- Open Access
Cough variant asthma and atopic cough
© Novamedia srl 2010
Received: 22 January 2010
Accepted: 7 February 2010
Published: 30 April 2010
Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians in the world, the third in Italy. Chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram could be a symptom of asthma and can be sub-classified into: cough-variant asthma, atopic cough, and eosinophilic bronchitis. This review discusses the differential diagnosis of these three disorders.
Asma variante con tosse e tosse atopica
La tosse cronica è la quinta causa che induce a consultare il proprio medico di famiglia nel mondo, in Italia è la terza. La tosse cronica in un adulto non fumatore che non assume ACEinibitori ed ha una Rx torace nella norma può essere un sintomo indicatore di asma in una delle sue tre varianti: asma variante con tosse, tosse atopica e bronchite eosinofila. La diagnosi differenziale di queste tre patologie è oggetto di questa rassegna.
Commonest causes of chronic cough in patients investigated in specialist clinics
Patients' mean age in years (range)
Diagnosis (% of total)
Most common other causes
Irwin et al. 1981 
Chronic bronchitis (12)
Poe et al. 1982 
Poe et al. 1989 
Irwin et al. 1990 
Chronic bronchitis (5)
Hoffstein 1994 
O'Connell et al. 1994 
Smyrnios et al. 1995 
Chronic bronchitis (11)
Mello et al. 1996 
Marchesani et al. 1998 
Chronic bronchitis (16)
McGarvey et al. 1998 
Palombini et al. 1999 
Brightling et al. 1999 
The most common causes worldwide of chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram include the upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD) and asthma syndromes [4, 7–15]. This indicates a group of related airway disorders including the "classic" asthma, the so-called cough variant asthma, nonasthmatic eosinophilic bronchitis (NAEB), and atopic cough. However, even if the guidelines on cough diagnosis and management [16–18] are followed in detail, the cause of chronic cough may remain unexplained in up to 33-46% of cases [6, 19]. The prevalence of UACS, GERD and asthma syndromes varies in different reports [4, 7–15]. This suggests the necessity of further examination to elucidate cough mechanisms and etiology . The differences in prevalence may depend upon racial and life style differences, access to specialists or differences in the definition of some cough causes [21, 22]. For instance, in the United Kingdom and Australia the two most common causes of cough are rhinitis for both (24% and 93% respectively), followed by asthma in UK (17.6%) and GERD in Australia (70%) [11, 23]. In Turkey, eosinophilic bronchitis is the cause of chronic cough in 33.3% of patients, while postnasal drip syndrome and GERD are each responsible for chronic cough in 22.2% of patients . In Japan, cough variant asthma and atopic cough are major causes of isolated chronic non-productive cough . Gastro-esophageal reflux-associated cough and post-nasal drip-induced cough, which are major causes of chronic cough in Western countries , are very rare in Japan .
Chronic cough can arise in asthma in various clinical settings, and is not always associated with airflow obstruction, wheezing or dyspnea. In addition, asthma may predominantly present with cough, which is often nocturnal; the diagnosis is supported by the presence of bronchial hyper-responsiveness . Elderly people with asthma can also present with a history of chronic cough, with little or no wheezing. Cough is often the symptom most report- ed by patients with chronic asthma, despite the fact they have achieved good asthma control with inhaled corticosteroids . Finally, cough can be the first sign of worsening of asthma; doctors should look for a fall in early morning peak flows .
Cough caused by eosinophilic airway diseases
Cough variant asthma
Cough, breathlessness, wheeze
Cough and sputum
As in general population
Variable airflow obstruction
Capsaicin cough hyper-responsiveness
Response to H1 antagonist
Progression to asthma
Sputum eosinophilia (> 3%)
Always (by definition)
Mast cells in ASM
Basement membrane thickness
Whether atopic cough represents a self-standing airway disease is still the object of debate . In 1992 Fujimura and others proposed the existence of a bronchodilator-resistant non productive chronic cough associated with atopy which they termed "atopic cough" . According to the authors , the pathological characteristics of atopic cough include eosinophilic tracheobronchitis without broncho alveolar lavage (BAL) eosinophilia, and the physiological characteristics of atopic cough include cough hypersensitivity without bronchial hyper responsiveness (BHR) . Conversely, cough variant asthma  appears to be similar to asthma, with mild BHR and eosinophilic inflammation of central and peripheral airways, and a cough responsive to bronchodilator treatment .
