Normal spirometry with high and asthma-defining bronchodilator responsiveness: An appraisal from real-life data

ABSTRACT

Background:

Spirometric exercise in symptomatic patients (with/without suspicion of airflow obstruction) often ends with results showing normal pre-bronchodilator values.

Methods:

We screened two different populations with prospectively archived spirometry, consisting of a) clinical suspicion of OAD (obstructive airway disease) and b) all other indications without any suspicion of OAD. Both populations underwent BDR (bronchodilator responsiveness) with salbutamol. We screened out the patients that displayed ‘normal spirometry’ [pre-bronchodilator (FEV1/FVC > 0.7 with FEV1 and FVC > 80%] and further looked for the presence of high (≥200 mL alone) or asthma-defining (>200 mL and 12%) BDR in them.

Results:

The two sets included 1019 and 3060 subjects in patients with or without suspected OAD. They showed the presence of 11.87% (121/1019) and 27.71% (848/3060) of normal spirometry. In the first set, 24.7% (n = 30) and 17.35% (n = 21), and in the second set, 12.26% (n = 104) and 4.7% (n = 40) patients had high (>200 mL) or asthma-defining (200 mL plus 12%) BDR. Thus, the asthma-defining BDR is present in 2.06% (21/1019) and 1.30% (40/3060) of patients with or without suspected OAD with normal pre-bronchodilator spirometry. The prevalence of isolated high BDR (200 mL) was present in 0.88% [9 (30–21) out of 1019] and 2.09% [n = 64 (135–54)/3060] of them.

Conclusion:

Some patients with respiratory symptoms with or without suspicion of airflow obstruction display pre-bronchodilator normal spirometry, and some of them demonstrate high or asthma-defining bronchodilator responsiveness. Performing BDR should be a routine in respiratory practice.

INTRODUCTION

Bronchodilator responsiveness means an improvement of FEV1 by 200 mL and 12% in response to inhalation with salbutamol.[1] Although performing BDR is integrated in the routine spirometry, the exercise is often abandoned once the pre-bronchodilator spirometry appears normal. This results from a perception that significant airflow limitation, including the asthma-defining one, cannot exist with normal pre-bronchodilator spirometry. Incidentally, asthma has global prevalence varying across different geographical and socioeconomic strata.[2] It is a treatable disease with significant global burden, showing an estimation that 262 million people were affected by asthma in 2019, and its diagnosis includes demonstration of a positive bronchodilator responsiveness.[3] It is diagnosed based on the presence of symptoms and demonstration of a critical responsiveness of FEV1 (200 mL and 20%) to salbutamol inhalation.[4]

Asthma diagnosis does not mean that a patient cannot have normal lung function.[5] Since the spirometric variables are dependent on several factors like age, BMI, ethnicity, and height,[6] there is no fixed cut-off point regarding any of the spirometric parameters to make a differentiation between ‘normal’ and ‘reduced’. A normal spirometry is decided by FEV1/FVC > 0.7 or the lower limit of normal, and FVC >80% of predicted.[7] Theoretically, a person with normal lung function can have a disease since the ‘normal’ of spirometric parameter values are ranged on a wide zone of 80–120% of their respective predicted values. The FEV1, however, is the key parameter to determine the degree of severity of obstruction and the degree of responsiveness or responsiveness to a short-acting bronchodilator, salbutamol for asthma.[4,8,9] The normal pre-bronchodilator values can offer a false sense of absence of any bronchodilator responsiveness. The statement applies to diagnosing asthma as well as finding the exact dimension of the problem of asthma with so-called normal spirometry. One needs to know the prevalence of such cases in his or her geographical area of practice.

The present manuscript deals with the frequency of normal spirometry in patients with OAD and any respiratory disease. Further, it elaborates on the prevalence of asthma, defining responsiveness (FEV1 change ≥200 mL and 12%) and high bronchodilator responsiveness (FEV1 change ≥200 mL alone) with normal pre-bronchodilator spirometry.

