Paradoxical bronchodilator-induced airway response (PBDR) is defined as the unexpected constriction of smooth muscle-lined walls of the bronchi in response to a bronchodilator. The paradox is caused by a discrepancy between the anticipated bronchodilation and the observed bronchoconstriction of the airway. Various β-agonists and other bronchodilators are associated with this adverse event.1 For instance, in a double-blind multicenter study involving 11,850 patients with asthma, 1.1% of participants exhibited a PBDR. The risk of experiencing this adverse event rose with increasing age, and lower peak expiratory flow.1 While the condition is intriguing due to its paradoxical nature and unknown biologic mechanisms, its association with asthma severity and exacerbations remains to be determined. The COPDGene® study noted that PBDR recorded during spirometry was associated with significantly worse respiratory outcomes, including greater frequency of Chronic Obstructive Pulmonary Disease (COPD) exacerbations, exercise intolerance, and dyspnea.2 Here, we test the hypothesis that asthmatics with PBDR are at increased risk for asthma exacerbations.
We analyzed data from electronic health records of 24,501 asthmatics treated at Cleveland Clinic Health System (CCHS) from 2010 through 2021. Patients with asthma (International Classification of Diseases (ICD), 9th Revision, codes: 493.XX and 10th Revision, codes: J45.XX) were included if they received asthma medications for ≥6 months and had spirometry with post-bronchodilator (post-BD) measurements. Patients younger than 18 years of age and those with a concurrent diagnosis of COPD (ICD-9 codes: 491.XX, 492.XX, 496.XX, and 506.XX, and ICD-10 codes: J41.XX-J44.XX and J68.XX) were excluded. A PBDR was defined as a post-BD change in percent of predicted forced expiratory volume in 1 second (FEV1%) below the 5th percentile limit of the healthy population (i.e. >4% drop in FEV1%).3 A positive bronchodilator response (BDR) is defined by a post-BD change in FEV1% ≥12% according to the American Thoracic Society (ATS) guidelines. A non-significant BD response represent a group of patients who failed to achieve this ATS threshold. An asthma exacerbation was defined by the need for short-term oral corticosteroid therapy that lasted <28 days with the indication for prednisone use specifically attributed to asthma.
To replicate our results, we used well-characterized data from the National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) I&II. Designed to study severe asthma (SA), SARP I&II recruited 1,131 participants with asthma (40% SA), age >18 years from nine sites across the United States and one site in the United Kingdom.4 In SARP, an asthma exacerbation was defined by the need of oral corticosteroid burst, specifically for asthma, lasting for more than 3 days. In addition, baseline lung function and reversibility testing were not performed for up to 30 days after an exacerbation.4
Of the 24,501 patients from the CCHS cohort who met inclusion criteria, 1,113 (4.5%) had a paradoxical drop in FEV1% of >4% (i.e. 5th percentile).3 Patients with PBDR had lower post-BD forced vital capacity (FVC), blood absolute eosinophil counts (AEC) and Immunoglobulin E (IgE) levels (Table 1). Using multivariable logistic regression (adjusted for age, sex, race, and BMI), patients with PBDR were at increased risk of asthma exacerbations (adjusted OR [95% CI] of 1.22 [1.06; 1.40] for having ≥1 exacerbations/patient-year and 1.26 [1.01;1.55] for ≥2 exacerbations/patient-year).
Table 1:
Demographics and clinical characteristics of patients from Cleveland Clinic Health System (CCHS) stratified by the type of response of FEV1 (%) post-bronchodilator therapy.
