Intensive bronchial dilation test: A modified method for evaluating airway reversibility

Abstract

Background:

A negative bronchial dilatation test (BDT) does not fully reflect the status of airway irreversibility in patients with severe obstructive or mixed ventilation dysfunction due to severe bronchospasm, mucus blockage, or insensitivity to bronchodilators, which will directly affect the subsequent diagnosis and treatment of those patients.

Objective:

We retrospectively examined the feasibility of using the “intensive bronchial dilation test” (IBDT) for excluding false-negative BDT.

Methods:

We retrospectively analyzed the clinical data of 82 patients with severe obstructive or mixed ventilation dysfunction in the Allergy department of Yantai Yuhuangding Hospital of Qingdao University. After the BDT, they all inhaled the triple atomized drugs (2 mg salbutamol, 1 mg budesonide, and 0.25 mg ipratropium) every 20 minutes in one hour and the lung function test was performed 15 minutes later, which was named as IBDT. All patients received another lung function test after 2 to 4 weeks of regular anti-inflammatory treatment. We compared the improvement of lung function indexes and the proportion of patients with reversible airway obstruction between BDT, IBDT, and 2 to 4 weeks of treatment groups.

Results:

The lung function indexes were significantly improved after the IBDT than those after the BDT (all P values < 0.01) and the number of patients with reversible airway obstruction significantly increased from 31 to 61 after the IBDT (P < 0.001), but the proportion of patients with reversible airway obstruction after the IBDT did not differ from that of patients with reversible airway obstruction after 2 to 4 weeks of treatment. The accuracy and sensitivity of the IBDT in evaluating airway reversibility reached 91.46% and 89.71%, respectively, both of which were significantly higher than for the BDT (54.88% and 45.59%, respectively).

Conclusion:

Our finding suggests that IBDT can more accurately and rapidly evaluate airway reversibility in patients with severe obstructive or mixed ventilation dysfunction when compared to BDT.

1. Introduction

Asthma is a chronic inflammatory disease of the airways, usually starting in childhood, characterized by reversible airflow obstruction [1, 2]. Chronic obstructive pulmonary disease (COPD) is an acquired and preventable disease typically caused by tobacco smoking and featured by persistent obstruction, and it usually develops after the fourth decade of life, and it is characterized by shortness of breath, cough, and sputum production [3, 4]. There are also cases that present the features of both asthma and COPD, which is known as asthma-COPD overlap (ACO) [5, 6]. Differential diagnosis of asthma, COPD, and ACO, the key to determining appropriate medical therapy, is based on a combination of history, physical examination, and confirmation of the presence of airflow reversibility using lung function test [7–9].

The bronchial dilation test (BDT) can usually be used to evaluate the reversibility of airflow [10]. However, some patients with severe ventilation dysfunction have a negative BDT. Sometimes, a single administration of bronchodilation drugs is insufficient to effectively dilate the bronchi because it is difficult for those drugs to reach their site of action in extremely narrow airways [11], and this is one of the most common reasons for a false-negative BDT. Some patients with severe ventilation dysfunction who have a negative BDT may show airway reversibility after 2 to 4 weeks of treatment with anti-inflammatory drugs, which can easily mislead doctors into making inappropriate diagnosis and treatment plans for those patients because of the negative BDT at the first visit. Therefore, it is important to have a method for excluding false-negative BDT rapidly in these patients so that appropriate treatment can be developed.

Global Initiative for Asthma (GINA) guidelines state that asthma exacerbation can be treated with bronchodilation drugs administered 3 times in a row within the first hour of an acute attack of asthma [12]. This is because those drugs can effectively relieve dyspnea by inducing continuous dilation of the constricted bronchus. Based on that guideline, we hypothesized that the illusion of airway irreversibility could be eliminated if the airway could be effectively dilated by bronchodilation drugs administered 3 times within an hour to patients with severe airway obstruction who had a negative BDT. Accordingly, we for the first time proposed the concept of an “intensive bronchial dilation test” (IBDT) for evaluating airway reversibility, which is the process of giving a lung function test after administering 3 cycles of 1 mg salbutamol, 1 mg budesonide, and 0.125 mg ipratropium nebulization within 1 hour. In this study, we retrospectively examined the feasibility of using the IBDT for excluding false-negative BDT rapidly in patients with severe obstructive or mixed lung dysfunction.