METHODS

This observation, approved by the Institutional Ethics Committee, included the prospective analysis of retrospective data from our research archive from March 2017 to January 2023. We decided to look for the presence of asthma-defining responsiveness (FEV1 improvement ≥200 mL and 12%)[9] and “high” bronchodilator responsiveness (high BDR). We defined the latter when the post-bronchodilator FEV1 change was ≥200 mL alone (but falling short of 12%) in the course of testing for BDR (bronchodilator responsiveness) to salbutamol.

We used the spirometry data collected for different research purposes from our archive. They were included following checking the validity and reproducibility when they were done following the ERS standard of performance.[10]

The collected data were in two sets; the first set was a record of patients where spirometry was done on clinical suspicion of obstructive airway diseases (asthma, COPD, asthma COPD overlap, unclassified). The second set was derived from a separate collection of serial patients with random spirometry being done for an indication suggesting any respiratory disease, including asthma. We accepted the definition of normal spirometry as the presence of baseline or pre-bronchodilator FEV1/FVC > 0.7 or the lower limit of normal with >80% of predicted FVC or FEV1.[7]

We looked for the presence of normal spirometry first in the two previously mentioned groups and then looked for the presence of ‘high-BDR’ and ‘asthma-defining BDR’ in them. The results are expressed in percentage value.

RESULTS

There were 1019 and 3060 entries in set-1 and set-2, respectively. Figure 1 elaborates the information about the number and percentage of ‘normal’ spirometry in them along with ‘high BDR’ and ‘asthma-defining BDR’ in those ‘normal’ population. The exercise revealed [Figure 2] that 2.06% of OADs and 1.3% of patients with any respiratory symptoms have asthma with normal spirometry.

Figure 1.

Elaborates the distribution of normal spirometry and subsequently the different degrees of BDR in a group of patients with clinical suspicion of OAD (obstructive airway diseases) and another symptomatic group with different respiratory diseases, including OAD

Figure 2.

Showing the distribution of different frequencies of patients with normal spirometry and the prevalence of different degree of responsiveness in the two sets of patients (known OADs on left side and all symptomatic respiratory patients on the right side)

DISCUSSION

The revelations are interesting. Roughly, 12% (11.87%) of the patients with suspected obstructive airway diseases had normal spirometry. Amongst them, 24.7% (n = 30) and 17.35% (n = 21) patients had 200 mL or 200 mL plus 12% FEV1 responsiveness. Thus, it makes the prevalence of asthma with normal lung function OAD as 2.06% (21/1019) and high BDR [200 mL but <12%] as 0.88% [9 (30–21) out of 1019]. Similarly, when all the spirometry reports with different diseases were considered, 27.71% (848/3060) had normal spirometry out of which 4.7% (n = 40) had asthma and 21.3% (n = 64) had the high absolute responsiveness (200 mL) but not asthma.

The results lead to several inferences that a) a good number of symptomatic patients having a diagnosis of OAD (historically and on previous investigations) can have normal lung function, b) a formidable bulk (27.71%) of all the respiratory patients have normal spirometry. Moreover, relatively small segments of patients (both suspected OAD and all respiratory problems) display a high BDR or asthma-defining responsiveness.

The observation provides two lessons to discuss. The first being that the post-bronchodilator spirometry is necessary in all patients with respiratory symptoms, irrespective of the diagnosis. The other lesson goes that those symptoms of asthma can happen even with normal pre-bronchodilator spirometry. It seems possible that normal spirometry with asthma could be a separate clinical phenotype, and it needs attention for further elaboration.

