Beruflich Dokumente
Kultur Dokumente
Division of Asthma, Allergy and Lung Biology, Kings College London, London, United Kingdom
Over the past 40 years much has been learned about how to
evaluate and treat chronic cough, but it is clear that there is much
further to go. In 1977, a systematic diagnostic approach was
proposed that encouraged evaluation of the sites of the sensory
limb of the cough reflex (1). Subsequent studies reported that
extrapulmonary conditions such as upper airway diseases and
gastroesophageal reflux disease (GERD) can cause cough. This
led to the introduction of the anatomic diagnostic paradigm,
which focuses on identifying the causes of cough (2) (Table 1).
Although many investigators have used the paradigm with a high
success rate, there are a significant number who have not. Success
rates as low as 58% have been reported and the reasons for this
are unclear (3). There is, however, agreement among clinicians
that some patients with chronic cough do not respond to therapy
despite extensive evaluation. This has led some investigators to
suggest that a new approach to chronic cough is necessary (4).
This article reviews the controversies in the evaluation of
chronic cough in adults, highlights concerns about the current
approach to cough, and suggests that therapy and future research
need more focus on important mechanisms such as cough reflex
hypersensitivity.
(Received in original form July 1, 2010; accepted in final form December 10, 2010)
Correspondence and requests for reprints should be addressed to Surinder S.
Birring, M.D., Kings College London, Division of Asthma, Allergy and Lung
Biology, Denmark Hill, London SE5 9RS, UK. E-mail: surinder.birring@nhs.net
Am J Respir Crit Care Med Vol 183. pp 708715, 2011
Originally Published in Press as DOI: 10.1164/rccm.201007-1017CI on December 10, 2010
Internet address: www.atsjournals.org
GASTROESOPHAGEAL REFLUXASSOCIATED
CHRONIC COUGH
The evaluation of GER is one of the key components of the
diagnostic pathway. Cough guidelines recommend an initial trial
of therapy rather than invasive investigations to identify GER
cough (5). Proton pump inhibitors (PPIs) are the most widely
used therapy; if medical therapy fails, further investigation may
result in antireflux surgery being recommended. A Cochrane
review meta-analysis, however, concluded that the effect of
antireflux therapy such as PPIs for chronic cough was inconsistent
and of uncertain magnitude (6). A number of other observations
have also led clinicians to question the importance of GER in
chronic cough.
Are Tests for GER Necessary?
The fact that not all GER is acidic and that some patients have
a poor response to acid suppression has focused attention on
esophageal dysmotility and nonacid GER. Esophageal dysmotility is a common finding in patients with chronic cough, although
its relevance to the pathogenesis is not known (12). It has been
suggested that cough and esophageal dysmotility may represent
a generalized abnormality of neural aerodigestive reflexes because of their coexistence. Decalmer and colleagues investigated
the importance of nonacid GER with esophageal impedance
studies in a large group of patients with chronic cough and
compared them with healthy subjects (13). They found no difference in the number of acid or nonacid GER episodes between
the groups. The temporal association between episodes of nonacid GER and cough has also been studied. Blondeau and colleagues have developed a statistical index of temporal association
called the symptom association probability (SAP), obtained from
esophageal impedance recordings (14). In their study, a positive
SAP was found in only a small proportion (5%) of patients with
chronic cough and cough itself caused episodes of GER. Smith
and colleagues also provide important insights into the association between GER and cough (15). In contrast to Blondeau and
colleagues, they found a positive symptom association for GER
709
Current guidelines recommend surgery such as Nissens fundoplication for selected patients with cough and persistent GER
despite optimal medical therapy (16). In practice, the use of
surgical treatment for GER cough is highly variable. A number of
case series of small numbers of patients report good success rates
with surgery but controlled trials, objective cough outcome data,
and long-term follow-up are lacking (5). Nissens fundoplication
is not without risks; severe dysphagia, flatulence, inability to
belch, and increased bowel symptoms are the most frequently
reported complications. Furthermore, the number of fundoplications performed in the United States for GER is steadily
declining because of lower than anticipated successful outcomes
and patient dissatisfaction (17). Controlled studies of surgical
therapy for GER cough are urgently needed. A placebo intervention is ethically and technically difficult to achieve but may
be possible with endoscopic therapies in future. The clinical trials
of bronchial thermoplasty for severe asthma highlight the importance of including a sham group when assessing an interventional
procedure (18). The authors view is that there are insufficient
data to support the recommendation for antireflux surgery for
patients with chronic cough.
