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Copyright ©ERS Journals Ltd 1993
European Respiratory Journal
ISSN 0903 - 1936
Eur Resplr J, 1993, 6; 743-747
Printed in UK - all rights reserved
REVIEW
Steroid resistant asthma: what is the clinical definition?
A.J. Woolcock
Steroid resistant asthma: what is the clinical definition? A.J. Woo/cock. ©ERS
Journals Ltd 1993.
ABSTRACT: Asthma is usually a steroid responsive disease. A few patients respond poorly to these drugs, and others need such high doses to control the disease that sid~ects become a serious problem. Tbe term steroid resistant asthma
is used for both groups. In some patients, factors may be operating to make the
asthma worse and, thus, to increase the requirement for steroids. In order to make
a clinical diagnosis of steroid resistant asthma, it is therefore necessary to investigate the factors that could be operating to prevent a "normal" response to steroids. These factors include wrong diagnosis, insufficient steroid reaching the airway
mucosa, continuing exposure to sensitizing agents, unrecognized aggravating agents,
excessive use of beta-agonist aerosols, and failure to undertake regular management
according to a strict management plan.
Using a strict clinical definition of steroid resistant asthma leads to better investigation and treatment of individual patients, aUows steroids to be stopped when
they are not indicated, allows other anti-inRammatory drugs to be used with confidence, and provides a weD-defined group of patients for further research relating
to the mechanisms of action of steroids.
Eur Respir J., 1993, 6, 743-747.
Soon after the introduction of adrenocorticotrophic
hormone (ACTH) in 1949 [1], it became evident that
asthma is a steroid-responsive disease. It appeared that
the disease could be controlled by oral steroids in almost
all patients, but their side-effects rapidly limited their
use. In 1968, SCHWARTZ et al. [2] described six patients
whose disease appeared to be relatively resistant to steroids, because they required larger doses for poorer control, had a decreased eosinopenic response, and had only
mild Cushing-like changes. They used the term "steroid
resistant asthma" (SRA) to describe these patients. It is
now well-established that there is a group of patients
whose tissue (skin, blood leucocytes and airways) respond
poorly to steroids, and a number of researchers are studying the mechanisms involved [3, 4].
Some patients with severe asthma respond to oral steroids, but only to very high doses, and it is not clear if
they have SRA, a severe form of the disease, or both [5].
Some appear to be responsive initially, and to become
progressively unresponsive with time, although this sequence of events is not documented in the literature. The
introduction of inhaled steroids has largely overcome the
problem of side-effects for those who do respond but only
to high oral doses, and in most patients inhaled steroids
in adequate doses allow oral steroids to be greatly reduced
or withdrawn completely [6, 7]. Today, most doctors
expect that their patients will improve once the regular
use of a sufficient dose of the inhaled form is introduced
[8, 9], and a poor response is usually diagnosed as SRA.
Sometimes there are reasons, other than true SRA, for fl\e
Institute of Respiratory Medicine, Sydney,
Australia.
Correspondence: A.J. Woolcock
Institute of Respiratory Medicine
University of Sydney
Sydney
NSW
Australia
Keywords: AsUuna
diagnosis
drug res.istance
glucoconicoids
Received: February 15 1993
Accepted for publication February 17
1993
apparent poor response, and this is the subject of this
review.
Why is a clinicaJ definition of steroid resistant
asthma important?
Clinical practice
The presence of SRA may be an indication for the use
of anti-inflanunatory drugs, such as methotrexate, cyclosporin or gold, in order to try to reduce the dose of steroids in those taking large oral doses, or to try to improve
the control of the disease in those who appear genuinely
steroid resistant. Because of the toxicity of these drugs,
physicians need to be sure that SRA is in fact present.
Additionally, in some patients, the steroids can simply be
stopped [5]. In the process of defining the steroid-resistant state, factors may be recognized that are preventing
the expected response to inhaled steroids.
Research
Patients in whom steroid resistance is well-defined are
needed, so that the nature of the abnormalities present can
be studied and, hopefully, corrected. Studies of steroid
resistance also provide mechanisms for understanding the
action of steroids.
A.J. WOOLCOCK
744
Dermitions
Bronchial biopsies can be performed safely in patients
with a'lthrna, being widely used in asthma for research,
and guidelines have been described [19, 20].
For research
In research studies, it is usual to define a patient as
having SRA if there is failure of the peak expiratory flow
(PEF), measured on waking, to improve after treatment
for 10-14 days with oral steroids given in high doses [3,
10].
