Primary Care Corner with Geoffrey Modest MD: Asthma “misdiagnosis”

By Dr. Geoffrey Modest

A recent Canadian study evaluated patients with physician-diagnosed asthma to see if they could be tapered off medications, and whether subsequent testing confirmed the diagnosis of asthma (see  Aaron SD. JAMA.2017;317(3):269)​.

Details:

• 701 patients who had physician-diagnosed asthma within the last five years were enrolled in a prospective multicenter study in 10 Canadian cities from 2012 to 2016. 613 people completed the study
• Mean age 51, 67% women, 90% white, BMI 30, 70% college-educated, 29% current smokers, mean age of asthma diagnosis was 45, spirometry or serial peak flow testing was done in the community in 56%, 18% had an urgent visit to healthcare facility for asthma in the past year, 90% using current asthma medications (49% using asthma controlling medications daily, 44% inhaled corticosteroids with or without long-acting beta-agonists, 7% leukotriene antagonists only), FEV1 pre-bronchodilator was 88% of predicted, 21% had a post bronchodilator improvement of >12%, 86% had dyspnea and 82% wheezing in the past 12 months, comorbidities included depression in 32%, history of GERD in 30%, vocal cord dysfunction 2%, diabetes in 6%, hypertension 20%
• All patients had spirometry done before and after bronchodilators. They used a cutpoint of FEV1 improving by at least 12% after bronchodilator administration as characteristic of current asthma. Those who did not have this level of improvement were then given a methacholine challenge at week 1. Individuals with a decrease in FEV1 of 20% or more on <=8 mg/ mL of methacholine were considered to have airway hyper-responsiveness characteristic of current asthma. The methacholine challenge was repeated at 4-5 and week 7-8. Those who did not have asthma by these tests were seen by a pulmonologist, had workup to consider other diagnoses. They had their asthma medications tapered over 6 weeks and kept a symptom diary and record of daily peak flow rates, though they could use PRN beta-agonists. These people then had another methacholine challenge at 6 and 12 months later.

Results:

• -62% were confirmed to have current asthma, by having: >12% improvement after albuterol on spirometry (in 23%), bronchial hyperresponsiveness on methacholine testing on either their 2^nd, 3^rd, or 4^th study visit (in 75%), or by worsening asthma symptoms during medication tapering (2%).
• Current asthma was ruled out in 203 of 613 people (33.1%).
• 12 people (2.0%) were found to have serious cardiorespiratory conditions that had been misdiagnosed as asthma
• Of those patients with no evidence of airflow obstruction, bronchial hyperreactivity, or worsening of asthma symptoms after having all medications withdrawn, 13% were still felt to have asthma by the study pulmonologists. [not sure what this means]
• After 12 months of follow-up, 22 people in whom current asthma had been ruled out by the initial spirometry and 3 initial methacholine challenges had a positive bronchial challenge test at either 6 or 12 months, of whom 16 were asymptomatic and did not have respiratory symptoms, and 6 needed asthma medications. 181 people (29.5%) continued to have no clinical laboratory evidence of asthma.
• Of note, these patients were less likely to have had airflow limitation documented at the time of the initial diagnosis (43.8% versus 55.6% of those with confirmed asthma, an absolute difference of 11.8%) [they make a big point of this: how the lack of confirmation of asthma was related to lack of firm diagnosis initially]
• Of the 273 people who were using asthma controlling medications daily at study entry, 71 (26%) had current asthma ruled out. After 12 months, 68 of the 71 remain free of current asthma
• Therefore, of adults with physician-diagnosed asthma, in this study 33.1% did not have a current diagnosis of asthma

Commentary:

