several important observations have been made, including the fact that more severe air trapping has been shown to be associated with severe asthma.41, 42, 43 This demonstrates that important physiologic mechanisms that do not necessarily relate to FEV1 might also relate to an irreversible component of airflow obstruction. Whether onset of asthma during childhood or adulthood results in more severe asthma is not clear because of conflicting data.44, 45 Importantly, enrollment in studies of severe asthma tends to be defined more by medication use, and morbidity,41, 46 low lung function (FEV1), and less bronchodilator reversibility are strongly associated with severity.

Table III. Selected severe asthma studies
National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP)43, 46Cross-sectional American study showing that in patients with severe asthma compared with those with nonsevere asthma, FVC was disproportionately reduced and air trapping was more severe. On average, best lung function obtained after bronchodilator challenge remained low in patients with moderate and severe asthma, whereas on average, it normalized in those with mild asthma.
The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR)50, 51, 52Large, prospective 3-year cohort study wherein persistent airflow limitation was associated with older age, male sex, duration of asthma, and cigarette smoking.
European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA)41, 53, 54Cross-sectional multicenter European study wherein asthma severity was mostly defined by medication use. Severe or poorly controlled asthma was associated with less atopy, lower FEV1, less bronchodilator reversibility (on average), more air trapping, and sputum neutrophilia. Female sex and higher body weight also were associated with more severe disease.
Royal Brompton Hospital, London, United Kingdom42Series of asthmatic subjects from clinics classified based on FEV1. In patients with severe asthma, FVC was lower, and there was more air trapping. On average, FEV1 was only partially reversible in the severe asthma group.
Montreal, Quebec, Canada48, 49Small series of clinic and hospital patients with severe asthma. Patients with chronic, persistent airflow obstruction did not differ with respect to sputum cell differential but had a higher proportion of sputum neutrophils plus eosinophils and more smooth muscle hypertrophy in the bronchial wall when compared with patients with “intermittent (airflow) obstruction.” Persistent obstruction was associated with earlier age of onset and longer disease duration.
Leiden University Medical Center, The Netherlands45, 55Series of 152 clinic patients with severe asthma. About half (48.5%) had persistent airflow limitation, which was associated with more BHR and sputum eosinophilia when compared with the nonpersistent group. Adult-onset asthma was more associated with persistent airflow limitation than early-onset disease.
National Jewish Medical and Research Center, Denver, Colo44, 47Cross-sectional study of subjects hospitalized at a referral center. Although lung function (FEV1 percent predicted) was better in children than in adults, children were as likely to require high-dose corticosteroid therapy. Lung function impairment was associated with duration of disease only when disease began in childhood.

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Airway remodeling mechanisms and pathophysiology 

A detailed discussion of mechanisms driving airway remodeling is beyond the scope of this review. These mechanisms have been discussed recently in the Journal3, 6, 8, 11 and elsewhere,56 and therefore they will be discussed only briefly here. Most studies that have examined tissue in asthmatic patients have been performed in patients with mild disease and without clinical evidence of remodeling, although some studies have been done in patients with severe asthma, and several are currently ongoing. Reticular basement membrane (RBM), or subepithelial basement membrane thickening,57, 58, 59 has been a consistently reported finding that can occur early in life,47, 60, 61 probably sometime after infancy (after 1 year of age).62 Although RBM thickness or subepithelial basement membrane thickening is a characteristic of the airway and asthma, the degree of thickening does not seem to be associated with the severity of asthma.63 Interestingly, the types of proteins expressed in the RBM can vary over time as asthma evolves. For example, in one study using airway challenge, RBM tenascin expression was upregulated early in bronchial biopsy specimens but resolved after 1 week as increased procollagen III expression was seen. In the same biopsy specimens at the same time, inflammation was seen at 24 hours after antigen challenge but resolved after 1 week, although BHR persisted.48 This example illustrates the principle that although inflammation might drive remodeling, different mechanisms can regulate the persistence of remodeling or BHR.

Another common finding in remodeled airways is the presence of increased airway smooth muscle mass.47, 49 This finding can also be found in children, but in contrast to RBM, smooth muscle mass tends to increase with increasing asthma severity. Findings of increased RBM thickness and airway smooth muscle area on biopsies performed in patients with severe asthma (remodeled airways) have led to interest in the use of noninvasive imaging techniques, such as computed tomography, to assess for changes in the bronchial wall thickness and structure. Studies correlating histopathology with imaging findings are ongoing. One recent retrospective study of patients with “difficult” asthma showed that bronchial wall thickening, bronchiectasis, and emphysema were common findings in patients with severe asthma and that reduced postbronchodilator FEV1/FVC ratio predicted the presence of bronchial wall thickening or bronchiectasis.64 Additionally, the infiltration of the airway wall or lumen (sputum)65 by granulocytes (eosinophils or neutrophils) or mast cells66 has been a consistent finding in patients with asthma, with some studies showing that the severity of eosinophilic inflammation in the epithelium is a determinant of BHR or persistent airflow limitation.45

The current dogma is that changes in structure that lead to changes in the function of the airway wall are primarily responsible for irreversible airflow obstruction. However, some physiologists, in nonhuman model systems, have shown that changes in the function of the airway, including increased airway smooth muscle contractibility, can be induced without apparent changes in airway wall structure by chronically changing lung volume.67 Indeed, it was shown many years ago that an impaired bronchodilatory response to airway wall stretch by deep breathing was characteristic of asthma in human subjects.68 The relationships of lung volume to smooth muscle function have recently been reviewed.69 These data have obvious implications in that obesity is a disease associated with both lower lung volumes and more severe asthma.

