Cough · 4: Cough in asthma and eosinophilic bronchitis
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《胸》
ABSTRACT
Airway eosinophilia and cough may be associated with asthma and with non-asthmatic eosinophilic bronchitis. Whether
cough variant asthma and eosinophilic bronchitis are distinct entities or a pathophysiological spectrum needs
further examination.
Eosinophilic bronchitis is commonly but not uniformly present in patients with asthma.1 Asthma and the relatively
recently described entity of non-asthmatic eosinophilic bronchitis (EB) are associated with a similar degree of
submucosal eosinophilia, as well as thickening of the basement membrane and lamina reticularis.2 EB can be
distinguished from asthma by the absence of reversible airflow obstruction, bronchial hyperresponsiveness to
methacholine, and airway smooth muscle infiltration by mast cells.2 In the subgroup of asthmatics in whom cough is
the predominant symptom, spirometric tests may also be normal but bronchial hyperresponsiveness can be
demonstrated. Whether EB represents a distinct clinical condition or is a precursor of asthma remains unknown at
this time.
COUGH ASSOCIATED WITH ASTHMA
A number of prospective studies have shown that asthma is one of the most common aetiologies of chronic cough (24–
29%) in adult non-smokers.3–5 In a subgroup of asthmatics, cough may be the predominant or sole symptom.6 This
condition is referred to as cough variant asthma (CVA).
The diagnosis of CVA often presents a challenge since physical examination and spirometric tests may be entirely
normal. Up to 50% of patients with CVA have associated EB, with the degree of eosinophilia being similar to that of
other asthmatics.1 Demonstration of bronchial hyperresponsiveness by methacholine inhalation challenge supports the
presence of CVA, but the diagnosis is confirmed only upon resolution of the cough with specific anti-asthma
treatment.7 Although cough due to EB typically responds to inhaled steroid therapy,1 bronchial hyperresponsiveness
is absent.
In general, the therapeutic approach to CVA is similar to that of typical asthma. Symptomatic improvement is often
noted after 1 week of inhaled bronchodilator treatment, but complete resolution of cough may require the addition
of inhaled corticosteroids for up to 8 weeks.7
Some patients may suffer a paradoxical exacerbation of cough with the use of inhaled steroids, probably due to a
constituent of the aerosol. The more common occurrence of cough with beclomethasone dipropionate than with
triamcinolone acetonide, for example, is thought to be due to a component of the dispersant in the former.8 The
possibility of inhaled steroid induced cough, as well as improper use of the inhaler device, should be excluded
before escalation of treatment.
For cough that is severe or only partially responsive to inhaled steroids, a diagnostic therapeutic trial of oral
corticosteroids (prednisone 40 mg or equivalent daily for 1 week) alone or followed by inhaled treatment9 has been
successful.
Anecdotal reports initially suggested that the leukotriene receptor antagonists (LTRAs) may be particularly
effective in treating asthmatic cough.10,11 Subsequently, a prospective, randomised, double blind, placebo
controlled trial has shown that the LTRA zafirlukast improves cough and suppresses cough reflex sensitivity to
inhaled capsaicin in patients with CVA, including a subgroup whose cough had been refractory to inhaled steroids.12
The ability of zafirlukast to inhibit cough that had been resistant to bronchodilators and inhaled steroids
suggests that LTRAs may more effectively modulate the inflammatory milieu of the afferent cough receptors residing
within the airway epithelium in patients with CVA. The mechanisms by which this antitussive effect occurs remain to
be elucidated.
Clearly, the LTRAs have earned a place in our therapeutic armamentarium against CVA. Whether these new agents
should replace or merely complement inhaled steroids is unclear at this time. At issue is the dearth of information
regarding the long term effects of LTRAs against chronic asthmatic inflammation and resultant remodelling of the
airway wall. Thickening of the subepithelial layer has been demonstrated in CVA, albeit to a lesser extent than in
typical asthma.13 Chronic anti-inflammatory therapy would therefore seem to be indicated for patients with CVA, but
whether monotherapy with LTRAs is sufficient to prevent progression of airway wall remodelling in this setting is
unknown. Prospective clinical trials are required to define the role of LTRAs in the chronic treatment of CVA. A
stepwise approach to the treatment of CVA is shown in box 1.