It should be noted that abnormal resting lung function
in itself, that does not return to normal after a course of
oral steroids, does not indicate SRA. There are many
patients with severe, long-standing disease, whose expiratory .flow rates are permanently reduced, but whose
asthma can be well controlled with inhaled steroids.
In clinical practice
There is no simple definition. However, the answer
"yes" to the six questions outlined below constitutes a reasonable basis for establishing the presence of SRA.
Questions to be answered before establishing a
diagnosis of steroid resistant asthma
Question 1
Does the patient have asthma? Sometimes the poor response to steroids results from the fact that the patient
has been misdiagnosed, and has another disease which
will not improve with steroid treatment. In adults, these
include chronic obstructive pulmonary disease (COPD)
[11), episodes of laryngeal stridor or vocal cord dysfunction [12, 13], tracheomalacia [14) hyperventilation with
panic attacks [15), a variety of endobronchial lesions [16,
17], as well as factitious asthma (18]. Patients with these
conditions sometimes acquire the diagnosis of astluna, and
many can simulate attacks.
To establish the diagnosis, a careful history, with these
conditions in mind, is needed. If doubt exists, a bronchodilator test, and/or a daily record of peak flow values for a week, usually establishes the diagnosis. The
presence of eosinophils in the sputum is also diagnostic
in this situation. If doul?t still exists, a bronchoscopy,
with a bronchial biopsy, can be helpful in a number of
ways. Firstly, endobronchial lesions can be excluded or
diagnosed. Secondly, if the biopsy has none of the features of asthma, then the diagnosis is almost certainly
wrong. If the biopsy shows "abnormalities consistent
with asthma" then the investigation can move directly to
Question 2. In addition, if the biopsy shows "severe asthmatic inflammation" with epithelial desquamation and
many eosinophils, it suggests that inadequate doses of
inhaled steroids are reaching the airways, although the
pathology of patients with well-documented SRA has not
been described.
Question 2
Are adequate doses of steroids reaching the airways? lt
seems likely that inhaled steroids, by acting at the surface of the airway, have an effect that can be achieved
only by large doses of oral steroids [21]. Thus, unless
adequate inhaled forms of the drugs are reaching the airways, SRA cannot be established. There are many reasons why sufficient drug may not be reaching the airways
of a patient who has been prescribed inhaled steroids.
Firstly, the dose prescribed may have been too low. Secondly, the patient may have misunderstood the instructions (confusing the dose, or even mistaking the steroid
for a bronchodilator and using it intermittently). Thirdly,
the patient may not be using the drug properly, e.g a
metered dose inhaler without a large volume spacing device. Fourthly, the patient may dislike the inhaled form
and simply not be taking it because of the local sideeffects (thrush, dysphonia). Others experience symptoms
on withdrawing oral steroids and return to using them,
instead of the inhaled form prescribed.
It is necessary to check the actual device and drug being used by the patient, as well as the inhaler technique.
In addition, the help of the family, the pharmacist, and
other medical persons involved in the management of the
patient, must be sought, in order to be satisfied that the
drug is being inhaled properly and in adequate doses.
The appearance of the patient is not particularly helpful.
The presence of steroid side-effects indicates that there
is steroid in the systemic circulation, and can be present
from either the inhaled or the oral form. Lack of evidence of any steroid effect in someone claiming to have
taken large doses (e.g. 2 mg or more daily of inhaled
steroid) for 6 or more months, suggests either that inadequate doses are being taken, or that true steroid resistance is present.
How much inhaled steroid should be prescribed? It
seems likely that 2 mg·day- 1 in divided doses is sufficient
in almost all patients, and there is no published evidence
that increasing doses above 2 mg·day·' increases the response. In a recent study, 1.5 mg was no more effective than 0.3 mg·day-1 in patients taking oral steroids [22].
However, many of the factors addressed in this review
were not controlled in that study.
Usually, the problem preventing adequate doses of inhaled steroid from reaching the airway mucosa can be
identified and corrected (although dysphonia remains a
problem in a few patients). A trial of the correct use of
the inhaled steroid for several months is then indicated.
Question 3
Have all provoking stimuli, especially domestic allergens
or occupational sensitizers, been removed from the
daily environme11! of the patient? The answer to this
CLINICAL DEFINITION OF STEROID RESISTANT ASTHMA
question requires a knowledge of the allergens to which
the patient is sensitized. The majority of patients with
severe asthma, if allergic, are sensitized to house dust
mites, and a measurement of mite allergen in the patient's
bed is needed. In the case of occupational sensitizers,
the history is extremely important, and a visit to the place
of work may be needed. A lot of effort is needed to
control exposures. If allergy to house dust mites exists,
the bedding must be treated thoroughly, with mattress and
pillow covers, and hot washing of all bedclothes [23].
