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A cough is by far the most common reason for a patient to seek medical advice.1 Most of these consultations are for acute cough caused by a myriad of respiratory viruses. In practice, we do not attempt to differentiate rhinovirus infection from adenovirus because no important consequence arises from this diagnostic precision. In chronic cough numerous studies have shown that the overwhelming majority of patients are suffering from one of three conditions—a form of asthma, gastro-oesophageal reflux, or rhinitis.2 The question is whether any further subdivision is justified or merely muddies the water.
In their recent paper published in Thorax Fujimura and colleagues, by inventing a diagnosis of “atopic cough”, have succeeded in adding further unnecessary complexity to the area.3 There are many aspects of this paper which cannot be left unchallenged and we have outlined these below.
The evidence to support a new clinical entity “atopic cough” is tenuous and is further hampered by the extremely vague term “probable atopic cough”. This point is well illustrated in their table 2 which outlines a variety of diagnostic permutations possible after interpretation of a series of investigations. We suspect the authors have, in a significant number of these “probable” patients, merely described atopic individuals with cough predominant asthma. Certainly the demonstration of bronchial hyperreactivity (BHR) in 15 such patients (median PC20 2.5 mg/ml, range 1.25–5.0), many of whom had airway eosinophilia and all of whom appear atopic, is suggestive. Such diagnostic imprecision may yet have therapeutic consequences, but the authors do not provide sufficient information in the paper to conclude that these patients failed to respond to steroids, and have indicated that response to bronchodilators was tested in neither a randomised nor a controlled way.
The authors have relied heavily on the “absence of transformation to typical asthma” to differentiate atopic cough from asthmatic cough. Such a conclusion can hardly be supported by a telephone follow up which relies on patient recall and subjective assessment of symptoms. In some series up to one third of patients with cough variant asthma may develop typical asthma symptoms,4 although in a 3 year follow up of 63 patients with cough variant asthma typical wheezing occurred in only 6%.5 Thus, lack of progression to typical asthma is well described and cannot be used to support the proposition that atopic cough is unique.
The statement “the defining physiological feature is increased cough sensitivity without BHR in atopic cough, and BHR without cough hypersensitivity in cough variant asthma” is simply untrue. Capsaicin hypersensitivity in patients with asthmatic cough has been reported by many researchers.6–9 This heightened cough sensitivity is, of course, not directly related to bronchomotor tone, but most probably reflects a different pattern of airway inflammation.10
With reference to the authors’ interpretation of the study by McGarvey et al,11 we strongly contest the suggestion that patients identified as having cough variant asthma may have been misclassified. In this study steroid efficacy was not a sole criterion for the diagnosis of cough variant asthma as all 10 patients had BHR (mean PC20 3.44 mg/ml, range 0.04–8). Only two of these patients were atopic.
We believe our 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 arbitrarily defined “diseases” such as atopic cough (or, indeed, eosinophilic bronchitis) is not helpful either diagnostically or therapeutically.
Since we proposed atopic cough as an aetiological entity in 1992, a number of Japanese chest specialists have used the same arguments as McGarvey and Morice to criticise the concept. They insist that, because corticosteroids are effective in atopic cough as well as in asthma and cough variant asthma, all of these should be categorised as “asthmatic”. We continue to suggest that such insistence runs counter to the progress of medical science. It is very important to recognise that there are different clinical manifestations of eosinophilic airway inflammation,1 and cough sensitivity and bronchomotor tone or bronchial responsiveness are entirely independent.2,3 Two mechanisms of non-productive cough are generally recognised: cough triggered by increased bronchomotor tone and cough based on increased cough sensitivity. Both may result from eosinophilic airway inflammation, although via different mechanisms. We do not yet fully understand why eosinophilic airway inflammation increases cough sensitivity in atopic cough while both asthma and cough variant asthma exhibit mild bronchial hyperresponsiveness (BHR) without increased cough sensitivity. We are hopeful that future studies will disclose the mechanism, thereby contributing to both our understanding of the pathophysiology of atopic cough and to better specific treatment.