Box 1 Stepwise approach to the treatment of cough variant asthma (CVA)
* Step 1: inhaled bronchodilators (? agonists)*
* Step 2: inhaled corticosteroids
* Step 3: leukotriene receptor antagonists (LTRAs)
* Step 4: system (oral) corticosteroids
Recent data support the concept that patients with CVA comprise a very distinct subgroup, rather than simply being
asthmatics who cough. For example, subjects with CVA have heightened cough reflex sensitivity to inhaled capsaicin
whereas typical asthmatics do not differ from healthy volunteers in terms of experimentally induced cough.12
Interestingly, despite having increased cough sensitivity, patients with CVA have a lesser degree of bronchial
hyperresponsiveness to methacholine than those with the typical form of asthma.12,14,15 These observations are an
excellent illustration of the concept that cough and bronchoconstriction are separate entities, controlled by
distinct afferent neural pathways.16
COUGH CAUSED BY NON-ASTHMATIC EOSINOPHILIC BRONCHITIS (EB)
The association of chronic cough with non-asthmatic EB has recently been described,17 and subsequent investigation
has established an important role for EB in the aetiology of cough. Two prospective trials evaluating patients
presenting to a specialist18 and primary care physician19 found EB to be the cause of chronic cough in 13% and 11%
of cases, respectively.
Individuals with EB typically respond to treatment with inhaled steroids.1 Since most clinicians do not have access
to sputum eosinophil determination or measurement of bronchial responsiveness to inhaled methacholine, it seems
likely that many patients with steroid responsive cough due to EB are misdiagnosed as having CVA. Evaluation for
sputum eosinophils would be an appropriate addition to the diagnostic protocols for chronic cough currently in
use.3,5
The natural history of EB awaits definition. This is a question of considerable significance since the
identification of EB as a precursor of asthma would appropriately raise the issue of early and long term anti-
inflammatory treatment to avoid potential sequelae of chronic inflammation such as airway wall remodelling with
resultant fixed airway obstruction, as has been described in a patient with non-asthmatic EB.20 A recent small
prospective study with follow up to 24 months demonstrated a progressive decrement in forced expiratory volume in 1
second (FEV1) and forced expiratory mid flow (FEF25–75) in a subgroup of patients with EB, with one subject
developing dyspnoea and wheezing within 1 year.21
CONCLUSION
Airway eosinophilia and cough may be associated with asthma as well as with non-asthmatic EB. EB differs from
asthma in that demonstrable bronchial hyperresponsiveness is absent. Although inhaled corticosteroids are
beneficial in both conditions, a subgroup of patients with CVA will require more aggressive treatment with systemic
steroids. Recent evidence supports the efficacy of LTRAs in the treatment of CVA, but the question of whether these
agents alone are sufficient to prevent the complications of chronic asthmatic inflammation remains unanswered.
Whether CVA and EB are distinct entities or conditions representing a pathophysiological spectrum awaits further
elucidation.
FOOTNOTES
* Although inhaled ? agonists may cause improvement in cough within a week, often inhaled steroids are also
required for complete elimination of cough (see text).
Whether LTRAs should be used instead of, rather than in addition to, inhaled corticosteroids for the chronic
treatment of CVA is unknown at this time. Studies evaluating the effect of chronic LTRA treatment on bronchial
inflammation and airway wall remodelling are required (see text).
REFERENCES
1. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment.
Thorax 2002;57:178–82.
2. Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J
Med 2002;346:1699–705.
3. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the
diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640–7.
4. Pratter MR, Bartter T, Akers S, et al. An algorithmic approach to chronic cough. Ann Intern Med 1993;119:977–
83.
5. McGarvey LP A, Heaney LG, Lawson JT, et al. Evaluation and outcome of patients with chronic non-productive cough
using a comprehensive diagnostic protocol. Thorax 1998;53:738–43.
6. Corrao WM, Braman SS, Irwin RS. Chronic cough as the sole presenting manifestation of bronchial asthma. N Engl J
Med 1979;300:633–7.
7. Irwin RS, French CL, Smyrnios NA, et al. Interpretation of positive results of a methacholine inhalation
challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma. Arch Intern Med
1997;157:1981–7.
8. Shim CS, Williams MH. Cough and wheezing from beclomethasone dipropionate aerosol are absent after triamcinolone
acetonide. Ann Intern Med 1987;106:700–3.
9. Doan T, Patterson R, Greenberger PA. Cough variant asthma: usefulness of a diagnostic therapeutic trial with
prednisone. Ann Allergy 1992;69:505–9.
