American Thoracic Society
Am J Respir Crit Care MedVol 162. pp 2341–2351, 2000Internet address: www.atsjournals.org
Proceedings of the ATS Workshop onRefractory Asthma
Current Understanding, Recommendations, and Unanswered Questions
T
HIS
O
FFICIAL
A
MERICAN
T
HORACIC
S
OCIETY
W
ORKSHOP
R
EPORT
W
AS
A
PPROVED
BY
THE
ATS B
OARD
OF
D
IRECTORS
, J
ULY
2000
Although severe, refractory asthma is an uncommon disease(likely
5% of total asthma), it is poorly understood and,therefore, often frustrating to treat. What follows is the pro-ceedings of an American Thoracic Society (ATS)-sponsoredworkshop. The participants hope it will serve as an aid to be-gin to define, understand, and manage these refractory pa-tients. Perhaps more importantly, it is also hoped that theseproceedings will highlight the many questions that remain,and eventually lead to improved outcomes.
REFRACTORY ASTHMA: DEFINITION AND DIAGNOSIS
John Fahy, M.D.
Asthma affects 5–7% of the population of North America andEurope, and the prevalence is increasing (1, 2). Most asthma ismild or moderate (3) and can be well controlled with
-ago-nists with or without usual or low doses of antiinflammatoryagents. A subgroup of patients with asthma (likely
5%)have more troublesome disease reflected by (
1
) high medica-tion requirements to maintain good disease control or (
2
) per-sistent symptoms, asthma exacerbations, or airflow obstruc-tion despite high medication use. In considering a term todescribe this subgroup of asthmatic patients with troublesomedisease, the workshop participants agreed on the term “refrac-tory asthma.” “Refractory asthma” is not meant to describeonly patients with “fatal” or “near fatal” asthma, but it ismeant to encompass the asthma subgroups previously de-scribed as “severe asthma,” “steroid-dependent and/or resis-tant asthma,” “difficult to control asthma,” “poorly controlledasthma,” “brittle asthma,” or “irreversible asthma.” Clinically,patients with refractory asthma may present with a variety of separate and/or overlapping conditions. These may include (
1
)widely varying peak flows (“brittle asthma”), (
2
) severe, butchronic airflow limitation, (
3
) rapidly progressive loss of lungfunction, (
4
) mucus production ranging from absent to copi-ous, and (
5
) varying responses to corticosteroids (CS).Whether these groups form distinct clinical, physiologic, andpathologic groups is unclear.Because severe/refractory asthma has not been consistentlydefined, and is relatively difficult to measure, the true size of the subgroup of patients with refractory asthma is unknown.In young male Israeli military recruits, Auerbach and cowork-ers (3) found the point prevalence of asthma to be 6.4%. Lessthan 1% of these patients had severe asthma, but severeasthma was defined narrowly as steroid dependence and anFEV
1
of less than 50% predicted. Woolcock (4) defined se-vere asthma as severe hyperreactivity to histamine (PC
20
hista-mine [provocative concentration of histamine causing a 20%fall in FEV
1
]
0.1 mg/ml). Using this definition, Woolcockfound that approximately 12% of Australian children oradults with asthma had severe asthma. It is unclear whetherthese studies over- or underestimate the prevalence of refrac-tory asthma as defined in Table 1. Although the precise size of the subgroup with refractory asthma is uncertain, the eco-nomic impact of the group is not. The total cost of illness re-lated to asthma likely ranges between 6 and 10 billion U.S.dollars (5, 6). More than 40% of its economic impact is be-lieved to be associated with emergency room use, hospitaliza-tion, and death. A more recent study from Europe estimatedthat the average cost per patient with severe asthma, as de-fined by the International Consensus Report, is nearly sixtimes the cost of care for a patient with mild asthma (7). It islikely that the treatment of refractory asthma described in thisreport utilizes even more health care dollars per patient.