In our study4 patients with a definite diagnosis of atopic cough did not go on to develop typical asthma, indicating that atopic cough is not a precursor to asthma. Only one of 58 patients with a probable diagnosis of atopic cough developed typical asthma 11.5 years after her first visit. Although the patient’s bronchial responsiveness was increased, her bronchial reversibility and diurnal variation in peak expiratory flow rate were within normal limits; bronchodilator treatment was not effective, leading to a probable diagnosis of atopic cough. Although some investigators believe that BHR is the key criterion for a diagnosis of cough variant asthma, this is incorrect. The most important feature of cough variant asthma is isolated chronic cough responsive to bronchodilators.5 Furthermore, it has been clearly shown that measurement of bronchial responsiveness cannot predict the efficacy of bronchodilators in the treatment of cough.6
Figure 1 shows a consensus opinion of the Japanese Cough Research Society concerning the diagnosis of cough variant asthma and atopic cough based on bronchial responsiveness and efficacy of bronchodilators. Only area C represents definite cough variant asthma for the purposes of selecting clinical research subjects; areas C + D represent probable cough variant asthma for general clinical practice, area B represents definite atopic cough, and areas A + B represent probable atopic cough. In addition, areas B + D represent eosinophilic bronchitis without asthma.7
Worldwide problems regarding the diagnosis of cough variant asthma, atopic cough, and eosinophilic bronchitis without asthma are as follows: (1) many researchers have recognised areas A + C as cough variant asthma regardless of responsiveness to bronchodilators; and (2) because inhaled corticosteroids are believed to be the definitive asthma treatment, the diagnosis of asthma is based on the responsiveness of the cough to corticosteroid therapy despite the presence of non-asthmatic eosinophilic airway disorders. We emphasise again that bronchodilators, which have no effect on cough sensitivity,2 are efficacious against coughing only in cough variant asthma. Thus, as the efficacy of bronchodilators is a key criterion for the diagnosis of cough variant asthma, many Japanese investigators use information regarding bronchodilator responsiveness of a cough to diagnose cough variant asthma, recognising the presence of non-asthmatic eosinophilic airway disorders.
While it is impossible to assess the efficacy of bronchodilator therapy in individual patients in a randomised and placebo controlled manner, the assessment we used is not difficult.4 Although the placebo effect may lead to an incorrect diagnosis of cough variant asthma, no effect is meaningful enough to exclude cough variant asthma or cough predominant asthma.
One fundamental feature of cough variant asthma is mildly increased bronchial responsiveness unrelated to cough sensitivity. It is well known that cough sensitivity is increased in some patients with cough variant asthma and asthma (asthmatic patients), as pointed out by McGarvey and Morice. Our opinion is that increased cough sensitivity is a complication in asthmatic patients but it is not a fundamental aspect of the asthmatic airway. We label such patients as having “cough variant asthma” or “asthma complicated with cough hypersensitivity”. In these patients bronchodilator therapy is not sufficient; histamine H1-antagonists are useful, as shown by Shioya et al.8 Corticosteroids do, of course, relieve the cough because they improve both cough hypersensitivity and BHR which are caused by eosinophilic airway inflammation via possibly different mechanisms.
The data presented in our paper4 showing that six of 20 patients with cough variant asthma not taking long term inhaled corticosteroid therapy developed typical asthma are consistent with previous reports. Although Orejas et al9 reported that typical asthma occurred in only 6% of 63 patients with cough variant asthma during a 3 year follow up period, there exists an important problem in the diagnostic criteria for cough variant asthma. Orejas et al and many other investigators have diagnosed cough variant asthma based on BHR without assessing the efficacy of bronchodilator therapy or measuring cough sensitivity, resulting in the inclusion of non-asthmatic patients who, in fact, have atopic cough.
McGarvey and Morice and other investigators feel that subdividing eosinophilic airway disorder causes unwieldy complexity in the diagnosis of chronic cough. We hold that delineating the pathophysiology of specific subdivisions such as atopic cough and cough variant asthma will allow more effective and specific treatments to be used rather than relying solely on inhaled corticosteroids which are non-specific to the actual cough mechanism. We continue to suggest that atopic cough should be considered as an entity separate from cough variant asthma, with a unique pathophysiology and its own rate of asthma onset.
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