• Although guidelines suggest testing expiratory airflow to confirm the diagnosis of asthma, less than half of patients with this diagnosis in the community have this testing done, similar to the findings in the above study. The issue here is that asthma can be difficult to diagnose, has different clinical presentations, and some of these clinical presentations are from non-asthma conditions.
• This article does not mean that these 33.1% of patients did not have asthma at the time they were diagnosed, just that they did not have it after 5 years. My guess is that some of them may have had asthma which resolved spontaneously over time (for which there are little data, though some retrospective data suggests it is less often in adults than kids). Or perhaps they had wheezing with a URI (some viruses cause asthma symptoms more than others), and perhaps even several times. Or they had asthma associated with allergic triggers that they subsequently avoided. Hard to know. But undoubtedly some did not have asthma and were misdiagnosed. Though it is important to emphasize that asthma can be a very intermittent disease: in this study 22 patients who had asthma “ruled out” subsequently had a positive methacholine challenge 6-12 months later. And it is notable that this pretty large group of randomly chosen asthmatics at the time of this study had pretty mild asthma (though 90% had been using asthma meds and 18% went to an urgent care setting for asthma, the mean FEV1 pre-bronchodilator was normal at 88% of predicted).
• I would make an argument that a significant subset of patients with perhaps milder forms of asthma do not need formal spirometry testing. I certainly agree that there are some cases where the diagnosis is uncertain, and spirometry testing is appropriate. But there are some patients who have episodic wheezing episodes, who have predictable allergic or viral triggers, who respond to beta-agonists, and have a remarkably high likelihood of having easily treated clinical asthma (i.e. they walk like a duck, quack like a duck, and probably are ducks). Although more of the patients who continued to have asthma did have objective testing done (55.6% versus 43.8%), this is pretty close to a 50-50 mix. I’m not sure what the added value is to having the formal testing done in every case. Also, I even wonder if the 2% of patients who had serious cardiorespiratory conditions in this study, who had been “misdiagnosed as asthma”, years previously may well that asthma: one third of them had ischemic heart disease, and I am not sure that their diagnosis of asthma several years before was necessarily related to the ischemic heart disease 5 years later
• One of the important findings in this study was that 33.1% of individuals with asthma were able to taper off their medications safely within 5 years of the diagnosis, including some who had prior spirometry confirming the asthma diagnosis. This reinforces the importance of trying to step down therapy when patients are asymptomatic on regular meds, perhaps at the 3 month interval suggested by the Global Initiative for Asthma guidelines. One thing to keep in mind (perhaps related to the 3 month number) is that after an asthma attack, there is bronchial hyperresponsiveness for around 3 months later (i.e., increased bronchoconstriction at much lower doses of precipitant than usual for that patient)

So, bottom line points:

• We should be sure of the diagnosis, since asthma symptoms can be mimicked by other problems (cardiac, other pulmonary, upper airways…). My sense, which is also stated in this article, is that periodic peak flows or a very convincing clinical presentation is reasonable for many patients to make the diagnosis (i.e., low peak flow which reliably improves with beta-agonists). Though that we should have a low threshold to confirm asthma by formal spirometry with pre- and post-bronchodilator measurements. The Global Initiative for Asthma guidelines (see ginasthma.org ) does accept variability of peak flow measurements (using the same peak flow meter) as an acceptable alternative to spirometry
• As with some other conditions (e.g. GERD), it makes sense to try to step down therapy in a slow but methodical manner in those on daily meds who are asymptomatic for at least 3 months. This study suggests that many may not need further meds (especially if no spirometry done, but even with documented prior asthma). I would add that it is important to understand the asthma precipitants for each individual and tailor therapy to them (e.g., if seasonal, perhaps meds only that season; if someone has intermittent but very severe asthma attacks, consider giving them oral steroids to keep at home to take at the onset of their symptoms, using meds with exercise or exposure to allergens, etc.). As a primary care physician, I am well aware of the many needs of patients, and the strong tendency to simply refill meds when a patient has a stable condition (as with GERD) in order to move on to deal with other problems for the patient. This trial is a reminder that we should periodically try to taper asthma meds to the minimally effective ones for that patient.
• And these really are the most important findings (be clinically convinced the patient has asthma, and periodically try to taper the meds), not the hype that clinicians are frequently misdiagnosing asthma — which I think this study did NOT show. Only that 5 years later many patients did not need meds…..