| Asthma Cohort | Cleveland Clinic Health System (CCHS) (N=24,501) | |||
|---|---|---|---|---|
| Maximum Response to Bronchodilator | Paradoxical* | Non-significant§ | Positive¶ | p-value |
| n (%) | 1,113 (4.5%) | 19,118 (78.0%) | 4,270 (17.5%) | |
| Age (years)† | 60.3 [42.6, 72.1] | 58.1 [42.4, 70.2] | 59.5 [43.0, 71.9] | <0.001 |
| Female Sex | 765 (68.7) | 13,071 (68.4) | 2,643 (61.9) | <0.001 |
| Race | <0.001 | |||
| Non-Hispanic White | 803 (72.1) | 14,526 (76.0) | 3,015 (70.6) | |
| Non-Hispanic Black | 230 (20.7) | 3,283 (17.2) | 956 (22.4) | |
| Body Mass Index (kg/m2) | 30.5 [25.2, 36.5] | 29.8 [25.4, 35.7] | 29.6 [25.1, 35.2] | 0.013 |
| Never Smoker | 659 (59.2) | 11,425 (59.8) | 2,358 (55.2) | <0.001 |
| Blood AEC (x103/μL)† | 0.16 [0.09, 0.28] | 0.17 [0.10, 0.30] | 0.19 [0.11, 0.34] | <0.001 |
| Immunoglobulin E (IU/mL)† | 56.9 [19.3, 325.5] | 98.2 [26.8, 491.5] | 162.5 [55.4, 838.8] | 0.032 |
| Pre-BD FEV1 %† | 84.0 [68.0, 97.0] | 89.0 [76.0, 100.0] | 71.0 [59.0, 82.0] | <0.001 |
| Post-BD FEV1 %† | 77.0 [62.0, 90.0] | 92.0 [80.0, 104.0] | 84.0 [70.0, 96.0] | <0.001 |
| Pre-BD FVC %† | 89.0 [75.0, 101.0] | 95.0 [83.0, 106.0] | 86.0 [74.0, 99.0] | <0.001 |
| Post-BD FVC %† | 83.0 [70.0, 97.0] | 96.0 [84.0, 107.0] | 94.0 [81.0, 105.0] | <0.001 |
| Pre-BD FEV1/FVC Ratio† | 0.78 [0.68, 0.84] | 0.75 [0.68, 0.81] | 0.66 [0.59, 0.72] | <0.001 |
| Post-BD FEV1/FVC Ratio† | 0.76 [0.66, 0.83] | 0.78 [0.71, 0.84] | 0.72 [0.64, 0.79] | <0.001 |
| Total Lung Capacity (%)† | 87.0 [76.0, 97.0] | 91.0 [80.0, 102.0] | 93.0 [81.0, 105.0] | <0.001 |
| Residual Volume (%)† | 90.5 [74.0, 115.0] | 90.0 [74.0, 111.0] | 111.0 [90.0, 134.3] | <0.001 |
| RV/TLC Ratio† | 106.4 [90.8, 128.8] | 101.3 [87.7, 116.5] | 120.8 [104.3, 138.6] | <0.001 |
| High Dose iCS | 366 (32.9) | 5,600 (29.3) | 1,289 (30.2) | 0.026 |
| iCS-LABA | 764 (68.6) | 12,981 (67.9) | 2,854 (66.8) | 0.329 |
| oCS bursts | 0.51 [0.17, 1.11] | 0.45 [0.13, 0.97] | 0.42 [0.11, 0.96] | 0.001 |
Data are presented as n (%) for categorical variables and median [interquartile range] for continuous variables. FEV1 % stands for percent of predicted forced expiratory volume in 1 second, AEC for Absolute Eosinophil Counts, BD for bronchodilators, FVC for forced vital capacity, RV for residual volume, and TLC for total lung capacity, iCS for inhaled corticosteroids, LABA for long-acting beta-agonists, and oCS for oral corticosteroids.
A Paradoxical bronchodilator response (PBDR) is defined by a post-BD change in FEV1 (%) below the 5th percentile limit of a healthy population (i.e. >4% drop in FEV1 after bronchodilator).
A maximum bronchodilator response that does not exceed 11% in FEV1 % or 200 ml in FEV1.
A Positive bronchodilator response (BDR) is defined by a post-bronchodilator change in FEV1 % ≥ 12% according to the ATS definition cut-off.