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Can available medications reverse airway remodeling? 

As stated above, to say that airway remodeling or airflow obstruction is truly irreversible, it would have to be shown that available medications would not effectively change the measurable airway remodeling or airflow obstruction. Several studies have been done in an attempt to prevent loss of lung function in patients already given a diagnosis of asthma, whereas others have been performed to prevent asthma from developing in children at risk. Most intervention studies have been performed with inhaled corticosteroids, and these drugs have been shown to universally reduce symptoms, reduce the frequency of asthma exacerbations, and reduce BHR while at the same time improving prebronchodilator FEV1. However, corticosteroids typically do not improve maximal lung function, as measured by postbronchodilator FEV1, when compared with other agents or even placebo. Corticosteroids have variable effects on histologic indicators of remodeling seen in tissue, and sometimes these effects are dependent on duration of treatment. Additionally, when corticosteroids are withdrawn, the FEV1 typically reverts or decreases to values similar to those obtained with placebo treatment. This suggests that corticosteroids suppressed some process that reduced lung function but did not alter the remodeling process.

In one study designed to test whether inhaled corticosteroids could prevent asthma in early life, inhaled corticosteroids were no more effective in preventing infants with intermittent wheezing from becoming persistent wheezers when compared with placebo.70 The Childhood Asthma Management Program was a randomized clinical trial (intervention study) in which inhaled corticosteroid was compared with placebo by using treatment over several years in young children. Interestingly, inhaled corticosteroids were not effective in preventing the gradual reduction in postbronchodilator FEV1 over time that was seen in all treatment groups; moreover, the FEV1/FVC ratio also decreased over time. However, inhaled corticosteroids had very salutary effects on BHR, frequency of exacerbations, and control of symptoms.18, 23

Similarly, in a subgroup of the Inhaled Steroid Treatment as Regular Therapy and Early Asthma study, inhaled corticosteroids did not completely prevent the gradual decrease in postbronchodilator FEV1 percent predicted that was seen, although this decrease was attenuated when compared with values seen in the placebo-treated group.71 In the Prevention of Early Asthma in Kids study long-term inhaled corticosteroids were compared with placebo in an attempt to prevent asthma in very young children (<3 years old) at risk for asthma. Whereas inhaled corticosteroids improved airway reactance (a measure of airway resistance) and the proportion of symptom-free days, this effect was lost on washout of medication, suggesting that corticosteroids suppressed but did not prevent the remodeling process.72

Clinical studies in adults have consistently demonstrated similar findings in that inhaled corticosteroids have salutary effects on exacerbations, symptoms, prebronchodilator FEV1, and BHR but tend not to improve maximal lung function (postbronchodilator FEV1).73, 74 Another retrospective study showed that inhaled corticosteroids helped reduce the rate of decrease in FEV1 when compared with placebo.75

Some studies have shown that corticosteroids can reduce subepithelial collagen III deposition,76, 77 whereas others have not shown this effect on collagen deposition.78, 79 Interestingly, one group using a brief oral corticosteroid trial showed that some patients exhibit corticosteroid resistance manifesting as minimal changes in FEV1 despite treatment with oral corticosteroids. Whereas corticosteroid-responsive patients showed good reversal of prebronchodilator and postbronchodilator FEV1, corticosteroid-resistant patients tend to have minimal to no improvement in lung function. However, improvements in lung function in corticosteroid-sensitive patients were not complete in that lung function did not return to normal ranges.80 The duration of corticosteroid treatment might be a factor because one bronchoscopy study showed that inhaled corticosteroids improved inflammatory parameters at 3 months with no further improvement at 12 months, whereas changes in the RBM thickness only occurred after 12 months of treatment. In that study FEV1 was improved at 3 months but did not improve further, whereas BHR continued to improve at 12 months.59

Because corticosteroids might not be particularly efficacious in modifying remodeling, other treatment strategies might be desirable. One study in which anti–IL-5 antibody (mepolizumab) was compared with placebo showed that anti–IL-5 treatment reduced tenascin and procollagen III deposition in airway walls.81 However, similar to what is seen with inhaled corticosteroids, mepolizumab did not change postbronchodilator FEV1 in patients with refractory asthma in a separate study.82

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Observations from the Asthma Phenotype Task Force and the Asthma Clinical Research Network 