10. Spector SL. Efficacy of anti-LT agents in the treatment of chronic asthma. Clin Rev Allergy Immunol 1999;17:235
–46.
11. Nishi K, Watanabe K, Ooka T, et al. Cough-variant asthma successfully treated with a peptide leukotriene
receptor antagonist (in Japanese). Jpn J Thoracic Dis 1997;35:117–23.
12. Dicpinigaitis PV, Dobkin JB, Reichel J. Antitussive effect of the leukotriene receptor antagonist zafirlukast
in subjects with cough-variant asthma. J Asthma 2002;39:291–7.
13. Niimi A, Matsumoto H, Minakuchi M, et al. Airway remodeling in cough-variant asthma. Lancet 2000;356:564–5.
14. Garcia CO, Pascual TP, Alvarez AA, et al. Tos como equivalente asmatico. Caracteristicas clinicas y
functionales. Estudio de 63 casos. Arch Bronconeumol (Barcelona) 1998;34:232–6.
15. Komaki Y, Miura M, Takahashi M. Distribution of airway hyperresponsiveness in adult-onset cough-variant asthma:
comparison with classic asthma. Am J Respir Crit Care Med 2001;163:A419.
16. Advenier C, Lagente V, Boichot E. The role of tachykinin receptor antagonists in the prevention of bronchial
hyperresponsiveness, airway inflammation and cough. Eur Respir J 1997;10:1892–906.
17. Gibson PG, Dolovich J, Denburg J, et al. Chronic cough: eosinophilic bronchitis without asthma. Lancet
1989;i:1346–8.
18. Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J
Respir Crit Care Med 1999;160:406–10.
19. Rytila P, Metso T, Petays T, et al. Eosinophilic airway inflammation as an underlying mechanism of undiagnosed
prolonged cough in primary healthcare patients. Respir Med 2002;96:52–8.
20. Brightling CE, Woltmann G, Wardlaw AJ, et al. Development of irreversible airflow obstruction in a patient with
eosinophilic bronchitis without asthma. Eur Respir J 1999;14:1228–30.
21. Park SW, Kim DJ, Lee JH, et al. Development of asthma in patients with eosinophilic bronchitis: prospective
follow up study. Eur Respir J 2002;20:51S.(P V Dicpinigaitis)
Airway eosinophilia and cough may be associated with asthma and with non-asthmatic eosinophilic bronchitis. Whether
cough variant asthma and eosinophilic bronchitis are distinct entities or a pathophysiological spectrum needs
further examination.
Eosinophilic bronchitis is commonly but not uniformly present in patients with asthma.1 Asthma and the relatively
recently described entity of non-asthmatic eosinophilic bronchitis (EB) are associated with a similar degree of
submucosal eosinophilia, as well as thickening of the basement membrane and lamina reticularis.2 EB can be
distinguished from asthma by the absence of reversible airflow obstruction, bronchial hyperresponsiveness to
methacholine, and airway smooth muscle infiltration by mast cells.2 In the subgroup of asthmatics in whom cough is
the predominant symptom, spirometric tests may also be normal but bronchial hyperresponsiveness can be
demonstrated. Whether EB represents a distinct clinical condition or is a precursor of asthma remains unknown at
this time.
COUGH ASSOCIATED WITH ASTHMA
A number of prospective studies have shown that asthma is one of the most common aetiologies of chronic cough (24–
29%) in adult non-smokers.3–5 In a subgroup of asthmatics, cough may be the predominant or sole symptom.6 This
condition is referred to as cough variant asthma (CVA).
The diagnosis of CVA often presents a challenge since physical examination and spirometric tests may be entirely
normal. Up to 50% of patients with CVA have associated EB, with the degree of eosinophilia being similar to that of
other asthmatics.1 Demonstration of bronchial hyperresponsiveness by methacholine inhalation challenge supports the
presence of CVA, but the diagnosis is confirmed only upon resolution of the cough with specific anti-asthma
treatment.7 Although cough due to EB typically responds to inhaled steroid therapy,1 bronchial hyperresponsiveness
is absent.
In general, the therapeutic approach to CVA is similar to that of typical asthma. Symptomatic improvement is often
noted after 1 week of inhaled bronchodilator treatment, but complete resolution of cough may require the addition
of inhaled corticosteroids for up to 8 weeks.7
Some patients may suffer a paradoxical exacerbation of cough with the use of inhaled steroids, probably due to a
constituent of the aerosol. The more common occurrence of cough with beclomethasone dipropionate than with
triamcinolone acetonide, for example, is thought to be due to a component of the dispersant in the former.8 The
possibility of inhaled steroid induced cough, as well as improper use of the inhaler device, should be excluded
before escalation of treatment.
