Novel predictive factors for patient discomfort and severe cough during bronchoscopy: A prospective questionnaire analysis.

During bronchoscopy, discomfort is mainly caused by an unavoidable cough; however, there are no reports of any predictive factors for strong cough during bronchoscopy identified before the procedure. To clarify the factors underlying the discomfort status and predictive factors for strong cough during bronchoscopy, we prospectively evaluated patients who underwent bronchoscopy at Kyorin University Hospital between March 2018 and July 2019. Before and after bronchoscopy, the enrolled patients answered a questionnaire regarding the procedure. At the same time, bronchoscopists evaluated cough severity using a four-grade cough scale. We evaluated patient characteristics and predictive factors associated with bronchoscopy from the perspective of discomfort and strong cough. A total of 172 patients were ultimately enrolled in this study. On multivariate logistic regression analysis, comparison of the subjective data between the discomfort and comfort groups revealed that factors that were more common in the former group were younger age (OR = 0.96, p = 0.002), less experienced bronchoscopist (OR = 2.08, p = 0.047), and elevation of cough score per 1 point (OR = 1.69, p < 0.001). Furthermore, the predictive factors for strong cough prior to performing bronchoscopy were female sex (OR = 2.57, p = 0.009), EBUS-TBNA (OR = 2.95, p = 0.004), and prolonged examination time of more than 36 min (OR = 2.32, p = 0.022). Regarding patients' discomfort, younger age, less experienced bronchoscopist, and the elevation of cough score per 1 point were important factors for discomfort in bronchoscopy. On the other hand, female sex, EBUS-TBNA, and prolonged examination time were crucial factors for strong cough.

Introduction

Flexible bronchoscopy is a pivotal tool for diagnosing diverse respiratory diseases, such as lung cancer, idiopathic or secondary interstitial pneumonias, and infectious lung diseases. In the modern era of evolutionarily developed personalized medicine for the management of lung cancer, it is mandatory to perform tissue biopsy and next-generation sequencing [1] and examine tumor PD-L1 expression [2]. However, bronchoscopy is widely recognized as a procedure in which discomfort is mainly caused by unavoidable cough [3-4]. Furthermore, there are no reports on the predictive factors for strong cough in bronchoscopy identified before the procedure. We conducted a prospective study to clarify factors that affect patients’ discomfort and cough severity during bronchoscopy using a questionnaire before and after performing the procedure.

Aim

To clarify the factors leading to discomfort and to determine the predictive factors for the occurrence of strong cough during bronchoscopy.

Materials and methods

Patients

We prospectively studied consecutive patients who underwent bronchoscopy at Kyorin University Hospital (a 1,100-bed tertiary center in Tokyo) in both inpatient and outpatient settings from March 2018 to July 2019. We enrolled adult patients aged over 18 years with no cognitive disorders who provided written informed consent.

Questionnaire and cough scores

Evaluation of comfort or discomfort based on the questionnaire after bronchoscopy

We administered questionnaires before and after bronchoscopy. The first questionnaire was administered before bronchoscopy (Table 1). The severity of anxiety was evaluated using a visual analog scale (VAS) ranging from 1 to 5, with a score of 1 representing the most positive outcome and 5 indicating the most negative outcome. After the patients recovered completely from the sedation for bronchoscopy, they responded to the six items of the second questionnaire (Table 1) based on a VAS, which was created based on a previously used questionnaire [5]. A VAS score of 1 meant no anxiety at all, no discomfort during pharyngeal anesthesia, or during or after bronchoscopy at all, and the examination time for bronchoscopy was very short or easily acceptable for performing repeat bronchoscopy. Furthermore, we specifically focused on the response to “Did you feel uncomfortable during bronchoscopy?” in the second questionnaire and divided all patients into two groups, which were defined as the comfort group (VAS score was 1 or 2) and discomfort group (VAS score was 3 to 5), and compared the two groups (Fig 1).

Table 1

Questionnaire.