Does Laryngopharyngeal Reflux Cause Cough?
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CONCLUSIONS
Figure 1. Evaluation of chronic cough. CXR 5 chest X-ray; EB 5
eosinophilic bronchitis.
714
Author Disclosure: S.B. has served on an advisory board for Pfizer, consultant for
Biocopea, was compensated as a lecturer for Schering Plough, received industrysponsored grants from Pfizer for research and occasional payments for use of the
Leicester Cough Questionnaire in commerically sponsored clinical trials.
Acknowledgment: The author thanks Dr. Richard Irwin for input into this review
article.
References
1. Irwin RS, Rosen MJ, Braman SS. Cough: a comprehensive review. Arch
Intern Med 1977;137:11861191.
2. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the
adult: the spectrum and frequency of causes and successful outcome
of specific therapy. Am Rev Respir Dis 1981;123:413417.
3. Haque RA, Usmani OS, Barnes PJ. Chronic idiopathic cough: a discrete
clinical entity? Chest 2005;127:17101713.
4. Pavord ID, Chung KF. Management of chronic cough. Lancet 2008;371:
13751384.
5. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP
evidence-based clinical practice guidelines. Chest 2006;129(1, Suppl):
80S94S.
6. Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske
LA. Systematic review and meta-analysis of randomised controlled
trials of gastro-oesophageal reflux interventions for chronic cough
associated with gastro-oesophageal reflux. BMJ 2006;332:1117.
7. Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic
cough due to gastroesophageal reflux: clinical, diagnostic, and pathogenetic aspects. Chest 1993;104:15111517.
8. Patterson RN, Johnston BT, MacMahon J, Heaney LG, McGarvey LP.
Oesophageal pH monitoring is of limited value in the diagnosis of
reflux-cough. Eur Respir J 2004;24:724727.
9. Kelsall A, Houghton LA, Jones H, Decalmer S, McGuinness K, Smith
JA. A novel approach to studying the relationship between subjective
and objective measures of cough. Chest (In press)
10. Fathi H, Faruqi R, Thompson R, Wright C, Morice AH. Chronic cough
and esomeprazole: a double-blind, randomised placebo-controlled
parellel study. Thorax 2008;63:S47.
11. Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT,
Teague WG, Wise RA, et al. Efficacy of esomeprazole for treatment
of poorly controlled asthma. N Engl J Med 2009;360:14871499.
12. Kastelik JA, Redington AE, Aziz I, Buckton GK, Smith CM, Dakkak
M, Morice AH. Abnormal oesophageal motility in patients with
chronic cough. Thorax 2003;58:699702.
13. Decalmer S, Stovold R, Jones H, Pearson J, Ward C, Houghton LA,
Kelsall A, McGuinness K, Woodcock AA, Smith JA. Relationships
between micro-aspiration, gastro-oesophageal reflux and cough in
chronic cough subjects. Thorax 2008;63:S46.
14. Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D. Improved
diagnosis of gastro-oesophageal reflux in patients with unexplained
chronic cough. Aliment Pharmacol Ther 2007;25:723732.
15. Smith JA, Decalmer S, Kelsall A, McGuinness K, Jones H, Galloway S,
Woodcock A, Houghton LA. Acoustic coughreflux associations in
chronic cough: potential triggers and mechanisms. Gastroenterology
2010;139:754762.
16. Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling
CE, Brown KK, Canning BJ, Chang AB, Dicpinigaitis PV, et al.
Diagnosis and management of cough executive summary: ACCP
evidence-based clinical practice guidelines. Chest 2006;129
(1, Suppl):1S23S.
17. Kahrilas PJ. Clinical practice: gastroesophageal reflux disease. N Engl J
Med 2008;359:17001707.
18. Bel EH. Bronchial thermoplasty: has the promise been met? Am J
Respir Crit Care Med 2010;181:101102.
19. Remacle M, Lawson G. Diagnosis and management of laryngopharyngeal reflux disease. Curr Opin Otolaryngol Head Neck Surg 2006;
14:143149.