Most importantly, the humidity of the bedroom should be
kept as low as possible [24, 25].
In the occupational setting, removal from the sensitizer
is essential (although this may be difficult for fmancial
reasons). Continued exposure is certainly associated with
deteriorating asthma [26]. If doubt exists about continuing exposure to sensitizing workplace or domestic agents,
it may be necessary for the patient to leave work. and/
or the house, for a period of time.
745
Question 5
Has the patient stopped taking regular doses of inhaled
beta-agonists? It is now known that regular doses of
some beta-agonists in high doses can increase the severity of asthma (32], although it is not known if all betaagonists affect all patients. It may be that regular use
of relatively small amounts (e.g. two inhalations of
salbutamol four times a day) is sufficient to make asthma
worse and to affect the response to steroids in some patients. A few patients take large amounts of these drugs
on a regular basis, and there is increasing anecdotal evidence for improvement in some patients when betaagonists are withdrawn.
Thus, SRA should not be diagnosed while the patient
is taking more than eight puffs a day of any of the six
hour duration aerosols. It is possible to reduce betaagonist use over a period of weeks, by introducing or increasing theophylline [33] and/or anticholinergics, by
avoidance of known trigger factors, and by giving support and reassurance [34].
Question 4
Have all potential aggravating factors such as gastrooesophageal reflux, obstructed breathing during sleep and
drugs been removed? Gastro-oesophageal reflux is very
common in patients with severe asthma, and sometimes the
disease improves when it is treated [27]. Obstructive sleep
apnoea can make asthma worse, as can snoring induced
by severe nasal obstruction due to rhinitis. Keeping
the nasal airway open at night, and treating sleep apnoea,
improves the control of asthma in some patients [28].
Several drugs make asthma worse. Most notably aspirin and related compounds, and beta-blockers. Although
these problems are well-known, asthmatics continue to be
prescribed them, usually by a second medical practitioner.
A careful drug history is indicated.
The presence of aspirin sensitivity needs to be established, or the drugs stopped, at least for a trial period.
Sometimes, asthma improves even though the patient has
not previously been recognized as having, aspirin induced
attacks. Although removing natural salicylates from the
diet usually does not improve the control of asthma, a
diet that is totally free of preservatives sometimes results
in greatly improved control of the disease [29]. A trial
of treatment with leukotriene antagonists, once they become widely available, may be indicated in such patients
[30).
Beta-blocking drugs are widely used and, although their
deleterious effects in asthma are well-known, including
the fact that eye drops can make asthma worse [3.1], patients occasionally continue to be prescribed them. They
should be stopped, at least for a trial period.
Although the treatment of the above conditions and the
removal of these drugs usually improves the symptoms,
a dramatic improvement in the disease, or in the response
to steroids, rarely occurs. Nevertheless, a small improvement occurring in conjunction with improvement consequent to other measures, such as allergen avoidance,
sometimes leads to an improvement in the severity of the
disease, and in the requirement for steroids.
Question 6
Has the patient followed a strict management plan, aimed
at reducing the severity of the disease, for at least 6
months? Improvement in the severity of asthma can take
up to six months, especially when the disease is severe,
both with treatment [35], and with withdrawal from allergen exposure [36]. It is, therefore, important to manage the patient under ideal conditions for a period of six
months, with an asthma management plan [37, 38].
In addition to appropriate doses of inhaled steroids,
minimal amounts of beta-agonists, removal from causal
agents, and treatment of aggravating factors, the management plan should include formal assessment of severity,
asthma education and support, and a written plan for
prompt treatment of exacerbations with adequate doses of
oral steroids.
Practical considerations
In many instances, the best way to address the first five
questions is to admit the patient to hospital for a week
for investigation, for supervision of therapy, including reduction of beta-agonists, and for removal from causal
agents. If the severity of the disease (as judged from
symptoms, morning peak flows and bronchodilator use)
improves in hospital but deteriorates on discharge, it is
likely that environmental factors are present, and a diagnosis of true SRA cannot be made. Deterioration on
leaving hospital indicates that the factors involved must
be identified and readdressed.
The steroid resistant state
Failure to improve or to maintain improvement of the
severity of asthma on doses of 2 mg of inhaled steroids
per day (regardless of the oral doses given) after all these
746
A.J. WOOLCOCK
factors have been addressed indicates SRA. In addition,
obtaining definite answers to the six questions means that
the patient will have been investigated thoroughly, and
have been given the opportunity to understand the disease, the drugs being used, and the options available for
further treatment.