Questionnaire before bronchoscopy
1. Is this the first time you have had a bronchoscopy?	Yes/No
2. How about your anxiety before the procedure?	VAS score 1 to 5
Questionnaire after bronchoscopy
1. How about discomfort in oropharyngeal anesthesia?	VAS score 1 to 5
2. Do you remember the detail of bronchoscopy?	Yes/No
3. Can you feel uncomfortable during bronchoscopy?	VAS score 1 to 5
4. Can you feel uncomfortable after bronchoscopy?	VAS score 1 to 5
5. How about the duration of examination?	VAS score 1 to 5
6. Repeat bronchoscopy would be acceptable for you?	VAS score 1 to 5

VAS: Visual analog scale.

Fig 1

Questionnaire-based visual analog scale for satisfaction during bronchoscopy.

Comfort group, VAS score 1 and 2; discomfort group, VAS score 3 to 5.

Cough scores evaluated by physicians

Soon after performing the bronchoscopy, before checking the results of the patients' questionnaire, the bronchoscopists and their assistants discussed and reached a consensus about the severity of cough during the procedure and divided patients into four grades, ranging from 0 to 3, which were defined as follows: 0, no cough; 1, slight cough:go ahead the procedure; 2, moderate cough: transient interruption of the procedure in the trachea; and 3, severe cough: removal of the bronchoscope from the trachea (Table 2). Thereafter, we classified the patients into strong (cough score = 2 or 3) and weak groups (cough score = 0 or 1) according to their cough score and compared the two groups. A schematic diagram of this study is shown in Fig 2. This study was approved by the Ethical Committee of Kyorin University (approval number: H29-174).

Table 2

Cough score.

Score	Cough severity
0	No cough
1	A slight cough:go ahead the procedure
2	Moderate cough: transient interruption of procedure in the trachea
3	Severe cough: removal of the bronchoscope from the trachea

Fig 2

Schema of this study.

Bronchoscopy procedure

All bronchoscopy procedures were performed using flexible bronchoscopes (BF-P290F, BF-1TQ290, or BF-UC260-OL8; Olympus, Tokyo, Japan). The procedures were performed in either an inpatient or an outpatient setting. Soon after arrival to the examination room, vital signs were evaluated. All patients were anesthetized by instillation of lidocaine (5 mL of 2%) into the throat with a Jackson-type spray. Midazolam for sedation and/or pethidine for analgesia was administered intravenously before bronchoscopy, and additional doses of midazolam were used to maintain moderate sedation. The initial use and additional dosages of midazolam and pethidine were at the discretion of the primary bronchoscopist. Some patients on dialysis did not receive pethidine. The scope was introduced through the mouth. When the bronchoscope was passed through the larynx and trachea or coughing occurred during the procedure, 2% lidocaine was administered through the bronchoscopy channel. Vital signs were monitored every 5 min in all patients. If oxygen saturation decreased, supplemental oxygen was administered to maintain 90% oxygen saturation, as measured using a pulse oximeter. After the procedure, 0.2 mg of flumazenil was administered intravenously and another 0.2 mg was co-injected as an antagonist when midazolam was used. When only pethidine was used, 0.2 mg of naloxone was injected intravenously as an antagonist. Bronchoscopies were performed by pulmonologists whose experience ranged from 1 year or less to 18 years.

Collection of associated data

The following data were retrieved from the patients: age, sex, weight, body mass index (BMI), bronchoscopy indications (lung tumor, infection, diffuse interstitial lung disease, sarcoidosis, and others), bronchoscopy examination time; the time from insertion of the tip of the bronchoscope into the oral cavity to removal from the mouth, method, and dose of sedative medications (pethidine alone, midazolam alone, or midazolam and pethidine), and type of bronchoscopy procedure (e.g., bronchoalveolar lavage [BAL], endobronchial ultrasound transbronchial biopsy with guide-sheath [EBUS-GS-TBB], endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA], transbronchial biopsy [TBB], endobronchial biopsy [EBB], transbronchial lung biopsy [TBLB], brushing, observation, and treatment such as bronchothermoplasty [BT], insertion of airway stent, or endobronchial Watanabe spigot [EWS]). If two or more procedures were performed at the same time, both were counted. Among all enrolled cases, more than half of them underwent bronchoscopy by two or three bronchoscopists. In such cases, bronchoscopist experience was recorded as the one who mainly performed the procedure. The physician who has been engaged in bronchoscopy for less than 3 years was defined as “less-experienced” bronchoscopist. The difference in vital signs before (baseline condition) and during the procedures (maximum values) were analyzed.