Clinical Features/Natural History of Refractory Asthma
(
See
Table 1.) Refractory asthma encompasses wide ranges inboth clinical symptoms and in natural history. Patients mayappear to have highly labile disease, with wide swings in peakflows, while others are more chronically and severely ob-structed (8, 9). Other patients produce copious amounts of phlegm, some have associated sinus disease and gastroesoph-ageal reflux, while others do not. Despite these differences inpresentation, the workshop participants considered it impor-tant to develop a “working” definition of refractory asthma.For this purpose the participants agreed that refractoryasthma should be defined on the basis of medication require-ments, asthma symptoms, frequency of asthma exacerbations,and degree of airflow limitation. Specifically, the group agreedon two major and seven minor criteria (Table 1), with refrac-tory asthma being defined as one or both major criteria and atleast two minor criteria. This definition is applicable only topatients in whom (
1
) other conditions have been excluded, (
2
)exacerbating factors have been optimally treated, and (
3
) pooradherence does not appear to be a confounding issue.In considering the features that define refractory asthma,Cockcroft and Swystun argue (10) that “well controlled
Workshop held
: Chicago–September 1997, Denver–September 1998.
Workshop Chair
: Sally E. Wenzel, M.D., National Jewish Medical and ResearchCenter/University of Colorado Health Sciences Center, Denver, Colorado.This Official Report was developed by an ad-hoc writing committee of the As-sembly on Allergy, Immunology and Inflammation. Members of the writingcommittee were: Sally E. Wenzel, M.D., Denver, CO; John V. Fahy, M.D., SanFrancisco, CA; Charles Irvin, Ph.D., Colchester, VT; Stephen P. Peters, M.D.,Ph.D., Philadelphia, PA; Sheldon Spector, M.D., Los Angeles, CA; and Stanley J.Szefler, M.D., Denver, CO.
Workshop Participants
: In addition to writing committee/speakers: Thomas B.Casale, M.D., Creighton University, Omaha, NE; Michelle M. Cloutier, M.D.,Connecticut Children’s Medical Center, Hartford, CT; Jack A. Elias, M.D., YaleUniversity School of Medicine, New Haven, CT; Mark C. Liu, M.D., Johns Hop-kins Asthma and Allergy Center, Baltimore, MD; Virginia Taggert, M.S., NationalInstitute of Health, Bethesda, MD.
2342
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1622000
asthma” does not exclude refractory asthma. This is likely trueif good asthma control and improved airway function (to thelevel of a mild–moderate persistent patient) can be achievedonly with high doses of inhaled or oral CS with the associatedconcerns for long term systemic toxicity. These patients arecaptured in the recommended diagnostic criteria. In contrast,some patients with refractory asthma continue to have persis-tent symptoms or reduction in airway caliber despite highdoses of inhaled or oral CS. Incompletely reversible airwaynarrowing in these patents may reflect airway remodeling con-sequent on long-standing severe airway inflammation, or, al-ternatively, an inability of currently available medications toreverse “potentially reversible” obstruction (
see
P
ATHOLOGYOF
R
EFRACTORY
A
STHMA
) (11).Whether there is a particular “natural history” that leads tothe development of refractory asthma is unclear. Althoughmean figures suggest that pulmonary function declines morerapidly over time in patients with asthma, the perception re-mains that “most” of these individuals do not progress to moresevere disease (12). This is especially true among children withasthma, of whom many will “outgrow” their disease (13, 14). In-triguingly, longitudinal studies suggest that the more severe theobstruction on initial presentation, the more likely the asthmais to progress or remain severe (15). In addition, two longitudi-nal studies now suggest that asthma presenting in adulthood islikely to have a more precipitous decline in lung function (andby inference, development of severity) than asthma that pre-sents in childhood (16, 17). However, the factors that deter-mine this “predisposition to severity” are not known.
Clinical Evaluation
In making the diagnosis of refractory asthma, it is important toconsider and exclude other diseases in the differential diagno-sis of wheeze, dyspnea, cough, and eosinophilia (18). Specifi-cally, patients should be evaluated for other diseases, such aschronic obstructive pulmonary disease, bronchiectasis (includ-ing allergic bronchopulmonary aspergillosis and cystic fibro-sis), and vocal cord dysfunction (Table 2). The diagnosticwork-up of patients suspected of having chronic refractoryasthma should consist of full pulmonary function tests includ-ing spirometry with a flow–volume curve, total lung capacity,residual volume, and diffusion capacity, as well as daily peakflow monitoring. Additional suggested clinical tests include se-rum IgE and eosinophil levels (Table 2) (18, 19). Only after di-agnosing and/or treating other disorders without clinical im-provement should patients be classified as having “asthma.”Finally, in any person with “refractory asthma,” a thoroughevaluation for factors that could contribute to the severity of the disease, such as sinus disease, gastroesophageal reflux, andcompliance/adherence issues (including random morning se-rum cortisol checks) should be performed. Patients should bethoroughly evaluated for their understanding of asthma andtheir ability to use a metered dose inhaler. Addressing theseissues may improve asthma outcomes in a poorly defined per-centage of patients with severe, but not truly “refractory,”asthma. However, a proportion of these patients will remainuncontrolled, even with the best approach to diagnosis andmanagement, and hence, qualify as having refractory asthma.