There is another important issue: what about those with >200 mL of responsiveness that falls short of 12% change (the high BDR phenotype)? These patients have relatively good lung function. Although they are asymptomatic and the BDR is not asthma-defining, the high BDR of 200 mL should be taken seriously in these patients for the very presence of symptoms, possibly mandating a therapeutic intervention. This is justified when 100 mL of FEV1 responsiveness is regarded as the minimal clinically significant value of bronchodilation in COPD[11]; suggesting that an improvement of the same volume on medication can allow an appreciation of a perceptible freedom or improvement of symptoms. While the severity of obstruction does not reflect the symptoms and the functionality adequately,[12] there is no reason to withhold low-dose inhaled corticosteroids (ICS) and long-acting β2 agonists in such patients. Similar findings have been observed and elaborated in several clinical trials,[13] and the EPR -3 (expert panel report 3) has recognized it, mentioning an FEV1 >80% predicted for mild persistent asthma.[9] Incidentally, there is no direction in the present guidelines and literatures with such situations where the issue of responsiveness in understanding the OAD seems relatively ignored. A term called PRISm (preserved ratio impaired spirometry) included subjects with reduced FEV1 or FVC with a normal (>0.70) FEV1/FVC.[14] The PRISm has actually amalgamated the erstwhile ‘nonspecific’[15] of ‘unclassified’[16] spirometric abnormalities. The condition (PRISm) has been discussed under ‘obstructive’ and ‘restrictive’ types, and a history of asthma and smoking was found to be related to obstructive PRISm.[17] Incidentally, there is another term, ‘Pre-COPD’, that deals with the risk of future development of COPD, where with normal ratio of FVE1/FVC, people look for >5% emphysema or bronchial wall thickening in CT chest and reduction of diffusion capacity as <80% of predicted value.[18] Ironically, despite so much of noise on spirometry related determination of relatively subtle abnormalities, another spirometric determinant of obstruction, the FEV1 responsiveness, has seemingly been overlooked.

In our population, in both sets, all the patients were essentially symptomatic. Asthma can persist without symptoms and turn symptomatic only on exposure to triggers (exposure to allergens, cold air, irritants, respiratory infection, and exercise). Often, the patients ignore the symptoms, and spirometry may remain undone in them most of the time. Therefore, one should keep a low threshold to suspect asthma and perform spirometry in real world practice. Beyond this, asthma cannot be excluded even if a patient has normal spirometry at a point in time.[19] Hence, repeat spirometry at the symptomatic stage or bronchoprovocation test is important in such cases.[19,20,21] Repeat spirometry may show high FEV1 responsiveness simply as a part of variability that is a known characteristic of the asthma behavior.[21,22] On the other hand, asthma can stay quiet or symptomatic without responsiveness.[19]

There are limitations in our efforts; we have not included the risk factors, demographic, clinical (symptomatology) data, and there is no repeat spirometry or longitudinal observation. It appears prudent to us to include the FEV1 responsiveness in the process of understanding and classification of obstructive airway diseases. We are not sure of the presence of glycopyrronium responsiveness (GPR) in such patients; the phenomenon has been quite prevalent in our experience.[23] A concomitant measurement of airway inflammation with Th2 markers as FeNO (fractional exhaled nitric oxide) would have been an interesting and useful adjunct in supporting the concept of treating these patients with inhaled corticosteroid and long acting β2-agonist combination. A concomitantly performed impulse oscillometry would have been revealing.

CONCLUSION

In a suspected case of OAD, spirometric exercise should include the BDR as it can unearth a good number of people with asthma, defining bronchodilator responsiveness (BDR), and subjects with high BDR. BDR appears to be an important parameter to appreciate OAD. Such exercise is important from the perspectives of possible prevention of loss of lung function and development of florid OAD and OAD-related complications on long term. A low threshold for performing spirometry with BDR should be a global policy for detection and care of obstructive airway diseases.

Abbreviations

• ADR: Asthma-defining responsiveness

• BDR: Bronchodilator responsiveness

• FEV1: Forced vital capacity in the first second

• OAD: Obstructive airway disease

• Pre-BD: Pre-bronchodilator

Conflicts of interest

There are no conflicts of interest to declare.

Funding Statement

Nil.