Statistical analyses

Continuous variables are expressed as the mean ± standard deviation, unless otherwise stated, and were compared using a Mann–Whitney U test or t-test, as appropriate. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. The VAS score and cough score were treated as continuous variables. Multivariable analyses were performed using multiple logistic regressions. Univariate and multivariate analyses were used to identify the set of variables that could be used to classify the patients in the following aspects: discomfort vs. comfort and weak cough vs. strong cough.

Regarding the ROC curve for examination time, the cutoff point was determined as the minimum value of [(1-sensitivity) + (1-specificity)]. P < 0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using EZR ver. 1.40 [6].

Results

During the study registration period, 493 patients underwent planned bronchoscopies and 187 patients agreed to participate in the study. However, 15 patients were excluded from this study due to a lack of data. Finally, 172 patients were enrolled in this study.

Examination time for each procedure

Participants were grouped depending on the procedure they underwent as follows: group 1 (EBUS-GS-TBB, n = 59), group 2 (EBUS-TBNA, n = 18), group 3 (BAL, n = 8), group 4 (TBLB, n = 4), group 5 (TBB, n = 3), group 6 (EBB, n = 6), group 7 (brushing, n = 9), group 8 (observation, n = 10), group 9 (BAL+TBLB, n = 14), group 10 (BAL+EBUS-TBNA, n = 5), group 11 (EBUS-TBNA+TBLB, n = 2), group 12 (EBB+EBUS-TBNA, n = 6), group 13 (GS-TBB+EBUS-TBNA, n = 16), group 14 (BAL+TBLB+EBUS-TBNA, n = 8), group 15 (Treatment [BT, airway stent, EWS], n = 4 [2, 1, 1, respectively]). The correlation between examination time and each procedure demonstrated that the procedure time in the EBUS-TBNA groups (groups 2 and 10–14; black column) was significantly longer than that in the non-EBUS-TBNA groups (groups 1, 3–9, 15; gray column) (41.3 ± 15.10 min vs. 33.4 ± 17.13 min, p < 0.001) (Fig 3A).

Fig 3

Bar charts showing the distribution of different factors across groups.

(A) Type of procedure with the required time split into EBUS-TBNA (black column) and non-EBUS-TBNA groups (grey column). The p-value indicates the results of the EBUS-TBNA and non-EBUS-TBNA group comparison. Each group was defined as follows: group 1 (EBUS-GS-TBB, n = 59), group 2 (EBUS-TBNA, n = 18), group 3 (BAL, n = 8), group 4 (TBLB, n = 4), group 5 (TBB, n = 3), group 6 (EBB, n = 6), group 7 (Brushing, n = 9), group 8 (Observation, n = 10), group 9 (BAL+ TBLB, n = 14), group 10 (BAL+EBUS-TBNA, n = 5) group 11 (EBUS-TBNA+TBLB, n = 2), group 12 (EBB+EBUS-TBNA, n = 6), group 13 (GS-TBB+EBUS-TBNA, n = 16), group 14 (BAL+TBLB+EBUS-TBNA, n = 8), and group 15 (Treatment [BT, airway stent, EWS] n = 4 [2, 1, 1, respectively]). (B) Proportion of comfort (black column) and discomfort patients (grey column) for each procedure. (C) Comparison of the strong cough (black column) and weak cough groups (grey column). BAL, bronchoalveolar lavage; EBB, endobronchial biopsy; EBUS-GS-TBB, endobronchial ultrasonography with a guide sheath transbronchial biopsy; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; TBB, transbronchial biopsy; TBLB, transbronchial lung biopsy.

Bronchoscopy comfort and discomfort group

Among all patients who underwent bronchoscopy (n = 172), the number in the discomfort and comfort groups was 84 and 88, respectively (Fig 2).

Proportion of discomfort group in each procedure

Among all procedures, the proportion of patients with discomfort seemed to be greater in the EBUS-TBNA group than in the non-EBUS-TBNA group (Fig 3B), but the difference was not statistically significant (33/22 [60.0%] vs. 51/66[43.6%]; p = 0.051).