20. McGarvey LP, Heaney LG, Lawson JT, Johnston BT, Scally CM, Ennis
M, Shepherd DR, MacMahon J. Evaluation and outcome of patients
with chronic non-productive cough using a comprehensive diagnostic
protocol. Thorax 1998;53:738743.
21. Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP, Wo JM,
Suurna M, Havas T, Howden CW, Vaezi MF. Proton pump inhibitor
therapy for suspected GERD-related chronic laryngitis: a metaanalysis of randomized controlled trials. Am J Gastroenterol 2006;
101:26462654.
22. Chan KK, Ing AJ, Laks L, Cossa G, Rogers P, Birring SS. Chronic cough in
patients with sleep-disordered breathing. Eur Respir J 2010;35:368372.
VOL 183
2011
23. Birring SS, Passant C, Patel RB, Prudon B, Murty GE, Pavord ID.
Chronic tonsillar enlargement and cough: preliminary evidence of
a novel and treatable cause of chronic cough. Eur Respir J 2004;23:
199201.
24. Sundar KM, Daly SE, Pearce MJ, Alward WT. Chronic cough and
obstructive sleep apnea in a community-based pulmonary practice.
Cough 2010;6:2.
25. Sadofsky LR, Campi B, Trevisani M, Compton SJ, Morice AH.
Transient receptor potential vanilloid-1mediated calcium responses
are inhibited by the alkylamine antihistamines dexbrompheniramine
and chlorpheniramine. Exp Lung Res 2008;34:681693.
26. McLeod RL, Mingo G, OReilly S, Ruck LA, Bolser DC, Hey JA.
Antitussive action of antihistamines is independent of sedative and
ventilation activity in the guinea pig. Pharmacology 1998;57:5764.
27. Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, Vernaglia PA,
Larkin AB, Baker SP. Cough and the common cold. Am Rev Respir
Dis 1988;138:305311.
28. Hunter CJ, Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. A
comparison of the validity of different diagnostic tests in adults with
asthma. Chest 2002;121:10511057.
29. Irwin RS, French CT, Smyrnios NA, Curley FJ. Interpretation of
positive results of a methacholine inhalation challenge and 1 week
of inhaled bronchodilator use in diagnosing and treating coughvariant asthma. Arch Intern Med 1997;157:19811987.
30. Chatkin JM, Ansarin K, Silkoff PE, McClean P, Gutierrez C, Zamel N,
Chapman KR. Exhaled nitric oxide as a noninvasive assessment of
chronic cough. Am J Respir Crit Care Med 1999;159:18101813.
31. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D,
Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and
sputum eosinophil counts: a randomised controlled trial. Lancet 2002;
360:17151721.
32. Singapuri A, McKenna S, Brightling CE. The utility of the mannitol
challenge in the assessment of chronic cough: a pilot study. Cough
2008;4:10.
33. Lee KK, Savani A, Patel A, Wood C, Morgan L, Fleming T, Pavord ID,
Birring SS. Short term oral corticosteroid trials in patients with
unexplained chronic cough. Eur Respir J 2010.
34. Tomerak AA, Vyas H, Lakenpaul M, McGlashan JJ, McKean M.
Inhaled b2-agonists for treating non-specific chronic cough in children. Cochrane Database Syst Rev 2005;3:CD005373.
35. Littenberg B, Wheeler M, Smith DS. A randomized controlled trial of
oral albuterol in acute cough. J Fam Pract 1996;42:4953.
36. Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID. Eosinophilic
bronchitis is an important cause of chronic cough. Am J Respir Crit
Care Med 1999;160:406410.
37. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical
manifestations and implications for treatment. Thorax 2002;57:178182.
38. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ,
Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma.
N Engl J Med 2002;346:16991705.
39. Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. Development of
irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma. Eur Respir J 1999;14:12281230.
40. Fujimura M, Ogawa H, Nishizawa Y, Nishi K. Comparison of atopic
cough with cough variant asthma: is atopic cough a precursor of
asthma? Thorax 2003;58:1418.
41. Niimi A, Matsumoto H, Mishima M. Eosinophilic airway disorders
associated with chronic cough. Pulm Pharmacol Ther 2009;22:114120.
42. Irwin RS. Unexplained cough in the adult. Otolaryngol Clin North Am
2010;43:167xii.