Using pairwise Wilcoxon test comparisons, Patients with positive BDR and PBDR were older than those with non-significant BDR (p <0.05). Patients with positive BDR had higher IgE levels and RV than those with PBDR and non-significant BDR (p <0.05). Blood AEC, Pre-BD FEV1%, Post-BD FEV1%, Pre-BD FVC%, Post-BD FVC%, pre-BD FEV1/FVC ratio, post-BD FEV1/FVC ratio, TLC, and RV/TLC ratio differed between all groups (p <0.05).
Exacerbations requiring oCS are presented as the number of oCS bursts /patient-year in the CCHS cohort.
In SARP I&II, 23 (2%) participants demonstrated a PBDR. They had lower percent sputum eosinophils (median [IQR]: 0.40 [0.30, 3.30]), compared to patients with non-significant BDR (median [IQR]: 0.80 [0.20, 3.50]) and those with a positive BDR (median [IQR]: 1.80 [0.50, 7.60]). PBDR was also associated with lower post-BD FVC and scores on asthma quality of life questionnaire (AQLQ) (Table 2). Multivariable logistic regression demonstrated higher odds of asthma exacerbation when comparing 93 those with PBDR (adjusted OR [95% CI]: 2.41 [1.02; 5.99]) and those with a positive BDR (adjusted OR [95% CI]: 1.40 [1.07; 1.84]) to those with a non-significant BDR.
Table 2:
Demographics and clinical characteristics of patients from Severe Asthma Research Program (SAP) I&II stratified by the type of response of FEV1 (%) post-bronchodilator therapy.
| Asthma Cohort | Severe Asthma Research Program (SARP) I&II (N=1,131) | |||
|---|---|---|---|---|
| Response to Bronchodilator | Paradoxical* | Non-significant§ | Positive¶ | p-value |
| n (%) | 23 (2.0%) | 781 (69.1%) | 327 (28.9%) | |
| Age (years) | 32.3 [25.5, 43.2] | 37.5 [26.9, 48.3] | 37.3 [24.8, 48.2] | 0.22 |
| Female Sex | 17 (73.9) | 532 (68.1) | 194 (59.3) | 0.014 |
| Race | 0.527 | |||
| Non-Hispanic White | 15 (65.2) | 525 (67.2) | 201 (61.5) | |
| Non-Hispanic Black | 8 (34.8) | 195 (25.0) | 105 (32.1) | |
| Body Mass Index (kg/m2) | 29.7 [23.9, 37.9] | 28.1 [23.8, 34.6] | 28.2 [24.3, 34.0] | 0.804 |
| Asthma Duration (years) | 16.4 [5.0, 24.4] | 21.5 [12.0, 32.4] | 20.6 [13.5, 29.6] | 0.106 |
| Never Smoker | 6 (69.6) | 632 (80.9) | 253 (77.4) | 0.201 |
| Blood AEC (x103/μL)† | 0.20 [0.10, 0.30] | 0.20 [0.10, 0.30] | 0.30 [0.10, 0.40] | 0.001 |
| Sputum eosinophils (%)† | 0.40 [0.30, 3.30] | 0.80 [0.20, 3.50] | 1.80 [0.50, 7.60] | 0.001 |
| Immunoglobulin E (IU/mL)† | 119.0 [54.5, 206.5] | 120.5 [42.0, 310.3] | 172.0 [62.0, 394.0] | 0.014 |
| FeNO (ppb)† | 25.0 [18.0, 34.2] | 24.6 [14.8, 42.9] | 37.8 [18.5, 73.2] | <0.001 |
| Number of positive skin tests† | 3.0 [1.8, 6.3] | 3.0 [1.8, 6.0] | 4.0 [2.0, 7.0] | 0.015 |
| Pre-BD FEV1 %† | 93.0 [74.0, 102.0] | 82.0 [66.0, 95.0] | 69.0 [54.5, 81.0] | <0.001 |
| Post-BD FEV1 % | 79.0 [67.0, 95.0] | 88.0 [74.0, 100.0] | 88.0 [75.0, 99.0] | 0.154 |