A recent task force consisting of members from the National Heart, Lung, and Blood Institute; the American Thoracic Society; and the American Academy of Allergy, Asthma & Immunology has been charged with defining different asthma phenotypes to better our understanding of these asthma subgroups. One of those phenotypes is “asthma with apparent airflow limitation.” The proposed definition of that phenotype has considered many of the issues discussed in this review and is as follows (Asthma Phenotype Task Force, unpublished):

Airway obstruction: FEV1/FVC ratio less than the lower limit of normal for age (8-19 years, 85%; 20-39 years, 80%; 40-59 years, 75%; 60-80 years, 70% [Expert Panel Report 3, 2007]) and FEV1 less than 90% of predicted value in a patient taking corticosteroids after acute administration of a rapid-onset bronchodilator. This is defined operationally as follows:

A.moderate- to high-dose inhaled corticosteroid for more than 4 weeks83

OR

B.systemic corticosteroids (>0.5 mg/kg of prednisone or equivalent) for more than 2 weeks

AND

after more than 4 puffs of albuterol (90 micrograms per puff [or equivalent]) administered before pulmonary function testing.

To gain further insight into the frequency with which patients with different severities of asthma display asthma symptoms with apparent irreversible airflow limitation, we applied this definition, as best as it could be applied, to patients who participated in 7 different Asthma Clinical Research Network studies. In 3 studies in which patients with mild asthma were studied, the percentage of subjects who displayed asthma with apparent irreversible airflow limitation was 0% (0/84) in the Beta-Adrenergic Response by Genotype study,84 0% (0/122) in the Smoking Modulates Outcomes of Glucocorticoid Therapy study,85 and 4.2% (11/262) in the Improving Asthma Control Trial (IMPACT).86 In 3 studies in which patients with moderate asthma were studied, the percentage of subjects who displayed asthma with apparent irreversible airflow limitation was 15.1% (13/86) in the Predicting Response to Inhaled Corticosteroid Efficacy trial,87 38.7% (12/31) in the Measuring Inhaled Corticosteroid Efficacy trial (MICE),88 and 43.2% (83/192) in the Salmeterol and Leukotriene Modifiers vs Salmeterol and ICS Treatment study.89 In 1 study in which patients with moderately severe asthma were studied, the Salmeterol ± Inhaled Corticosteroid trial,90 the percentage of subjects who displayed asthma with apparent irreversible airflow limitation was 87.4% (153/175; Asthma Clinical Research Network unpublished data). Therefore we conclude that irreversible airflow obstruction or limitation is increasingly common as the apparent severity of asthma increases.

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Alternative approaches to preventing irreversible asthma 

Attempts to treat asthma by targeting a single cytokine or mediator have yielded disappointing results thus far. What is apparent is that the mechanisms that modulate the inflammation and remodeling in asthma are complex and that reductionist approaches, such as targeting a single cytokine or pathway, are not likely to work. Thus it is not surprising that the most efficacious anti-inflammatory drugs are corticosteroids, which are drugs that have broad effects modulating many inflammatory pathways. Many studies have previously identified potential therapeutic targets in patients with asthma, and newer examples in smooth muscle,91 epithelial cells,92 and novel inflammatory cell networks, such as the TH17 pathway,93 have recently been described or reviewed. Approaches that more directly target structural elements (eg, protease-antiprotease networks) might have greater potential than broadly anti-inflammatory approaches and should be explored. However, it is our opinion that continued attempts to treat or modulate the inflammation and airway remodeling of asthma by selecting single or narrowly defined targets will not be fruitful and that new systems biology approaches that simultaneously account for the effect of a drug on inflammatory and remodeling signaling networks will be needed.94

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Conclusions 

Much indirect evidence from longitudinal asthma studies and cross-sectional studies of severe asthma strongly suggests that a subgroup of asthmatic subjects have a component of irreversible airflow obstruction. In many patients this irreversible component probably occurs early in life. As smoking rates decrease, we might expect that this subgroup of patients will comprise an increasing proportion of the population of patients with COPD. Unfortunately, as shown in a few randomized clinical trials, current medications, such as corticosteroids, appear to be ineffective in preventing the development of irreversible airflow obstruction, at least in some patients. Efforts toward understanding the irreversible component of asthma will be aided by the development of a standardized definition of irreversible airflow obstruction similar to that developed for severe asthma.95 New strategies for preventing asthma in the first place, as well as new noncorticosteroid treatments for airway wall remodeling, are needed.

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References 

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 (Supported by an educational grant from Merck & Co., Inc.)

 Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

 Supported in part by grants U10HL074225 and 1R21AI076699 to S.P.P. and 1K12HL 089992 to R.M.P.

 Terms in boldface and italics are defined in the glossary on page 884.

PII: S0091-6749(09)01466-3

doi:10.1016/j.jaci.2009.09.047

The Journal of Allergy and Clinical Immunology
Volume 124, Issue 5 , Pages 883-890, November 2009

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