43. Birring SS, Brightling CE, Symon FA, Barlow SG, Wardlaw AJ, Pavord
ID. Idiopathic chronic cough: association with organ specific autoimmune disease and bronchoalveolar lymphocytosis. Thorax 2003;58:
10661070.
44. Birring SS. Developing antitussives: the ideal clinical trial. Pulm Pharmacol Ther 2009;22:155158.
45. Morice AH. The cough hypersensitivity syndrome: a novel paradigm for
understanding cough. Lung 2010;188:S87S90.
46. Birring SS, Murphy AC, Scullion JE, Brightling CE, Browning M,
Pavord ID. Idiopathic chronic cough and organ-specific autoimmune
diseases: a casecontrol study. Respir Med 2004;98:242246.
47. Cornia PB, Hersh AL, Lipsky BA, Newman TB, Gonzales R. Does this
coughing adolescent or adult patient have pertussis? JAMA 2010;304:
890896.
48. Ogawa H, Fujimura M, Takeuchi Y, Makimura K. The importance of
basidiomycetous fungi cultured from the sputum of chronic idiopathic
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
715
63. Barnes PJ. The problem of cough and development of novel antitussives.
Pulm Pharmacol Ther 2007;20:416422.
64. McGarvey L, McKeagney P, Polley L, MacMahon J, Costello RW. Are
there clinical features of a sensitized cough reflex? Pulm Pharmacol
Ther 2009;22:5964.
65. Watkin G, Mutalithas K, Willig BW, Wardlaw AJ, Pavord ID, Birring
SS. Improvement in health status following outpatient chest physiotherapy for patients with chronic cough. Thorax 2006;61:ii92.
66. Yousaf N, Birring SS, Pavord ID. Long term outcome of patients with
unexplained chronic cough. Thorax 2009;64:S25.
67. Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF,
Dicpinigaitis PV, Kastelik JA, McGarvey LP, Smith JA, Tatar M,
et al. ERS guidelines on the assessment of cough. Eur Respir J 2007;
29:12561276.
68. Materazzi S, Nassini R, Gatti R, Trevisani M, Geppetti P. Cough
sensors. II. Transient receptor potential membrane receptors on
cough sensors. Handb Exp Pharmacol 2009;187:4961.
69. Birring SS, Matos S, Patel RB, Prudon B, Evans DH, Pavord ID. Cough
frequency, cough sensitivity and health status in patients with chronic
cough. Respir Med 2006;100:11051109.
70. Choudry NB, Fuller RW. Sensitivity of the cough reflex in patients with
chronic cough. Eur Respir J 1992;5:296300.
71. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitorinduced
cough: ACCP evidence-based clinical practice guidelines. Chest
2006;129(1, Suppl):169S173S.
72. Dicpinigaitis PV, Dobkin JB, Reichel J. Antitussive effect of the
leukotriene receptor antagonist zafirlukast in subjects with coughvariant asthma. J Asthma 2002;39:291297.
73. Raj AA, Birring SS. Clinical assessment of chronic cough severity. Pulm
Pharmacol Ther 2007;20:334337.
74. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID.
Development of a symptom specific health status measure for patients
with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax
2003;58:339343.
75. French CT, Irwin RS, Fletcher KE, Adams TM. Evaluation of a coughspecific quality-of-life questionnaire. Chest 2002;121:11231131.
76. Baiardini I, Braido F, Fassio O, Tarantini F, Pasquali M, Tarchino F,
Berlendis A, Canonica GW. A new tool to assess and monitor the
burden of chronic cough on quality of life: Chronic Cough Impact
Questionnaire. Allergy 2005;60:482488.
77. Brignall K, Jayaraman B, Birring SS. Quality of life and psychosocial
aspects of cough. Lung 2008;186:S55S58.
78. Birring SS, Fleming T, Matos S, Raj AA, Evans DH, Pavord ID. The
Leicester Cough Monitor: preliminary validation of an automated cough
detection system in chronic cough. Eur Respir J 2008;31:10131018.
79. Barry SJ, Dane AD, Morice AH, Walmsley AD. The automatic
recognition and counting of cough. Cough 2006;2:8.
80. Smith JA, Earis JE, Woodcock AA. Establishing a gold standard for
manual cough counting: video versus digital audio recordings. Cough
2006;2:6.