FEV₁ reversibility for asthma diagnosis: a critical evaluation

KEYWORDS:

• Asthma
• airway obstruction
• bronchodilator response
• COPD
• diagnosis
• FEV₁
• methacholine challenge test
• spirometry

1. Introduction

Asthma is a chronic inflammatory disease of the airways characterized by varying degrees of bronchoconstriction and airway hyperresponsiveness, leading to classic symptoms of airway obstruction that is often reversible. The current standard for asthma diagnosis is based on the typical clinical features in addition to presence of airway dysfunction documented objectively with a significant change in forced expiratory volume in 1 second (FEV₁) after bronchodilator administration or with airway hyperresponsiveness (i.e. bronchoprovocation with methacholine or mannitol). The American Thoracic Society defines a significant post-bronchodilator response as an increase in FEV₁ of 200 ml or greater and 12% improvement from baseline after inhalation of short acting beta2-agonists [1]. Although the reversibility criteria are included in many guideline documents [2], there are other definitions of bronchodilator reversibility described in the literature [3]. The need for bronchoprovocation testing often arises when patients with symptoms compatible with asthma present with normal baseline lung function and a lack of FEV₁ reversibility.

2. FEV₁ reversibility in asthma

The importance of objective confirmation of asthma diagnosis is outlined in a recent report by Aaron et al., who showed that among adults (n = 613) with physician-diagnosed asthma, a current diagnosis of asthma was ruled out in 33.1% of patients who were not using daily asthma medications or had medications weaned [4]. Although spirometry is recommended as a first-line test for asthma diagnosis in the clinical setting, several studies have highlighted its low sensitivity [5,6]. The variable nature of airway obstruction in asthma makes objective diagnosis difficult, especially since many asthmatics have normal lung function at the time of testing. Reports by Aaron et al. and Luks et al. found that asthma diagnosis was confirmed in only 16% and 10.8% of patients with post-bronchodilator spirometry, respectively [5,6]. In the latter study, asthma was confirmed in the majority of patients with methacholine challenge test (MCT). Goldstein et al. have reported that post-bronchodilator FEV₁ responses cannot substitute MCT in the assessment of patients with suspected asthma with normal baseline spirometry [7]. Furthermore, Hunter et al. indicate that methacholine responsiveness is more than twice as sensitive as bronchodilator reversibility for FEV₁ for identifying mild asthma [8]. Yurdakul et al. also report a much higher sensitivity for MCT compared with FEV₁ reversibility for asthma diagnosis among patients attending a community clinic [9].

In contrast, a study by Macy et al., which looked at asthma patients with lower lung function compared to the previous studies highlighted above, found that 62% of asthmatics were identified with FEV₁ reversibility [10]. Thus, baseline lung function may also influence bronchodilator responsiveness. These factors pose an important challenge in primary care with respect to asthma diagnosis among patients with mild disease since the appearance of normal lung function and lack of FEV₁ reversibility can be taken to imply absence of disease. Simple spirometry for asthma diagnosis is promoted in favor of MCT because the latter is a more complex test and potentially less accessible [4]. However, it seems counterintuitive to recommend a first line test that, because of very low sensitivity, ultimately leads one to carry out an MCT. If the limitations and barriers to MCT are not overcome in the community, the recommended approach of simple spirometry may actually lead to underdiagnosis of asthma if MCT is not utilized as a second-line test. It should also be noted that emerging tests that evaluate inflammatory biomarkers may prove useful for asthma diagnosis in primary care [11].

3. Spirometry overlap between asthma and COPD

In adults, the challenge of asthma diagnosis may be compounded by a history of smoking. The latter is related to the fact that chronic obstructive pulmonary disease (COPD) often presents for the first time among patients 40 years of age and older with prevalence peaks in the fifth and sixth decades of life and beyond [12]. In the BOLD study, the prevalence of COPD in a subgroup of heavy smokers was 15.5–33.9% among men and 2.7–29.7% among women across various countries [13]. Clinical phenotypes that include FEV₁ reversibility and persistent reductions in FEV₁/FVC underscore the spirometric overlap between asthma and COPD and the potential for disease misclassification.

Similar to asthma, COPD is a chronic respiratory illness that is associated with airflow obstruction. Although the two share some common spirometric features, they have different causative factors, pathological features, natural history, treatment priorities, and prognosis. Given the narrow scope of our topic, we do not discuss how prematurity may contribute to chronic airflow limitation and response to bronchodilator challenge [14]. Differentiation between these two conditions is important because first-line treatments are different in fundamental ways. COPD has traditionally been described as a condition with relatively fixed airway obstruction, but more recently it has become clear that a phenotype of COPD includes the finding of partial reversibility. For example, COPD is defined spirometrically by a persistent reduction in FEV₁/FVC ratio of <0.70 or below the lower limit of normal; the latter reflecting reports that the fixed ratio of 0.70 may overestimate airflow obstruction in the elderly [15]. However, there are no restrictions on the magnitude of FEV₁ reversibility as long as the FEV₁/FVC ratio remains reduced. An increase in FEV₁ greater than a threshold value is assumed to represent ‘reversibility’ of airway obstruction and, by implication, to favor a diagnosis of asthma [16,17]. However, in a large COPD cohort (N = 5756) study, Tashkin et al. found that about 54% of patients showed an improvement in FEV₁ values greater than 12% and 200 ml [18], suggesting that FEV₁ reversibility may represent a particular phenotype of COPD. However, a caveat to note is that reversibility in this trial was assessed 90 min after administration of ipratropium and salbutamol, which differs from the reversibility testing in clinical practice. Important to note are findings that report varying numbers of patients who change reversibility status depending on the criteria employed [19]. Furthermore, recent reports highlight that bronchodilator responsiveness appears to be a consistent variable within individual patients in the short term and quite variable between patients [19].