Univariable analysis of discomfort and comfort groups

Comparison of discomfort and comfort groups revealed that younger age (64.06 ± 14.10 vs. 71.43 ± 11.77 years; p < 0.001), sarcoidosis as the indication for bronchoscopy (n = 10 [11.9%] vs. 3 [3.4%]; p = 0.044), BAL (n = 23 [27.4%] vs. n = 12 [13.6%]; p = 0.041), less-experienced bronchoscopist (n = 64 [76.2%] vs. n = 52 [59.1%]; p = 0.024), long examination time (41.96 ± 17.46 vs. 35.15 ± 16.36 min; p = 0.009), elevation of cough score per 1point (1.43 ± 1.04 vs. 0.73 ±0.93; p < 0.001), prominent discrepancy between baseline and maximum values in systolic blood pressure (25.64 ± 26.60 vs. 14.74 ± 26.70 mmHg; p = 0.004), heart rate (18.95 ± 19.23 vs. 11.26 ± 19.35; p = 0.006), and high anxiety score on the VAS scale (3.81 ± 1.15 vs. 3.28 ± 1.39; p = 0.016) were more common in the discomfort group (Table 3).

Table 3

Patient characteristics and univariate analysis for discomfort of bronchoscopy.

Factor	Total n = 172	Discomfort n = 84	Comfort n = 88	p value
Age (year) a	67.83 ± 13.44	64.06 ± 14.10	71.43 ±11.77	< 0.001
Gender (Male/Female), n (%)d	117/55 (68.0/32.0)	51/33 (60.7/39.3)	66/22 (75.0/25.0)	0.065
Suspected disease
Lung tumor, n (%)d	106 (61.6)	48 (57.1)	58 (65.9)	0.305
Interstitial pneumonia, n (%)d	30 (17.4)	16 (19.0)	14 (15.9)	0.733
Sarcoidosis, n (%)c	13 (7.6)	10 (11.9)	3 (3.4)	0.044
Infectious disease, n (%)c	11 (6.4)	4 (4.8)	7 (8)	0.536
Other, n (%)d	12 (7.0)	6 (7.1)	6 (6.8)	1.000
Weight (kg) a	57.60 ± 11.52	56.71 ± 11.51	58.53 ± 11.53	0.628
BMI (kg/m2) a	22.1 ± 3.35	22.43 ± 3.67	21.83 ± 3.00	0.565
Outpatient, n (%)c	8 (4.65)	4 (4.8)	4 (4.5)	1.000
Procedure
BAL, n (%)d	35 (20.3)	23 (27.4)	12 (13.6)	0.041
TBLB, n (%)d	28 (16.3)	18 (21.4)	10 (11.4)	0.114
EBUS-GS-TBB, n (%)d	75 (43.6)	35 (41.7)	40 (45.5)	0.730
EBUS-TBNA, n (%)d	55 (32.0)	33 (39.3)	22 (25.0)	0.065
EBB, n (%)d	12 (7.0)	6 (7.1)	6 (6.8)	1.000
TBB, n (%)c	3 (1.7)	0 (0)	3 (3.4)	0.246
Brushing, n (%)c	9 (5.2)	4 (4.8)	5 (5.7)	1.000
Observation, n (%)c	10 (5.8)	2 (2.4)	8 (9.1)	0.100
Treatment, n (%)c	4 (2.3)	3 (3.6)	1 (1.1)	0.359
Less-experienced bronchoscopist, n (%) d	116 (67.4)	64 (76.2)	52 (59.1)	0.024
Drug
Midazolam and pethidine, n (%)d	159 (92.4)	77 (91.7)	82 (93.2)	0.930
Midazolam only, n (%)c	2 (1.2)	1 (1.2)	1 (1.1)	1.000
Pethidine only, n (%)c	11 (6.4)	6 (7.1)	5 (5.7)	0.763
Total midazolam (mg) a	2.70 ± 1.58	2.95 ± 1.75	2.45 ± 2.36	0.050
Total pethidine (mg) a	34.59 ± 5.97	34.58 ± 6.06	34.60 ± 5.92	0.977
Examination time (min) b	38.48 ± 17.20	41.96 ± 17.46	35.15 ± 16.36	0.009
Cough score a	1.07 ± 3.35	1.43 ± 1.04	0.73 ±0.93	< 0.001
Δ systolic BP (mmHg) a	20.06 ± 27.13	25.64 ± 26.60	14.74 ± 26.70	0.004
Δ Heart rate (/min) a	15.02 ± 19.62	18.95 ± 19.23	11.26 ± 19.35	0.006
Questionnaire before bronchoscopy
Retry (1st time/≧ 2nd time), n (%)d	135/37 (78.5/21.5)	65/19 (77.4/22.6)	70/18 (79.5/20.5)	0.873
Anxiety a	3.54 ± 1.30	3.81 ± 1.15	3.28 ± 1.39	0.016