2. Methods

2.1. Study design

This is a self pre-post control group design. We retrospectively analyzed the clinical data of 82 patients with severe obstructive or mixed ventilation dysfunction who had primary symptoms of wheezing, chest tightness, or dyspnea patients in the Allergy department of Yantai Yuhuangding Hospital of Qingdao University from January 2018 to August 2021 (Table 1). A percentage of predicted value of the forced expiratory volume (FEV) in the first second (FEV₁ % predicted) < 50% was evaluated as severe obstructive or mixed ventilation dysfunction [13]. Since atomized drugs do not improve lung function in patients with restrictive ventilatory dysfunction, the patients with restricted ventilatory dysfunction were excluded. Patients with nonreversible airway obstruction, patients who are allergic to aerosolized drugs, patients with severe cardiac insufficiency, patients who were unable to tolerate the lung function test, and other patients who are not suitable for lung function tests are excluded. They all inhaled the triple atomized drugs (2 mg salbutamol, 1 mg budesonide, and 0.25 mg ipratropium) every 20 minutes in 1 hour and the lung function test was performed 15 minutes later. All patients received another lung function test after 2 to 4 weeks of regular anti-inflammatory treatment (salmeterol xinafoate and fluticasone propionate inhalation aerosol or budesonide and formoterol fumarate powder for inhalation). Asthma and ACO were diagnosed according to GINA guidelines [12]. COPD was diagnosed according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [14]. The study protocol was approved by Gao ZL, the Ethics Committee of Yantai Yuhuangding Hospital of Qingdao University, on November 10, 2021 (Approval NO. 2021-319). The researchers remained blinded in terms of intervention methods when they collected all relevant data. An a priori sample size calculation was performed. The sensitivity of IBDT in the diagnosis of airway reversibility was estimated to be 81.82%, the specificity was 93.75%, the tolerance error was 10%, and the confidence 1-α=0.95, we calculated a sample size of 66 patients and 33 patients, respectively.

Table 1.

Clinical characteristics of 82 patients with severe obstructive or mixed lung dysfunction

Variables	Cases (n)	Percentage (%)
Sex
Male	54	65.85
Female	28	34.15
Smoking	38	46.34
Positive skin prick test*	34	50.75
Diagnosis
Asthma	32	39.02
COPD	10	12.20
Asthma-COPD overlap	40	48.78

COPD, chronic obstructive pulmonary disease.

^*67 of 82 patients underwent a skin prick test.

2.2. Lung function test

The process of BDT was that the patients inhaled 2 mg salbutamol, 1 mg budesonide, and 0.25 mg ipratropium after the lung function test, and the lung function test was performed 15 minutes later. The process of IBDT was that the triple atomized drugs were inhaled every 20 minutes in 1 hour and the lung function test was performed 15 minutes later. The percentage of predicted value of the FEV in the first second (FEV1% pre), percentage of predicted value of the ratio of FEV1/FVC (FEV1/FVC% pre), percentage of predicted value of peak expiratory flow (PEF% pre), percentage of predicted value of maximal mid-expiratory flow (MMEF% pre), percentage of predicted value of MMEF mid-expiratory flow (MEF% pre) values were analyzed. A positive BDT was defined as follows: FEV1% pre was increased by 12% and the increase in absolute value was ≥200 mL after inhalation of a β2 agonist medication when compared with its value before medication [12]. A positive IBDT was defined as follows: FEV1% pre was increased by 12% and the increase in absolute value was ≥200 mL after applying the triple atomization drug 3 times in 1 hour when compared with its value before medication. Pre-post differences of the lung function indexes and the proportion of these same patients with reversible airway obstruction after BDT, IBDT, and 2 to 4 weeks of treatment were compared, respectively.

2.3. Statistical analysis

All statistical calculations were performed using GraphPad Prism 7. Measurement data were presented as mean ± SD. The Wilcoxon signed-rank test was used for comparing paired data for each patient. Categorical variables were analyzed using the chi-square test. Values of P < 0.05 were considered to be significant.

3. Results

3.1. Side effects of IBDT

The doctors monitored the patients’ heart rate during the process. If the patients’ heart rate increased after atomization, accompanied by flustered feeling and shaking, the doctors would reduce the dose of albuterol, or even abandon it, and the dose of budesonide and ipratropium did not change. No adverse reactions such as tachycardia, tremor, urine retention, and nausea occurred during the entire BDT and IBDT process.