PHYSIOLOGY OF REFRACTORY ASTHMA
Charles Irvin, Ph.D.
Whether the abnormalities of pulmonary physiology in pa-tients with severe refractory asthma are intrinsically differentfrom those seen in milder forms of disease is poorly under-stood. However, there is general agreement that residual air-flow limitation (a persistently low FEV
1
) after optimization of a patient’s asthma therapy represents an undesirable situationthat warrants further therapeutic intervention.There are three principal physiologic features of “asthma”:(
1
) reversible airflow limitation with a significant (
12%change in FEV
1
or FVC) response to acute, inhaled broncho-dilator treatment, (
2
) airway hyperresponsiveness, either tonaturally encountered stimuli, for example, exercise, or tochemical stimuli in a laboratory setting, for example, metha-choline, and (
3
) episodic airflow limitation in response to vari-ous triggers such as antigen or chronic, periodic changes suchas nocturnal worsenings. Patients with mild or moderate dis-ease may not exhibit all three of these features and can move
TABLE1REFRACTORYASTHMA:WORKSHOPCONSENSUSFORTYPICALCLINICALFEATURES*
,†
Major Characteristics
In order to achieve control to a level of mild–moderate persistent asthma:1.Treatment with continuous or near continuous (
50% of year) oral corticosteroids2.Requirement for treatment with high-dose inhaled corticosteroids:DrugDose (
g/d
)Dose (
puffs/d
)a.Beclomethasone dipropionate
1,260
40 puffs (42
g/inhalation
20 puffs (84
g/inhalationb.Budesonide
1,200
6 puffsc.Flunisolide
2,000
8 puffsd.Fluticasone propionate
880
8 puffs (110
g),
4 puffs (220
g)e.Triamcinolone acetonide
2,000
20 puffs
Minor Characteristics
1.Requirement for daily treatment with a controller medication in additionto inhaled corticosteroids, e.g., long-acting
-agonist, theophylline, or leukotriene antagonist2.Asthma symptoms requiring short-acting
-agonist use on a daily or near daily basis3.Persistent airway obstruction (FEV
1
80% predicted; diurnal PEF variability
20%)4.One or more urgent care visits for asthma per year 5.Three or more oral steroid “bursts” per year 6.Prompt deterioration with
25% reduction in oral or inhaled corticosteroid dose7.Near fatal asthma event in the past
* Requires that other conditions have been excluded, exacerbating factors treated, and patient felt to be generally adherent.
†
Definition of refractory asthma requires one or both major criteria and two minor criteria.
American Thoracic Society
2343
in and out of the normal range, sometimes rapidly. It is gener-ally believed that patients with refractory asthma exhibit allthree of these physiologic features, but to a more marked de-gree than patients with milder asthma (20). That is, airflowlimitation can be demonstrated at all times, especially off medi-cations, and is often markedly reduced (
70% predicted);definite hyperresponsiveness is present (e.g.,
1 mg/ml formethacholine PC
20
); and/or wide swings in lung function occur(e.g.,
20% peak expiratory flow [PEF] diurnal variability).However, most studies and treatment guidelines have usedlung function (specifically FEV
1
) to stage asthma disease se-verity. The relationship among these three variables in re-sponse to treatment remains less clear.Patients with refractory disease often fail to respond ornormalize lung function in response to
-agonist or CS treat-ment; that is, their lung function is residually low (9). There islikely another category of patients with severe or refractoryasthma, who have relatively normal FEV
1
at baseline, andwho then can rapidly decompensate to known or unknownstimuli (i.e., “brittle asthmatics”) (8). Whether there are inthese patients with asthma specific differences that lead to therapid decompensation is not clear (21).