BAL, bronchoalveolar lavage; BMI, body mass index; BP, blood pressure; EBB, endobronchial biopsy; EBUS-GS-TBB, endobronchial ultrasonography with a guide sheath transbronchial biopsy, EBUS-TBNA: Endobronchial ultrasound-guided transbronchial needle aspiration, TBB: transbronchial biopsy, TBLB: transbronchial lung biopsy, Data are presented as mean ± standard deviation.

a: Mann–Whitney U test

b: t-test.

c: Fisher’s exact test

d:χ2 test.

Based on the patient questionnaire administered after bronchoscopy, the discomfort group was more aware and felt the examination time was too long during bronchoscopy (Table 4).

Table 4

Univariate analysis of questionnaire after bronchoscopy for discomfort of bronchoscopy.

Questionnaire after bronchoscopy	Total n = 172	Discomfort n = 84	Comfort n = 88	p value
Oropharyngeal anesthesia a	2.54 ± 1.32	2.00 ± 1.02	3.06 ± 1.38	< 0.001
Memory, n (%)b	113 (65.7)	64 (76.2)	49 (55.7)	0.008
Feeling after examination a	2.70 ± 1.00	3.11 ± 0.98	2.31 ± 0.86	< 0.001
Feeling about examination time a	2.84 ± 0.86	3.26 ± 0.78	2.44 ± 0.83	< 0.001
Willing for repeat bronchoscopy a	2.83 ± 1.23	3.36 ± 1.13	3.32 ± 1.12	< 0.001

Data are presented as mean ± standard deviation.

a: Mann–Whitney U test

b: χ2 test.

Multivariate analysis of the discomfort and comfort groups

We performed logistic regression analysis using the significant variables in the univariate analysis, such as age, sarcoidosis as the indication for bronchoscopy, BAL, less-experienced bronchoscopist, examination time, cough score, Δ systolic BP (mmHg), Δ Heart rate (/min), and anxiety. Only three factors, younger age (odds ratio [OR] = 0.96; 95% confidence interval [CI]: 0.93–0.98; p = 0.002), less-experienced bronchoscopist (OR = 2.08; 95%CI: 1.01–4.28; p = 0.047), and elevation of cough score per 1point (OR = 1.89; 95% CI: 1.35–2.65; p < 0.001) (Table 5) were significantly associated with discomfort.

Table 5

Multivariate analysis for discomfort of bronchoscopy.

	Odds ratio	95%CI	p value
Age	0.96	0.93–0.98	0.002
Less-experienced bronchoscopist	2.08	1.01–4.28	0.047
Cough score per 1 point	1.89	1.35–2.65	< 0.001

95%CI: 95% confidence interval.

Cough score evaluated by physicians

Among all patients who underwent bronchoscopy (n = 172), the number of patients in the strong cough and weak cough groups was 67 and 105, respectively (Fig 2).

Proportion of patients with strong cough in each procedure

The proportion of patients with strong cough (scores 2 and 3) was significantly greater in the EBUS-TBNA group than in the non-EBUS-TBNA group (34/21 [61.8%] vs. 33/84 [28.2%]; p < 0.001) (Fig 3C).