For cough that is severe or only partially responsive to inhaled steroids, a diagnostic therapeutic trial of oral
corticosteroids (prednisone 40 mg or equivalent daily for 1 week) alone or followed by inhaled treatment9 has been
successful.
Anecdotal reports initially suggested that the leukotriene receptor antagonists (LTRAs) may be particularly
effective in treating asthmatic cough.10,11 Subsequently, a prospective, randomised, double blind, placebo
controlled trial has shown that the LTRA zafirlukast improves cough and suppresses cough reflex sensitivity to
inhaled capsaicin in patients with CVA, including a subgroup whose cough had been refractory to inhaled steroids.12
The ability of zafirlukast to inhibit cough that had been resistant to bronchodilators and inhaled steroids
suggests that LTRAs may more effectively modulate the inflammatory milieu of the afferent cough receptors residing
within the airway epithelium in patients with CVA. The mechanisms by which this antitussive effect occurs remain to
be elucidated.
Clearly, the LTRAs have earned a place in our therapeutic armamentarium against CVA. Whether these new agents
should replace or merely complement inhaled steroids is unclear at this time. At issue is the dearth of information
regarding the long term effects of LTRAs against chronic asthmatic inflammation and resultant remodelling of the
airway wall. Thickening of the subepithelial layer has been demonstrated in CVA, albeit to a lesser extent than in
typical asthma.13 Chronic anti-inflammatory therapy would therefore seem to be indicated for patients with CVA, but
whether monotherapy with LTRAs is sufficient to prevent progression of airway wall remodelling in this setting is
unknown. Prospective clinical trials are required to define the role of LTRAs in the chronic treatment of CVA. A
stepwise approach to the treatment of CVA is shown in box 1.
Box 1 Stepwise approach to the treatment of cough variant asthma (CVA)
* Step 1: inhaled bronchodilators (? agonists)*
* Step 2: inhaled corticosteroids
* Step 3: leukotriene receptor antagonists (LTRAs)
* Step 4: system (oral) corticosteroids
Recent data support the concept that patients with CVA comprise a very distinct subgroup, rather than simply being
asthmatics who cough. For example, subjects with CVA have heightened cough reflex sensitivity to inhaled capsaicin
whereas typical asthmatics do not differ from healthy volunteers in terms of experimentally induced cough.12
Interestingly, despite having increased cough sensitivity, patients with CVA have a lesser degree of bronchial
hyperresponsiveness to methacholine than those with the typical form of asthma.12,14,15 These observations are an
excellent illustration of the concept that cough and bronchoconstriction are separate entities, controlled by
distinct afferent neural pathways.16
COUGH CAUSED BY NON-ASTHMATIC EOSINOPHILIC BRONCHITIS (EB)
The association of chronic cough with non-asthmatic EB has recently been described,17 and subsequent investigation
has established an important role for EB in the aetiology of cough. Two prospective trials evaluating patients
presenting to a specialist18 and primary care physician19 found EB to be the cause of chronic cough in 13% and 11%
of cases, respectively.
Individuals with EB typically respond to treatment with inhaled steroids.1 Since most clinicians do not have access
to sputum eosinophil determination or measurement of bronchial responsiveness to inhaled methacholine, it seems
likely that many patients with steroid responsive cough due to EB are misdiagnosed as having CVA. Evaluation for
sputum eosinophils would be an appropriate addition to the diagnostic protocols for chronic cough currently in
use.3,5
The natural history of EB awaits definition. This is a question of considerable significance since the
identification of EB as a precursor of asthma would appropriately raise the issue of early and long term anti-
inflammatory treatment to avoid potential sequelae of chronic inflammation such as airway wall remodelling with
resultant fixed airway obstruction, as has been described in a patient with non-asthmatic EB.20 A recent small
prospective study with follow up to 24 months demonstrated a progressive decrement in forced expiratory volume in 1
second (FEV1) and forced expiratory mid flow (FEF25–75) in a subgroup of patients with EB, with one subject
developing dyspnoea and wheezing within 1 year.21
CONCLUSION
Airway eosinophilia and cough may be associated with asthma as well as with non-asthmatic EB. EB differs from
asthma in that demonstrable bronchial hyperresponsiveness is absent. Although inhaled corticosteroids are
beneficial in both conditions, a subgroup of patients with CVA will require more aggressive treatment with systemic
steroids. Recent evidence supports the efficacy of LTRAs in the treatment of CVA, but the question of whether these
agents alone are sufficient to prevent the complications of chronic asthmatic inflammation remains unanswered.