Until the 1970s cough was commonly associated with episodic wheezing and dyspnea in symptomatic asthmatic patients. Corrao et al.  studied six patients with chronic persistent cough as the sole manifestation of bronchial asthma as diagnosed according to the criteria of the American Thoracic Society : all had persistence for an average of six months, inducible diffuse airway broncho constriction and disappearance of cough with specific bronchodilator therapy. The return of cough when bronchodilators were discontinued, the disappearance of cough with the re-institution of this medication and the subsequent development of wheezing in two patients further supported the authors' contention that these cases represented a variant group of asthma . Some years later Braman and Corrao  re-studied patients diagnosed with cough variant asthma and found that 37% of these patients had developed intermittent wheezing. As nearly 30% of patients with cough variant asthma have been found to develop typical asthma, cough variant asthma has been considered a precursor of typical asthma. However, the evolution of atopic cough, particularly with regard to its progression to typical asthma, has not been elucidated . Determining whether atopic cough is a precursor of asthma may be important  in terms of the possibility of early intervention in asthma therapy.
Non-productive cough lasting for more than 8 weeks without wheezing or dyspnea.
Presence of one or more findings indicative of an atopic constitution, including a past history and/or complications of allergic diseases excluding asthma, peripheral blood eosinophilia (= 6% or = 400 cells/mL), raised total IgE level in serum (= 200 IU/mL), positive specific IgE antibody to aeroallergens and positive allergen skin test and/or induced sputum eosinophilia (= 2.5%).
No bronchial reversibility, defined as less than a 10% increase in forced expiratory volume in 1 sec (FEV1) after inhalation of 300 µg salbutamol sulphate.
Normal bronchial responsiveness (positive responsiveness being the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) < 10 mg/mL).
Increased cough reflex sensitivity (capsaicin concentration eliciting five or more coughs (C5) = 3.9 mmol/L).
Cough resistant to bronchodilator therapy (oral clenbuterol 40 mg/day plus inhaled procaterol or salbutamol at bedtime and on demand for = 1 week).
No abnormal findings indicative of cough etiology on chest X-ray.
Normal FEV1 (= 80% of predicted value), forced vital capacity (FVC) (= 80% of predicted value), and FEV1/FVC ratio (= 70%).
The diagnosis of atopic cough was made according to the following criteria proposed by the Japanese Cough Research Society:
When all criteria were satisfied, a definite diagnosis of atopic cough was made. If one or more criteria were not satisfied (or assessed), a diagnosis of probable atopic cough was made when all of the following were present: i) non-productive cough lasting more than 8 weeks without wheezing or dyspnea; ii) cough resistant to bronchodilator therapy; iii) presence of one or more findings indicative of atopic constitution as a global feature described above and/or induced sputum eosinophilia (≥ 2.5%); and iv) complete relief of cough after treatment with histamine H1-antagonists and/or corticosteroid therapy.
The complete relief of cough within 2 months of treatment was an important factor in making a probable diagnosis of atopic cough even if 2-3 weeks of oral corticosteroids were required for severe patients. The diagnosis of cough variant asthma was made according to the following criteria proposed by the Japanese Cough Research Society: i) isolated chronic non-productive cough lasting more than 8 weeks; ii) absence of a history of wheeze or dyspnea, and no adventitious lung sounds on physical examination; iii) absence of postnasal drip to account for the cough; iv) FEV1, FVC, and FEV1/FVC ratio within normal limits; v) presence of bronchial hyper responsiveness (PC20 < 10 mg/mL); vi) cough reflex sensitivity within normal limits (C5 > 3.9 mmol/L); vii) no abnormal findings indicative of cough etiology on chest radiograph; and viii) relief of cough with bronchodilator therapy.
The efficacy of bronchodilator therapy was assessed according to the following criteria: i) 'excellent' when cough was totally resolved; ii) 'good' when sleep and daytime quality of life were improved; iii) 'fairly good' when severity and frequency of cough were somewhat decreased; and iv) 'poor' when the cough was unchanged. An assessment of 'excellent' or 'good' was judged as effective. When all criteria were satisfied, a definite diagnosis of cough variant asthma was made. If one or more criteria were not satisfied (or assessed), a diagnosis of probable cough variant asthma was made when all of the following were present: i) cough without wheezing lasting 8 weeks or more and no wheezes on auscultation; ii) no upper respiratory tract infection within 8 weeks; and iii) relief of cough with bronchodilator therapy. The results showed that in patients with cough variant asthma the onset of typical asthma occurred in 5.7% of patients in the group treated with inhaled corticosteroid therapy and in 30% of patients in the group not treated. In patients with atopic cough the onset of typical asthma was confirmed in only 1.2% of the total. The onset of typical asthma was thus significantly less prevalent in patients with atopic cough than in those with cough variant asthma. In addition, long term inhaled steroids significantly decreased the development of typical asthma in patients with cough variant asthma. If mild asthma benefits from early intervention with long term inhaled steroids, it will be also useful for cough variant asthma. As atopic cough differs from cough variant asthma with regard to both outcome and pathophysiological features, the authors recommended that atopic cough be recognized as a new clinical entity characterized by isolated chronic non-productive cough .