Once a diagnosis of SRA is established, the use of
other anti-inflanunatory drugs can be considered, especially in those patients who are partially controlled on
high oral doses. If steroids are reduced, theoretically at
least, the patient's disease may become steroid sensitive
again [3).
Other anti-inflarrunatory drugs including methotrexate,
[39, 40] cyclosporin [41] or gold [42] can be tried. However, these drugs are toxic, and methotrexate, in particular, has limited usefulness because it is not uniformly
effective [43], or effective only as long as adequate doses
are being taken [44], and has even been a cause of
asthma [45]. For these reasons, and because inhaled steroids are so effective, these toxic drugs should be given
only when there is good evidence of resistance to the action of inhaled corticosteroid.
References
1.
Bordley JE, Cacey RA, McGhee Harvey A, et al. - Pre-
liminary observations on effect of adrenocorticotrophic hormone
(ACfH) in allergic diseases. Bull Johns Hopkins Hosp 1949;
85: 396-398.
2. Schwartz ID, Lowell FC, Melby JC. - Steroid resistance in bronchial asthma. Ann Intern Med 1968; 69: 493-499.
3. Alvacez J, SW'S W, Leung DY, et al. - Steroid-resistant
asthma: immunologic and pharmacologic features. J Allergy
Clin lmmunol 1992; 89: 714-721.
4. Brown PH, Teelucksingh S, Matusiewicz SP, et al. Cutaneous vasoconstrictor response to glucocorticoids in
asthma. Lancet 1991; 337: 576-580.
5. Carmichael J, Peterson IC, Diaz P, et al. - Corticosteroid resistance in chronic asthma. Br Med J 1981; 282: 14191422.
6. Cameron SJ, Cooper ET, Crompton GK, Hoare MV,
Grant I. - Substitution of beclomethasone aerosol for oral
prednisolone in the treatment of chronic asthma. Br Med J
1973; 4: 205- 207.
7. Tarlo SM, Broder I, Davies GM, et al. - Six-month
double-blind, controlled trial of high dose, concentrated
beclomethasone dipropionate in the treatment of severe asthma.
Chest 1988, 93: 998-1002.
8. Clarke PS. - The effect of beclomethasone dipropionate
on bronchial hyperreactivity. J Asthma 1982; 19: 91- 93.
9. Salmeron S, Guerin JC, Godard P, et al. - High doses
of inhaled corticosteroids in unstable chronic asthma. Am Rev
Respir Dis 1989; 140: 167-171.
10. Corrigan J, Brown PH, Barnes NC, et al. - Glucocorticoid resistance in chronic asthma. Am Rev Respir Dis 1991;
144: 1016-1025.
11. Meslier N, Racineux JL, Six P, Lockhart A. - Diagnostic value of reversibility of chronic obstruction to separate
asthma from chronic bronchitis: a statistical approach. Eur
Respir J 1989; 2: 497-505.
12. Lim TK. - Vocal cord dysfunction presenting as broncllial asthma: the association with abnormal thoracoabdominal
wall motion. Singapore Med J 1991; 32: 208-210.
13. Fields CL, Roy TM, Ossorio MA. - Variable vocal cord
dysfunction: an asthma variant SouJh Med J 1992; 85: 422-424.
14. McLeod DT, Teasdale AR. - Tracheomalacia masquerading as asthma. Cent Afr J Med 1987; 33: 154-156.
15. Alt HL. - Psychiatric aspects of asthma. Chest 1992;
101 (Suppl. 6): 415S-417S.
16. Johnsoo RC. Kollef MH. - Roentgenogram of the
month. A patient referred for steroid-resistant asthma. Chest
1990; 98: 1495- 1496.
17. Coleman SA, Cooper PD. - Upper airway obstruction
misdiagnosed as asthma. Br J Hosp Med 1989; 41: 184.
18. Pannbacker M. - Dysphonia associated with factitious
asthma. Ear Nose Throat 1990; 69: 656-657.
19. Workshop. - Investigative use of bronchoscopy, lavage
and bronchial biopsies in asthma and other airways diseases.
Eur Respir J 1992; 5: 115-121.
20. Fabbri LM, Ciaccia A. - Investigative bronchoscopy
in astluna and other airway diseases. Eur Respir J 1992, 5: 8-11.
21. Jenkins CR, Woolcock AI. - Effect of prednisone and
beclomethasone dipropionate on airway responsiveness in
asthma: a comparative study. Thorax 1988; 43: 378-384.