| Pre-BD FVC %† | 92.8 [79.3, 100.7] | 90.3 [77.5, 101.6] | 85.6 [72.8, 96.9] | 0.001 |
| Post-BD FVC %† | 82.5 [72.6, 91.0] | 92.0 [80.3, 102.4] | 96.9 [87.7, 106.8] | <0.001 |
| Pre-BD FEV1/FVC Ratio† | 0.81 [0.72, 0.86] | 0.75 [0.66, 0.81] | 0.66 [0.58, 0.73] | <0.001 |
| Post-BD FEV1/FVC Ratio† | 0.82 [0.72, 0.87] | 0.78 [0.70, 0.84] | 0.73 [0.66, 0.80] | <0.001 |
| PC20† | 1.21 [0.78, 2.88] | 1.48 [0.51, 4.72] | 0.58 [0.26, 1.56] | <0.001 |
| Total Lung Capacity (%) | 99.4 [92.1, 107.1] | 100.9 [91.3, 111.5] | 105.1 [93.4, 115.0] | 0.122 |
| Residual Volume (%)† | 101.3 [94.9, 110.6] | 112.4 [95.3, 141.1] | 131.9 [106.1, 165.0] | <0.001 |
| RV/TLC Ratio† | 115.4 [97.4, 120.4] | 114.1 [97.7, 136.4] | 129.5 [110.0, 149.8] | <0.001 |
| High Dose iCS | 9 (39.1) | 302 (38.7) | 154 (47.1) | 0.033 |
| iCS-LABA | 13 (59.1) | 496 (63.7) | 193 (59.4) | 0.387 |
| Total AQLQ | 3.8 [2.7, 5.0] | 4.8 [3.7, 5.7] | 4.4 [3.4, 5.4] | <0.001 |
| oCS bursts ‡ | 14 (60.9) | 333 (42.6) | 160 (48.9) | 0.047 |
Data are presented as n (%) for categorical variables and median [interquartile range] for continuous variables. FEV1 % stands for percent of predicted forced expiratory volume in 1 second, AEC for Absolute Eosinophil Counts, FeNO for fractional exhaled nitric oxide, ppb for particles per billion, BD for bronchodilators, FVC for forced vital capacity, PC20 for provocative concentration of methacholine that cause 20% fall in FEV1 %, RV for residual volume, and TLC for total lung capacity, iCS for inhaled corticosteroids, LABA for long-acting beta-agonists, and oCS for oral corticosteroids.
A Paradoxical bronchodilator response (PBDR) is defined by a post-BD in FEV1 (%) below the 5th percentile limit of a healthy population (i.e. > 4% drop in FEV1(%) after bronchodilator).
A maximum bronchodilator response that does not exceed 11% in FEV1 % or 200 ml in FEV1.
A Positive bronchodilator response (BDR) is defined by a post-bronchodilator change in FEV1 % ≥ 12% according to the ATS definition cut-off.
Using pairwise Wilcoxon test comparisons, Blood AEC, sputum eosinophils (%), blood IgE levels, the number of positive skin tests, FeNO, RV, and RV/TLC ratio were higher in patients with positive BDR vs. those with and non-significant BDR (p <0.05). Pre-BD FVC% was lower in higher in patients with positive BDR vs. those with and non-significant BDR (p <0.05). Pre-BD FEV1% and PC20 is lower in patients with positive BDR vs. those with PBDR (p <0.05), and non-significant BDR (p <0.05). Post-BD FVC%, pre-BD FEV1/FVC ratio, post-BD FEV1/FVC ratio differed between all groups (p <0.05).
Exacerbations requiring oCS are presented as the presence or absence of exacerbations in the year prior to enrollment in SARP I&II.