Morice and McGarvey  in a letter to Fujimura and collegues expressed their dismay at reading the paper . The diagnosis of "atopic cough", they claimed, would succeed only in adding further unnecessary complexity to the cough-related conditions . The evidence to support a new clinical entity "atopic cough" they felt was tenuous and further hampered by the extremely vague term "probable atopic cough", that merely described atopic individuals with cough predominant asthma. Such diagnostic imprecision may yet have therapeutic consequences but Morice and McGarvey claimed that the authors did not provide sufficient information in the paper to conclude that these patients had failed to respond to steroids, and claimed that the response to bronchodilators was tested in neither a randomized nor a controlled way . The "absence of transformation to typical asthma" was considered too heavily to differentiate atopic cough from asthmatic cough . The lack of progression to typical asthma is well described both in atopic cough and in cough variant asthma, so it cannot be used to support the proposition that atopic cough is unique . Summing up, Morice and McGarvey believe their clinical understanding of asthmatic cough is enhanced by the recognition that an individual patient may show different features of the disease process. The unnecessary subdivision into an arbitrarily defined "disease" such as atopic cough (or, indeed, eosinophilic bronchitis) is not helpful either diagnostically or therapeutically.
In conclusion, the confusion or lack of consensus in cough-related disorders may be affecting the etiology of chronic cough reported from various countries . Issues such as site of inflammation, mediators involved, and allergens in "atopic" causes for these entities remain to be clarified in more detail in future studies .
Conflict of interests statement
None of the authors has any conflict of interest to declare in relation to the subject matter of this manuscript.
- French CL, Irwin RS, Curley FJ, Krikorian CJ: Impact of chronic cough on quality of life. Arch Intern Med. 1998, 158: 1657-1661. 10.1001/archinte.158.15.1657.View ArticlePubMedGoogle Scholar
- 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: 339-343. 10.1136/thorax.58.4.339.PubMed CentralView ArticlePubMedGoogle Scholar
- Braman SS, Corrao WM: Chronic cough. Diagnosis and treatment. Prim Care. 1985, 12: 217-225.PubMedGoogle Scholar
- 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: 640-647. 10.1164/ajrccm/141.3.640.View ArticlePubMedGoogle Scholar
- Yamada T, Yoshimura M, Nago N, Asai Y, Koga Y, Inoue Y, Hamasaki K, Mise J, Lamberts H: What is the Common Diseases and Common Health Problems? The use of ICPC in the community-based project. Jpn J Prim Care. 2000, 23: 80-89.Google Scholar
- Chung KF, Pavord ID: Prevalence, pathogenesis and causes of chronic cough. Lancet. 2008, 371: 1364-1374. 10.1016/S0140-6736(08)60595-4.View ArticlePubMedGoogle Scholar
- Poe RH, Harder RV, Israel RH, Kallay MC: Chronic persistent cough. Experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest. 1989, 95: 723-728. 10.1378/chest.95.4.723.View ArticlePubMedGoogle Scholar
- Pratter MR, Bartter T, Akers S, DuBois J: An algorithmic approach to chronic cough. Ann Intern Med. 1993, 119: 977-983.View ArticlePubMedGoogle Scholar
- French CL, Irwin RS, Curley FJ, Krikorian CJ: Impact of chronic cough on quality of life. Arch Intern Med. 1998, 158: 1657-1661. 10.1001/archinte.158.15.1657.View ArticlePubMedGoogle Scholar
- Mc Garvey 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: 738-743. 10.1136/thx.53.9.738.View ArticleGoogle Scholar
- 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: 406-410.View ArticlePubMedGoogle Scholar
