Affiliations: Ipswich Hospital, Suffolk, UK,
Kuopio University Hospital, Kuopio, Finland,
Royal Prince Alfred Hospital, Camperdown, NSW, Australia,
University of Sydney, Sydney, NSW, Australia
Correspondence to: Daniel K.C. Lee, MBBCh, Department of Respiratory Medicine, Ipswich Hospital, Heath Rd, Ipswich IP4 5PD, Suffolk, UK; e-mail: firstname.lastname@example.org
To the Editor:
I read with interest the recent article in CHEST by Koskela et al (December 2003),1which demonstrated that bronchial mannitol challenge was more sensitive to cold air and was comparable to bronchial histamine challenge at a lower cutoff value. As I understand it, the study looked at patients in whom asthma had recently been diagnosed, albeit with difficulty, but who fell within the realms of both the Finnish Social Insurance Institution2criteria and the Global Initiative for Asthma3 classification. Yet, in a test that was meant to aid clinicians, the sensitivity of bronchial mannitol challenge was only 51% (ie, half the patients with difficult-to-diagnose asthma did not respond). This can be interpreted in the two following ways: half the patients wrongly received a diagnosis of asthma in the first place; or the mannitol bronchial challenge was only half effective in correctly identifying patients with difficult-to-diagnose asthma. I agree that airway hyperresponsiveness is a real and important component of asthma, and therefore should be incorporated into asthma guidelines to aid severity classifications and treatment. However, I am not sure whether the choice of patients used in the study was appropriate, as the results raise more questions than they give answers.
We thank Dr. Lee for his interest in our article. Airway hyperresponsiveness (AHR) is a common feature in asthma, but not a synonym for it. AHR can be demonstrated in a proportion of asthmatic subjects, and the size of this proportion probably depends on the characteristics of the population studied as well as on the test used.
The sensitivity of indirect challenges to demonstrate AHR has been a matter of a debate for decades, and the majority of the information comes from studies using exercise as the provocative stimulus. Early laboratory-based studies of children suggested that exercise-induced bronchoconstriction can be demonstrated in as many as 70 to 90% of asthmatic subjects.1–3 However, in population-based studies, the sensitivity of exercise test to detect symptomatic subjects with a doctors’ diagnosis of asthma is usually only 22 to 50%.4 Even when dry inhaled air was used during the exercise challenge, the sensitivity was just 57% among children with recent wheezing.4This discrepancy in sensitivity values between laboratory- and population-based studies probably reflects the selection of asthmatic patients with severe illness to clinical asthma studies, as highlighted by Cockcroft et al.5
The situation may be the same with newer indirect challenges. Adenosine monophosphate provocation has been a subject of active clinical research during the recent years.6Fowler et al7 analyzed their database consisting of unselected 487 asthmatic subjects with a mean age of 37 years, whose asthma was diagnosed by a primary or secondary care physician. The sensitivity of adenosine challenge was 50% using 200 mg/mL and 37% using 100 mg/mL provocative concentrations causing a 20% fall in FEV1 as a cut-off value for a positive response. In a subgroup of patients with steroid-naive asthma, these numbers were as low as 31% and 26%, respectively.,7
Compared with these results, the 51% sensitivity of mannitol challenge in our study is not a low value, especially considering the special characteristics of our asthmatic subjects.8 They were referred to our outpatient clinic because primary care physicians had been unsure about their diagnosis. As we highlight in our article, the patients showed many features that are known to cause diagnostic difficulties. Our result indicates that, given the high specificity of mannitol challenge (no healthy subject has this far responded to mannitol), 51% of these kind of clinically challenging patients can receive a correct diagnosis using mannitol challenge. In the asthmatic subjects who did not respond to mannitol, there probably were insufficient numbers of inflammatory cells in the airways or insufficient concentration of mediators to make the bronchial smooth muscle contract.
Dr. Lee also argued that the choice of patients in our study may not have been appropriate for this kind of study. We strongly argue the opposite: the power of a diagnostic test must be evaluated in a study population that reflects that faced in real-life clinical work. Since bronchial provocation tests are mainly used to confirm or exclude the diagnosis of asthma in a situation where there is a high level of uncertainty,9 we believe that our patient material was appropriate.
Furthermore, Dr. Lee also raised doubts about the validity of our patient’s diagnosis. As there is no “gold standard” for the diagnosis of asthma, one can never be absolutely sure about the correct diagnosis. However, in our study, the diagnosis was based on patient history and repeated clinical examinations in addition to objective evidence of variable airway obstruction in every patient, as documented in ambulatory peak flow monitoring. Therefore, we think that the diagnostic criteria in our study were more strict than in several published clinical studies.
Dr. Lee wrote that our study raised more questions than answers, which we take as a compliment. We hope that our study would raise at least the following question in the readers of CHEST: does the study population in a study evaluating the power of a diagnostic test reflect the patients the reader faces in his/her everyday clinical work? If not, the reader should interpret the results of that study with caution. We hope that this addresses the concerns of Dr. Lee.
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