Airflow Limitation
The fixed airflow limitation of most patients with refractoryasthma can be defined as a postbronchodilator FEV
1
of
80%pred (in the presence of a reduced FEV
1
/FVC) after a7- to 14-d course of oral CS (40 mg/d for adults and 2 mg/kgper day in children). The mechanisms behind the inability tototally reverse airflow obstruction in response to CS in refrac-tory asthma are unclear. Although some studies have sug-gested that patients with more severe asthma have more pro-nounced subepithelial collagen deposition, a study of oral CS-dependent asthma patients failed to confirm this association(
see
P
ATHOLOGY
OF
R
EFRACTORY
A
STHMA
) (22–24). Additionalexplanations for residual airflow limitation could include mu-cous plugging, smooth muscle hypertrophy and/or hyperpla-sia, and edema formation. Unfortunately, there is a paucity of structure–function studies in this patient population.It is also common for some patients with “refractory asthma”to demonstrate a poor acute bronchodilator response to
-ag-onists, either before or after a course of high-dose CS (9). This“irreversibility” is often attributed to long-standing, uncon-trolled inflammation that then eventually leads to increasinglyfibrotic airways, although there are no studies that have ade-quately addressed this issue (25–28), This “failure to respond”could be due to a variety of factors, including (
1
) a downregu-lation of
receptors, (
2
) fibrosis or other structural alterationsthat limit dynamic responses, (
3
) unknown elements of the ob-structive process that do not improve with bronchodilators orCS (but which could improve with “other therapies”), or (
4
) adifferent disease process altogether. Distinguishing amongthese possibilities represents a fruitful area of research.Progressive loss of lung function is not seen in all individu-als with asthma (14, 29). In contrast, asthmatic children withlow lung function at early timepoints are predisposed to fur-ther problems in adulthood (30–32). Studies also suggest thatthe average rate of decline in lung function may differ be-tween asthma that begins in childhood (usually associatedwith atopy) versus asthma that begins in adulthood (often“nonatopic”), with adult onset asthma having a more rapid de-cline in FEV
1
(16, 17). The mechanisms by which some indi-viduals more rapidly lose lung function are not clear, but alongitudinal study of patients with asthma (including smokingpatients with asthma) suggested that increased sputum pro-duction was at least one factor associated with a more rapiddecline in lung function (12).
Airway Hyperresponsiveness
Airway hyperresponsiveness is a physiologic feature charac-teristic of asthma (20, 33–35). However, studies of more ho-mogeneous patient populations suggest that bronchial chal-lenge testing has a high degree of sensitivity but a lowerspecificity. Other airway diseases also demonstrate airway hy-perresponsiveness (36), but not to the degree observed in pa-tients with moderate to severe asthma.It is known that airway responsiveness varies in a temporalfashion, and this is generally thought to reflect changes in dis-ease activity and severity (36). However, this is often of littlemore than statistical value, as there is considerable overlap
TABLE2EVALUATIONOFPATIENTSWITHREFRACTORYASTHMA
1.Confirm reversible airflow limitation and quantify severity:a.FEV
1
, peak flow, and flow–volume loop before and after bronchodilator treatment*b.Total lung capacity and residual volume
†
c.Diffusion capacity (in adults—usually not indicated in children)
‡
2.Consider other diagnoses in differential diagnosis of cough, dyspnea, and wheeze:a.Chronic obstructive pulmonary diseaseb.Cystic fibrosisc.Vocal cord dysfunction, or other mechanical upper airway obstructiond.Obstructive sleep apneae.Churg–Strauss syndrome f.Cardiac dysfunctiong.Allergic bronchopulmonary aspergillosis (ABPA)3.Investigate for the presence or absence of concomitant disorders that can exacerbate asthma:a.Allergen skin tests (atopy and allergic rhinitis)b.CT scan of the sinuses (sinus disease)c.Twenty-four-hour esophageal pH monitoring (gastroesophageal reflux disease)d.Chest radiograph (pulmonary infiltrates, interstitial lung disease, bullous lung disease)e.Blood for eosinophil count, immediate hypersensitivity skin testing to aspergillus, IgE level (Churg–Strauss or allergicbronchopulmonary aspergillosis)
* Lung function assessment is often limited to the measurement of peak flow and a single value of FEV
1
. Obtaining flow–volume charac-teristics often reveals other causes of airflow limitation or wheezing such as fixed obstruction or vocal cord dysfunction.
†
Indicated in this group of patients to confirm obstructive disease and rule out restrictive disease.
‡
Asthma is characterized by a high D
L
CO value or a value in the high normal range. A low diffusing capacity suggests emphysema, pul-monary vascular disease, or interstitial lung disease.
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