22. Humme1 S, Lehtonen L, Group S. - Comparison of oralsteroid sparing by high-dose and low-dose inhaled steroid in
maintenance treatment of severe asthma. Lancet 1992; 340:
1483-1487.
23. McDonald LG, Tovey E. - The role of water temperature and laundry procedures in reducing house dust mite
popu1ations and allergen content of bedding. J Allergy Clin
lmmunol1992, 90: 59~8.
24. Platts-Mills TAE, Thomas WR, Aalberse RC, Verv1oet D,
Chapman MD. - Dust mite allergens and asthma: report of
a second international workshop. J Allergy Clin Immunol1992;
89 (5): 1046-1060.
25. Korsgaard I. - House-dust mites and absolute indoor
humidity. Allergy 1983; 38: 85- 92.
26. Cote J, Kennedy S, Chan YM. - Outcome of patients
with cedar asthma with continuous exposure. Am Rev Respir
Dis 1990; 141: 373-376.
27. Harper PC, Bergner A, Kaye MD. - Antireflux treatment for asthma: improvement in patients with associated
gastroesophageal reflux. Arch Intern Med 1987; 147: 56-60.
28. Chan CS, Grunstein RR, Bye PT, Woolcock AI, Sullivan
CE. - Obstructive sleep apnea with severe chronic airflow
limitation. Comparison of hypercapnic and eucapnic patients.
Am Rev Respir Dis 1989; 140: 1274-1278.
29. Ogle KA, Bullock ID. - Children with allergic rhinitis
and/or bronchial asthma treated with elimination diet: a five
year follow-up. Ann Allergy 1980; 44: 273-275.
30. Christie PE, Smith CM, Lee TH. - The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353,
inhibits aspirin-induced asthma. Am Rev Respir Dis 1991; 144:
957-958.
31. Dunn TL, Gerber MI, Shen AS, et al. - The effect of
topical ophthalmic instillation of timolol and betaxolol on lung
function in asthmatic subjects. Am Rev Respir Dis 1986; 133:
264-268.
32. Sears MR, Taylor DR. Print CG, et al. - Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;
336: 1391-1396.
33. Nassif EG, Weinberer M, Thomson MS, Huntley W. The value of maintenance theophylline in steroid-dependent
asthma. N Engl J Med 1981; 304: 71-75.
34. Woolcock AI, Sears MK, Barnes PI. - Beta-agonists and
death from asthma. New Engl J Med 1992; 327: 354.
35. Woolcock AI, Yan K, Salome CM. - Effect of therapy
on bronchial hyperresponsiveness in the long-term management
of asthma. Clin Allergy 1988; 18: 165-176.
CLINICAL DEFINITION OF STEROID RESISTANT ASTHMA
36. Platts MT, Tovey ER, Mitchell EB, Mozarro H. - Longtenn effects of living in a dust-free room on patients with allergic asthma: reversal of bronchial hyperreactivity. Morwgr
Allergy 1983; 18: 153-155.
37. Woolcock AJ, Rubinfeld AR, Seale JLL, et al. - Asthma
management plan, 1989. Med J Aust 1989; 151: 650-653.
38. Hargreave FE, Dolovich J, Newhouse MT. - The assessment and treatment of asthma: a conference report. J Allergy Clin lmmunol 1990; 85: 1098-1111.
39. Mullarkey MF, Blumenstein BA, Andrade WP, er al. Methotrexate in the treatment of corticosteroid-dependent
asthma. A double-blind, cross-over study. N Engl J Med 1988;
318: 60~7.
40. Geddes DM. - Methotrexate in astluna. Clin Exp Allergy 1991; 21: 541-543.
747
41. Alexander A, Barnes N, Kay A. - Trial of cyclosporin
in corticosteroid-dependent chronic severe asthma lAncet 1992;
339: 324-328.
42. Klaustermeyer WB, Noritalce DT, Kwong FK. - Chrysotherapy in the treatment of corticosteroid-dependent asthma.
J Allergy Clin lmmunol 1987; 79: 720-725.
43. Erzwum SC, Jeff JA, <::ochran JE, et al. - Lack of benefit of methotrexate in severe, steroid-dependent astluna. A
double-blind, placebo-controlled study. Ann Intern Med 1991;
114: 353-360.
44. Shiner RI, Nunn AJ, Fan CK, Geddes DM. - Randornised, double-blind, placebo-controlled trial of methotrexate
in steroid-dependent asthma. Lancet 1990; 336: 137- 140.
45. Jones G, Mierins E, Karsh J. - Methotrexate-induced
asthma. Am Rev Respir Dis 1991; 143: 179-181.