In a recent landmark COPD trial, the mean reversibility in FEV₁ was greater than 12% and 200 ml [20]. It is also important to note that among asthmatic patients the FEV₁/FVC ratio may be persistently reduced despite appropriate therapy, reminding us that there could be complete overlap of spirometric variables typically used to diagnose conditions with different pathological pathways. These data highlight the significant challenge of using FEV₁ reversibility for asthma diagnosis given the high likelihood of reversibility in the COPD population.

The potential clinical implications linked to spirometric overlap between asthma and COPD are described in reports that evaluate the consequences of using a spirometry interpretation algorithm (SIA) [21]. The algorithm uses FEV₁ reversibility to distinguish between asthma and COPD and does not include logic strings and decision nodes that take into account the spirometric overlap between asthma and COPD [22]. These data suggest that family physicians will interpret the same spirometry data differently using two different SIA, including decisions that favor a diagnosis of asthma when the data are also consistent with a consideration of COPD [21]. Given the issues described above, there is much need for well-controlled studies to evaluate how the spirometric overlap between asthma and COPD may guide decision-making in terms of interpretation of spirometry data and how this in turn may influence clinical diagnosis and management of these two very common conditions.

Asthma-COPD overlap syndrome (ACOS) has been recently described by the joint project of Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung disease (GOLD) [23]. ACOS is defined as ‘persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.’ The mechanism underlying ACOS is largely unknown. Reported prevalence rates of ACOS were highly variable: between 15% and 55% depending on the diagnostic criteria applied. In a recent large cohort of well-characterized patients with COPD, Cosio et al. applied precise diagnostic criteria and identified ACOS in 15% of patients [24]. These criteria were sustained after 1 year. This finding is in keeping with the results of similar well-characterized cohorts of patients with COPD such as the COPDGene study, which reported 13% overlap between COPD and asthma [25]. GINA/GOLD recommends a stepwise approach to diagnosis using usual features (historical and diagnostic) of COPD and asthma. If there are similar number of features of both diseases, the diagnosis of ACOS should be considered [23]. It can be seen that in asthma COPD and ACOS, spirometry and clinical overlap would be expected and the selection of appropriate therapy would hinge on identifying other relevant markers of disease activity for accurate diagnosis.

4. Other useful testing modalities and diagnostic criteria

Clinical history is a vital part of asthma diagnosis. A recent report published by the joint project of GINA/GOLD advocated for a stepwise approach focusing on the features that are most helpful in identifying and distinguishing typical asthma and typical COPD (i.e., age of onset, pattern of symptoms, personal history or family history, and time course) [23]. In addition, inflammatory biomarkers are specialized investigations that can be helpful in distinguishing asthma and COPD. A high level (>50 ppb) of fraction excretion of nitric oxide in non-smokers support a diagnosis of eosinophilic airway inflammation. Similarly, blood eosinophilia supports asthma diagnosis. Positive test for atopy, which includes skin prick tests and serum specific IgE for aeroallergens, modestly increases probability of asthma [23].

5. Summary

Traditionally FEV₁ reversibility has been used to provide objective confirmation of asthma and to distinguish between asthma and COPD. The promotion of simple spirometry for widespread adoption in primary care has been driven by factors related to access, affordability, and for its potential therapeutic utility [26]. However, the very low sensitivity of simple spirometry for asthma confirmation in primary care calls into question its role as a first-line test since most patients are likely to present with mild disease and normal lung function at time of testing. The high likelihood that COPD patients will also exhibit FEV₁ reversibility that would meet asthma FEV₁ reversibility criteria raises the real possibility of disease misclassification among smoking adult patients presenting with airflow limitation. These factors suggest a need to re-evaluate the role of FEV₁ reversibility testing for asthma diagnosis in primary care and the need to supplement this approach with detailed clinical history and evaluation of relevant biomarkers associated with asthma. It is relevant to note that MCT and other tests evaluating inflammatory markers for asthma diagnosis appear to be safe in routine clinical practice [4,27].

6. Conclusion

Few can argue with the usefulness of simple spirometry for assessing the relationship between flow and volume and for evaluating responses to inhaled therapies designed to improve airway caliber in patients with established respiratory illness. However, the data presented above and a lack of relevant studies that directly evaluate the role of FEV₁ reversibility in asthma diagnosis compared to other strategies suggest a need to re-examine its inclusion into current guidelines as a first-line strategy for objective confirmation in primary care without a thorough description of its limitations. Spirometry, given its insensitive and nonspecific nature, should be supplemented with additional tests such as inflammatory biomarkers in the diagnosis of asthma. Studies focusing on such an approach should, ideally, be carried out in primary care. Current guidelines on asthma diagnosis should include more thorough discussion about the spirometric overlap between asthma and COPD and the limitations of using FEV₁ reversibility for objective confirmation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.