Whether CVA and EB are distinct entities or conditions representing a pathophysiological spectrum awaits further
elucidation.
FOOTNOTES
* Although inhaled ? agonists may cause improvement in cough within a week, often inhaled steroids are also
required for complete elimination of cough (see text).
Whether LTRAs should be used instead of, rather than in addition to, inhaled corticosteroids for the chronic
treatment of CVA is unknown at this time. Studies evaluating the effect of chronic LTRA treatment on bronchial
inflammation and airway wall remodelling are required (see text).
REFERENCES
1. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment.
Thorax 2002;57:178–82.
2. Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J
Med 2002;346:1699–705.
3. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the
diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640–7.
4. Pratter MR, Bartter T, Akers S, et al. An algorithmic approach to chronic cough. Ann Intern Med 1993;119:977–
83.
5. McGarvey LP A, Heaney LG, Lawson JT, et al. Evaluation and outcome of patients with chronic non-productive cough
using a comprehensive diagnostic protocol. Thorax 1998;53:738–43.
6. Corrao WM, Braman SS, Irwin RS. Chronic cough as the sole presenting manifestation of bronchial asthma. N Engl J
Med 1979;300:633–7.
7. Irwin RS, French CL, Smyrnios NA, et al. Interpretation of positive results of a methacholine inhalation
challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma. Arch Intern Med
1997;157:1981–7.
8. Shim CS, Williams MH. Cough and wheezing from beclomethasone dipropionate aerosol are absent after triamcinolone
acetonide. Ann Intern Med 1987;106:700–3.
9. Doan T, Patterson R, Greenberger PA. Cough variant asthma: usefulness of a diagnostic therapeutic trial with
prednisone. Ann Allergy 1992;69:505–9.
10. Spector SL. Efficacy of anti-LT agents in the treatment of chronic asthma. Clin Rev Allergy Immunol 1999;17:235
–46.
11. Nishi K, Watanabe K, Ooka T, et al. Cough-variant asthma successfully treated with a peptide leukotriene
receptor antagonist (in Japanese). Jpn J Thoracic Dis 1997;35:117–23.
12. Dicpinigaitis PV, Dobkin JB, Reichel J. Antitussive effect of the leukotriene receptor antagonist zafirlukast
in subjects with cough-variant asthma. J Asthma 2002;39:291–7.
13. Niimi A, Matsumoto H, Minakuchi M, et al. Airway remodeling in cough-variant asthma. Lancet 2000;356:564–5.
14. Garcia CO, Pascual TP, Alvarez AA, et al. Tos como equivalente asmatico. Caracteristicas clinicas y
functionales. Estudio de 63 casos. Arch Bronconeumol (Barcelona) 1998;34:232–6.
15. Komaki Y, Miura M, Takahashi M. Distribution of airway hyperresponsiveness in adult-onset cough-variant asthma:
comparison with classic asthma. Am J Respir Crit Care Med 2001;163:A419.
16. Advenier C, Lagente V, Boichot E. The role of tachykinin receptor antagonists in the prevention of bronchial
hyperresponsiveness, airway inflammation and cough. Eur Respir J 1997;10:1892–906.
17. Gibson PG, Dolovich J, Denburg J, et al. Chronic cough: eosinophilic bronchitis without asthma. Lancet
1989;i:1346–8.
18. Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J
Respir Crit Care Med 1999;160:406–10.
19. Rytila P, Metso T, Petays T, et al. Eosinophilic airway inflammation as an underlying mechanism of undiagnosed
prolonged cough in primary healthcare patients. Respir Med 2002;96:52–8.
20. Brightling CE, Woltmann G, Wardlaw AJ, et al. Development of irreversible airflow obstruction in a patient with
eosinophilic bronchitis without asthma. Eur Respir J 1999;14:1228–30.
21. Park SW, Kim DJ, Lee JH, et al. Development of asthma in patients with eosinophilic bronchitis: prospective
follow up study. Eur Respir J 2002;20:51S.(P V Dicpinigaitis)