To the Editors:
We read with interest the recent paper by ten Brinke et al. 1, which describes the prevalence of comorbidities in “difficult-to-treat” asthmatics and the association with recurrent exacerbations. This adds to other papers examining these factors in similar populations but reached some differing conclusions, which we felt merit further discussion.
The study involved 136 patients initially; however, only 63 patients were included in the main analysis. A total of 54 patients were excluded because of their continuous use of oral steroids as the authors reported that defining an exacerbation was difficult in this group. We are unclear why this could not have been defined as the requirement for an increase in oral steroid above the usual maintenance dose. This would have increased the number of patients in the study and included those with more severe disease. The reader can only assume that the remaining 29 patients are those with two exacerbations in a year and, thus, the “study population” of 136 seems a little misleading, and rather selected, when the number of subjects analysed was 63.
The definition of difficult-to-treat asthma was made on the basis of treatment requirements and persistent symptoms. Two published systematic evaluation protocols, performed independently in populations defined in this way, have shown that a significant proportion of patients have unidentified or alternative diagnoses 2, 3. When these are identified and managed, it results in a significant proportion of these patients becoming straightforward to manage 2, 3. If this important differentiation was not made prior to this study, then a significant proportion of patients entered in this study may not have had persisting symptoms due to asthma.
Another issue, which does not seem to be addressed, is poor adherence. Both recent systematic protocol studies in difficult asthmatics assessed adherence to systemic steroids, and found that 32% 3 and 56% 2 were nonadherent. Using 6-monthly prescription refill records, 45% of patients attending the Belfast Difficult Asthma Clinic (Belfast, UK) were filling <50% of their prescribed combination inhaler (personal communication, J. Gamble, A. Lazenbatt, L.G. Heaney, Regional Respiratory Unit, Belfast City Hospital, Belfast, UK), despite reporting they were adherent with therapy. Thus, nonadherence appears to be prevalent in difficult asthma, and self-reported adherence and physician assessment are known to be unreliable 4, 5.
The study by ten Brinke et al. 1 reported an association between exacerbation and reflux (odds ratio (OR) 4.9), but a definition based on the presence of reflux on pH profiling or severe reflux symptoms with response to treatment was used. Only 39 of the initial 136 patients underwent 24-h pH monitoring. It is well documented that the absence of reflux symptoms is not an accurate predictor of the absence of this condition, since many asymptomatic patients will have “silent” reflux 6. ten Brinke et al. 1 highlight this in their discussion, with only 36% of the patients who underwent 24-h pH measurement reporting symptoms of reflux, but 77% of these had reflux using objective pH criteria. Therefore, it seems surprising that, in the other subjects, the presence or absence of reflux were accepted on clinical grounds alone. Debate exists as to whether the treatment of this condition actually has any bearing on asthma control 7, 8, and the study by ten Brinke et al. 1 does not appear to add significantly to this debate.
The association of respiratory infection (OR 6.9) as defined by “episodes of increased dyspnoea, cough and purulent sputum for which the attending physician or respiratory specialist had prescribed a course of antibiotic drug” is difficult to interpret 1. We accept that objectively capturing all infective episodes with, for example, bacteriological, radiological or haematological markers is difficult, but the criteria used would seem to capture all other exacerbations, which may be independent of infection.
This paper by ten Brinke et al. 1 adds to other studies looking in detail at this difficult group of patients, but has reached some differing conclusions regarding exacerbating factors. This patient group with difficult-to-manage asthma requires a detailed systematic analysis to identify those subjects with other comorbidities, which, when managed, make persisting symptoms easier to control. The first question to be addressed is “Are all the symptoms due to asthma?” and, secondly, “Is the subject taking their medication?” (supported by objective measurement). At this stage, exacerbating factors should be explored, but, in order to advance the debate about the relationship between these factors and difficult asthma, groups studying in this area need to agree and apply standard assessment protocols and definitions, so that meaningful comparisons between studies can be made.
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