To the best of our knowledge, this is the first study assessing the incidence, characteristics, and exacerbation risk in asthmatic patients with PBDR in a real-world clinical setting. The incidence of PBDR in the CCHS cohort was similar to previously published studies on COPD and asthma,2,5 but higher than the 2.0% and 1.1% prevalence in SARP I&II and a study in the United Kingdom respectively.4
In these the two cohorts, patients with PBDR had a greater likelihood of adverse respiratory outcomes and have low AQLQ. However, they are at risk of being misclassified as not having asthma because they have baseline normal FEV1%, normal FEV1/FVC, and do not demonstrate a bronchodilator response (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org). Yet, SARP data show they are hyper-responsive on methacholine challenge (PC20 median [IQR]: 1.21 [0.78, 2.88]) which is consistent with the diagnosis of symptomatic asthma. Therefore, despite the apparent infrequency of PBDR, the higher risk for asthma exacerbations highlights the need for better understanding of PBDR and the mechanisms that contribute to this condition. Consistent with our findings, a study involving COPD patients revealed a notable reduction in FVC post-BD in PBDR group (%FVC change in PBDR group: −14.9 ±9.1 vs. non-PBDR: 4.6±10.3, p<0.001).2 We speculate that decreases in FVC post-BD therapy may be associated with worsening air-trapping. Unfortunately, post-BD changes in RV and RV/TLC ratio were not available to test this hypothesis.
The underlying biologic mechanisms responsible for PBDR are not well known. While patients with asthma usually respond to deep inspiration with bronchodilatation, some patients, especially those with SA, show paradoxical airflow obstruction and impaired smooth muscle relaxation during a deep inspiration, which may occur during pulmonary function testing.6,7 Although uncommon, adverse reactions causing bronchoconstriction can occur after the use of metered-dose inhalers, and might be caused by one of its inert constituents.1 It is also possible that genetic variations in the Adrenoreceptor Beta 2 (ADBR2) gene may cause paradoxical bronchoconstriction in the setting of frequent usage of short-acting bronchodilators.8 Additionally, the β2-adrenergic receptor signaling may be altered by S-nitrosylation of an intracellular Cysteine residues (C265), which may results in receptor desensitization causing reduced BDR, or in other cases, it may lead to paradoxical bronchoconstriction.9 Consistent with this finding, mice with a Cys265Ser mutation are resistant to bronchoconstriction.9 Compared to positive BDR, PBDR was associated with lower IgE and blood eosinophil counts in both cohorts and lower sputum eosinophils in SARP, which is consistent with a T2-low asthma subphenotype. This suggests an association of PBDR with inflammatory mechanisms independent of allergic and eosinophilic pathways activation.4 Another possible hypothesis, PBDR could be linked to airway remodeling, which potentially leads to hyperresponsiveness to certain stimuli, including bronchodilators, and can contribute to paradoxical responses.
Our study has several limitations. Although spirometry is recommended for all asthmatics, only a small proportion of asthma patients have spirometry assessed in clinical settings (25.2% in CCHS). Bias may also have been introduced by the usage of ICD-CM codes to diagnose asthma in the CCHS cohort. Additionally, our data lacked information on the time between prednisone use and lung function and methacholine challenge test measurements. Despite these limitations, our findings from the CCHS real-world data were replicated in the well characterized NHLBI SARP I&II and support the importance of identifying bronchodilator-induced airway obstruction.
In conclusion, PBDR is uncommon in asthma but associated with an increased risk for exacerbations. Our findings highlight the need for future studies to replicate our results in separate cohorts and determine the optimal therapeutic approach for these patients in randomized control trials.
Supplementary Material
Clinical implication:
Since bronchodilator response is the major criterion for asthma diagnosis and beta agonist are a mainstay in asthma management, understanding paradoxical bronchodilator-induced airway constriction is important in asthma diagnosis, tailored management, and risk stratification.
Funding/support:
This research was funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL161674, PI: Joe Zein; 1P01HL158507, PI: Benjamin Gaston, MD)
Footnotes
Financial/nonfinancial disclosures: None declared.
Conflict of Interest: None of the authors declare any conflict of interest related to this work.
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