- Kastelik JA, Aziz I, Ojoo JC, Thompson RH, Redington AE, Morice AH: Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J. 2005, 25: 235-243. 10.1183/09031936.05.00140803.View ArticlePubMedGoogle Scholar
- Palombini BC, Villanova CAC, Araújo E, Gastal OL, Alt DC, Stolz DP, Palombini CO: A pathogenic triad in chronic cough: asthma, postnasal drip syndrome, and gastroesophageal reflux disease. Chest. 1999, 116: 279-284. 10.1378/chest.116.2.279.View ArticlePubMedGoogle Scholar
- Ribeiro M, De Castro Pereira CA, Nery LE, Beppu OS, Silva CO: A prospective longitudinal study of clinical characteristics, laboratory findings, diagnostic spectrum and outcomes of specific therapy in adult patients with chronic cough in general respiratory clinic. Int J Clin Pract. 2006, 60: 799-805. 10.1111/j.1368-5031.2006.00876.x.View ArticlePubMedGoogle Scholar
- Fujimura M, Abo M, Ogawa H, Nishi K, Kibe Y, Hirose T, Nakatsumi Y, Iwasa K: Importance of atopic cough, cough variant asthma and sinobronchial syndrome as causes of chronic cough in the Hokuriku area of Japan. Respirology. 2005, 10: 201-207. 10.1111/j.1440-1843.2005.00686.x.View ArticlePubMedGoogle Scholar
- Morice AH, Fontana GA, Sovijarvi AR, Pistolesi M, Chung KF, Widdicombe J, O'Connell F, Geppetti P, Gronke L, De Jongste J, Belvisi M, Dicpinigaitis P, Fischer A, McGarvey L, Fokkens WJ, Kastelik J, ERS Task Force: The diagnosis and management of chronic cough. Eur Respir J. 2004, 24: 481-492. 10.1183/09031936.04.00027804.View ArticlePubMedGoogle Scholar
- Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, Brown KK, Canning BJ, Chang AB, Dicpinigaitis PV, Eccles R, Glomb WB, Goldstein LB, Graham LM, Hargreave FE, Kvale PA, Lewis SZ, McCool FD, McCrory DC, Prakash UB, Pratter MR, Rosen MJ, Schulman E, Shannon JJ, Smith Hammond C, Tarlo SM, American College of Chest Physicians (ACCP): Diagnosis and management of cough executive summary: ACCP evidence- based clinical practice guidelines. Chest. 2006, 129 (1 Suppl): 1S-23S.PubMed CentralView ArticlePubMedGoogle Scholar
- Committee for the Japanese Respiratory Society Guidelines for Management of Cough, Kohno S, Ishida T, Uchida Y, Kishimoto H, Sasaki H, Shioya T, Tokuyama K, Niimi A, Nishi K, Fujimura M, Matsuse H, Suzaki H: The Japanese Respiratory Society guidelines for management of cough. Respirology. 2006, 11 (Suppl 4): S135-S186.View ArticleGoogle Scholar
- Pratter MR: Unexplained (idiopathic) cough: ACCP evidence- based clinical practice guidelines. Chest. 2006, 129 (1 Suppl): 220S-221S.View ArticlePubMedGoogle Scholar
- Grabczak EM, Dabrowska M, Krenke R, Domeracka- Kolodziej A, Domagala-Kulawik J, Arcimowicz M, Hamera M, Chazan R: Does the established cause of chronic cough depend on diagnostic approach?. J Physiol Pharmacol. 2008, 59 (Suppl 6): 285-296.PubMedGoogle Scholar
- Niimi A: Geography and cough aetiology. Pulm Pharmacol Ther. 2007, 20: 383-387. 10.1016/j.pupt.2006.10.014.View ArticlePubMedGoogle Scholar
- Morice AH: Epidemiology of cough. Pulm Pharmacol Ther. 2002, 15: 253-259. 10.1006/pupt.2002.0352.View ArticlePubMedGoogle Scholar
- Carney IK, Gibson PG, Murree-Allen K, Saltos N, Olson LG, Hensley MJ: A systematic evaluation of mechanisms in chronic cough. Am J Respir Crit Care Med. 1997, 156: 211-216.View ArticlePubMedGoogle Scholar
- Ayik SO, Başoğlu OK, Erdínç M, Bor S, Veral A, Bílgen C: Eosinophilic bronchitis as a cause of chronic cough. Respir Med. 2003, 97: 695-701. 10.1053/rmed.2003.1503.View ArticlePubMedGoogle Scholar
- Fujimura M: Cough variant asthma and related disorders: atopic cough. Arerugi no rinsho. 1996, 16: 22-27.Google Scholar
- Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein V, Ing AJ, McCool FD, O'Byrne P, Poe RH, Prakash UB, Pratter MR, Rubin BK: Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest. 1998, 114 (2 Suppl Managing): 133S-181S.View ArticlePubMedGoogle Scholar
- Nishi K, Amemiya T, Mizuguchi M, Ooka T, Fujimura M, Matsuda T: A case of chronic persistent cough caused by gastro-esophageal reflux. Nihon Kyobu Shikkan Gakkai Zasshi. 1995, 33: 652-659.PubMedGoogle Scholar
- Corrao WM, Braman SS, Irwin RS: Chronic cough as the sole presenting manifestation of bronchial asthma. N Engl J Med. 1979, 300: 633-637. 10.1056/NEJM197903223001201.View ArticlePubMedGoogle Scholar
- Osman LM, McKenzie L, Cairns J, Friend JA, Godden DJ, Legge JS, Douglas JG: Patients weighting of importance of asthma symptoms. Thorax. 2001, 56: 138-142. 10.1136/thorax.56.2.138.PubMed CentralView ArticlePubMedGoogle Scholar
- Chung KF, Pavord ID: Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008, 371: 1364-1374. 10.1016/S0140-6736(08)60595-4.View ArticlePubMedGoogle Scholar
- 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: 14-18. 10.1136/thorax.58.1.14.PubMed CentralView ArticlePubMedGoogle Scholar
- Fujimura M, Sakamoto S, Matsuda T: Bronchodilator-resistive cough in atopic patients: bronchial reversibility and hyperresponsiveness. Intern Med. 1992, 31: 447-452. 10.2169/internalmedicine.31.447.View ArticlePubMedGoogle Scholar
- Fujimura M, Ogawa H, Yasui M, Matsuda T: Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough. Clin Exp Allergy. 2000, 30: 41-47. 10.1046/j.1365-2222.2000.00698.x.View ArticlePubMedGoogle Scholar
- Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F: Eosinophilic inflammation in cough variant asthma. Eur Respir J. 1998, 11: 1064-1069. 10.1183/09031936.98.11051064.View ArticlePubMedGoogle Scholar
- American Thoracic Society Committee on Diagnostic Standards for Nontuberculous Diseases: Definitions and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis. 1962, 85: 762-768.Google Scholar
- Gibson PG, Fujimura M, Niimi A: Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. 2002, 57: 178-182. 10.1136/thorax.57.2.178.PubMed CentralView ArticlePubMedGoogle Scholar
- McGarvey L, Morice AH: Atopic cough: little evidence to support a new clinical entity. Thorax. 2003, 58: 736-737. 10.1136/thorax.58.8.736.PubMed CentralView ArticlePubMedGoogle Scholar
- 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: 413-417.PubMedGoogle Scholar
- Poe RH, Israel RH, Utell MJ, Hall WJ: Chronic cough: bronchoscopy or pulmonary function testing?. Am Rev Respir Dis. 1982, 126: 160-162.PubMedGoogle Scholar
- Hoffstein V: Persistent cough in nonsmokers. Can Respir J. 1994, 1: 40-47.Google Scholar
- O'Connell F, Thomas VE, Pride NB, Fuller RW: Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med. 1994, 150: 374-380.View ArticlePubMedGoogle Scholar
- Smyrnios NA, Irwin RS, Curley FJ: Chronic cough with a history of excessive sputum production. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Chest. 1995, 108: 991-997. 10.1378/chest.108.4.991.View ArticlePubMedGoogle Scholar
- Mello CJ, Irwin RS, Curley FJ: Predictive values of the character, timing, and complications of chronic cough in diagnosing its cause. Arch Intern Med. 1996, 156: 997-1003. 10.1001/archinte.1996.00440090103010.View ArticlePubMedGoogle Scholar
- Marchesani F, Cecarini L, Pela R, Sanguinetti CM: Causes of chronic persistent cough in adult patients: the results of a sistematic management protocol. Monaldi Arch Chest Dis. 1998, 53: 510-514.PubMedGoogle Scholar
- Niimi A, Matsumoto H, Mishima M: Eosinophilic airway disorders associated with chronic cough. Pulm Pharmacol Ther. 2009, 22: 114-120. 10.1016/j.pupt.2008.12.001.View ArticlePubMedGoogle Scholar