3.2. Improvement of lung function after atomization treatment

We analyzed the lung function indexes (e.g., FEV1% pre, FEV1/FVC% pre, PEF% pre, MEF50% pre, MEF25% pre, and MMEF% pre) of baseline, BDT, IBDT and 2 to 4 weeks of treatment groups. The indexes of lung function were improved significantly after BDT, IBDT, and 2 to 4 weeks of treatment compared with the baseline. In addition, lung function indexes were significantly improved after the IBDT than those after the BDT (all P values < 0.01) (Table 2).

Table 2.

Comparison of lung function indicators in 82 patients with severe obstructive or mixed lung dysfunction

Lung function indexes median (interquartile range), % predicted	Baseline	BDT	IBDT	2 to 4 weeks of treatment	BDT vs baseline P value	IBDT vs baseline P value	2 to 4 weeks of treatment vs baseline P value	IBDT vs BDT P value
FEV1	34.00 (28.75–42.25)	39.00 (32.00–51.00)	46.00 (32.00–55.00)	56.00 (43.25–62.00)	<0.001	<0.001	<0.001	<0.001
FEV1/FVC%	61.00 (56.00–66.00)	60.00 (54.00–65.25)	63.00 (58.00–72.00)	64.00 (58.50–81.00)	0.215	<0.001	<0.001	<0.001
PEF	39.00 (27.75–50.25)	44.00 (32.25–52.00)	49.00 (38.75–57.75)	57.00 (42.75–77.00)	<0.001	<0.001	<0.001	<0.001
MEF50%	15.00 (11.00–17.25)	17.00 (12.75–22.25)	19.00 (14.00–24.25)	22.00 (15.75–29.00)	<0.001	<0.001	<0.001	<0.001
MEF25%	20.00 (16.00–25.25)	21.00 (17.75–25.25)	23.00 (20.75–28.75)	29.00 (22.75–35.00)	0.003	<0.001	<0.001	<0.001
MMEF	17.00 (13.75–20.00)	18.00 (14.75–23.00)	21.00 (17.00–29.00)	25.00 (19.00–36.00)	<0.001	<0.001	<0.001	<0.001

BDT, bronchial dilation test; IBDT, intensive bronchial dilation test; MEF, mid-expiratory flow; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

3.3. The accuracy and sensitivity of the IBDT in evaluating airway reversibility

To further verify that the IBDT is a valid method for excluding false-negative BDT, we compared the proportion of patients with reversible airway obstruction between BDT, IBDT, and 2 to 4 weeks of treatment. We found that the number of patients with reversible airway obstruction significantly increased from 31 to 61 after the IBDT (P < 0.001), but the proportion of patients with reversible airway obstruction after the IBDT did not differ from that of patients with reversible airway obstruction after 2 to 4 weeks of treatment (Table 3). The accuracy and sensitivity of the IBDT in evaluating airway reversibility reached 91.46% and 89.71%, respectively, both of which were significantly higher than for the BDT (54.88% and 45.59%, respectively; both P < 0.001).

Table 3.

Evaluation of airway reversibility in 82 patients with severe obstructive or mixed lung dysfunction

	BDT*	IBDT	2 to 4 weeks of treatment	χ2	P value
Reversible airflow obstruction	31	61	68	41.44	<0.001
Nonreversible airflow obstruction	51	21	14

BDT, bronchial dilation test; IBDT, intensive bronchial dilation test.

^*P < 0.001 for BDT vs. the other two groups.

4. Discussion

Asthma and COPD are chronic airway inflammatory diseases and lead to a major public health problem [15, 16]. Severe acute asthma and COPD are medical emergencies that require immediate recognition and treatment [17]. The diagnosis of COPD, asthma, and ACO initially requires an evaluation of exposure to respiratory risk factors, identification of the type and pattern of respiratory symptoms, and spirometry with a BDT [18]. The BDT can be used to test the reversibility of airflow, but false-negative BDT sometimes affects the diagnosis of asthma, COPD, and ACO [19]. Compared with previous studies, our study focused on the application of IBDT (a modified BDT) in patients with severe obstructive or mixed ventilatory dysfunction. According to GINA guidelines, a variable expiratory airflow restriction exists if the FEV1% predicted value increases by >12% and 200 mL from baseline after 2 to 4 weeks of anti-inflammatory treatment. We used that criterion and found that the IBDT was as accurate for excluding false-negative BDT as the lung function assessment after 2 to 4 weeks of administering anti-inflammatory drugs, and IBDT could more rapidly exclude false-negative BDT when compared to lung function test after 2 to 4 weeks of anti-inflammatory therapy. The number of patients with reversible airway obstruction increased from 31 to 61 after IBDT, therefore, IBDT played a stronger role in evaluating airway reversibility in patients with severe obstructive or mixed ventilatory dysfunction when compared to BDT.

The inhalation pattern of the inhaled drugs (e.g., breath-hold time, flow, and volume), airflow obstruction, and the severity and type of lung disease are factors that influence aerosol deposition in the lung, which affects the amount of drug available for distal distribution into the obstructed area and thus affects clinical outcomes [20]. Many lung function departments use larger doses of bronchodilation drugs once to ensure the accuracy of BDT, but it is still difficult for those drugs to reach their site of action in extremely narrow airways all at once, and adverse reactions caused by aerosolized drugs may occur. In some patients with acute and severe dyspnea, the BDT was negative due to the airway spasm and the obstruction of the airway by secretions in the narrow airway, and a single inhalation of β2-agonist cannot identify the reversibility of airflow limitation well. In our study, patients with severe obstructive dyspnea and severe mixed dyspnea were treated with triple therapy every 20 minutes, and their symptoms and lung function improved significantly after 3 consecutive inhalations. Frequent administration of bronchodilators is thought to dilate the proximal bronchial tree, allowing the subsequent bronchial dilatings to further deposit in the distal bronchial tree, resulting in a continuous bronchial dilatation and preventing the bronchial rebound [21, 22].

Triple therapy improved disease control, especially nocturnal symptoms, faster than dual therapy in patients with moderate-to-severe asthma [23]. International guidelines recommend medium- or high-dose inhaled corticosteroids, inhaled β2-agonists, and long-acting muscarinic antagonists combinations as the preferred controller options for patients with moderate-to-severe asthma [24, 25]. At the same time, the concurrent aerosol inhalation of salbutamol, ipratropium bromide, and budesonide produces a strong synergistic effect on reducing airway inflammation and dilating bronchi. Salbutamol can enhance hormone receptor sensitivity, and budesonide can promote the synthesis of β2 receptors on the airway cell membrane [26]. Ipratropium combined with salbutamol can induce a greater effect of bronchodilatation and further improve lung function compared to salbutamol alone for these patients who have a poor response to short-acting β2 agonists [27]. Our previous study showed that concurrent aerosol inhalation of salbutamol, ipratropium bromide, and budesonide could improve pulmonary dysfunction of different severity rapidly and effectively [28]. In the present study, the modified method of aerosol inhalation not only significantly improved lung function but also provided rapid relief of chest tightness and dyspnea in patients with severe obstructive or mixed ventilation dysfunction.

In summary, the IBDT provides a new method of excluding false airway irreversibility for patients with severe obstructive or mixed ventilation dysfunction, as it might help the physician to make an early diagnosis and treatment of asthma and COPD. This was a small pilot study only including 82 patients. Additional randomized controlled trials with larger sample sizes need to be conducted to verify the clinical safety and efficacy of the IBDT.

Acknowledgment

The authors thank all patients who participated in this study, as well as staff members in the Departments of Allergy.

Financial support

The research was supported by the National Natural Science Foundation of China (82271146 and 82271147) and the Major Scientific and Technological Innovation Project of Shandong Province (2020CXGC011302 and 2022CXGC020506).

Conflicts of interest

The authors have no conflicts of interest.

Author contributions

All authors contributed to the study conception and design. Material preparation was performed by Yujuan Yang, Yu Zhang, Ningbo Tang and Yuemei Sun. Data collection and analysis were performed by Yujuan Yang, Yu Zhang, Yuemei Sun, Liping Liu, Jianwei Wang, Pengyi Yu, Jiayu Cao, Ningbo Tang. Critical revision of the article for important intellectual content: Xicheng Song and Ningbo Tang. All authors read and approved the final manuscript.