Univariable analysis of weak cough and strong cough groups

In the univariable analysis, predisposing factors for strong cough were female sex (n = 30 [44.8%] vs. n = 25 [23.8%]; p = 0.007), sarcoidosis as an indication for bronchoscopy (n = 10 [14.9%] vs. n = 3 [2.9%]; p = 0.006), BAL (n = 22 [32.8%] vs. n = 13 [12.4%]; p = 0.002), TBLB (n = 19 [28.4%] vs. n = 9 [8.6%]; p = 0.001), EBUS-TBNA (n = 34 [50.7%] vs. n = 21 [20.0%]; p < 0.001), non-performed EBUS-GS-TBB (n = 46 [68.7%] vs. n = 51 [48.7%]; p = 0.015), non-performed observation (n = 67 [100%] vs. n = 95 [90.5%]; p = 0.007) and examination time (44.58 ± 15.67 vs. 34.58 ± 17.07 min; p < 0.001). On further analysis, it was found that if the threshold of the examination time was set at 36 min, the diagnostic yield for strong cough had a sensitivity of 68.7%, specificity of 60.0%, and area under the curve of 0.68 (95%CI: 0.60–0.76). The proportion of patients with prolonged examination time (≥36 min) was also greater in the strong cough group (n = 46, 68.6%) than in the weak cough group (n = 42, 40.0%; p < 0.001) (Table 6).

Table 6

Univariate analysis for strong cough.

	Weak cough n = 105	Strong cough n = 67	p value
Age (year) a	69.35 ± 12.17	65.45 ± 15.02	0.141
Gender (Male/Female), n (%)d	80/25 (76.2/23.8)	37/30 (55.2/44.8)	0.007
Suspected disease
Lung tumor, n (%)d	68 (64.8)	38 (56.7)	0.370
Interstitial pneumonia, n (%)d	16 (15.2)	14 (20.9)	0.455
Sarcoidosis, n (%)c	3 (2.9)	10 (14.9)	0.006
Infectious disease, n (%)c	9 (8.6)	2 (3)	0.205
Other, n (%)c	9 (8.6)	3 (4.5)	0.371
Weight (kg) a	57.70 ± 11.97	57.43 ± 10.88	1.000
BMI (kg/m2) a	21.83 ± 3.44	22.59 ± 3.17	0.097
Outpatient, n (%)c	6 (5.7)	2 (3.0)	0.485
Procedure
BAL, n (%)d	13 (12.4)	22 (32.8)	0.002
TBLB, n (%)d	9 (8.6)	19 (28.4)	0.001
EBUS-GS-TBB, n (%)d	54 (51.4)	21 (31.3)	0.015
EBUS-TBNA, n (%)d	21 (20.0)	34 (50.7)	< 0.001
EBB, n (%)c	5 (4.8)	8 (11.9)	0.136
TBB, n (%)c	0 (0)	3 (4.5)	0.058
Brushing, n (%)c	7 (6.7)	2 (3.0)	0.485
Observation, n (%)c	10 (9.5)	0 (0)	0.007
Treatment, n (%)c	3 (2.9)	1 (1.5)	1.000
Less-experienced bronchoscopist, n (%)d	66 (62.9)	50 (74.6)	0.131
Drug
Midazolam and pethidine, n (%)c	96 (91.4)	63 (94.0)	0.769
Midazolam only, n (%)c	1 (1.0)	1 (1.5)	1.000
Pethidine only, n (%)c	8 (7.6)	3 (4.5)	0.532
Total midazolam (mg) a	2.10 ± 1.27	3.63 ± 1.56	< 0.001
Total pethidine (mg) a	34.50 ± 5.67	34.74 ± 6.46	0.695
Examination time (min) a	34.58 ± 17.07	44.58 ± 15.67	< 0.001
Examination time (min) ≧ 36, n (%)d	42 (40.0)	46 (68.6)	< 0.001
ΔSystolic BP (mmHg)b	11.57 ± 22.97	33.37 ± 27.95	< 0.001
ΔHeart rate (/min)a	8.79 ± 16.84	24.78 ± 19.80	< 0.001
Questionnaire before bronchoscopy
Retry (1st time/≧ 2nd time), n (%)d	83/22 (79.0/21.0)	52/15 (77.6/22.4)	0.974
Anxiety a	3.41 ± 1.30	3.75 ± 1.28	0.056

BAL, bronchoalveolar lavage; BMI, body mass index; BP, blood pressure; EBB, endobronchial biopsy; EBUS-GS-TBB, endobronchial ultrasonography with a guide sheath transbronchial biopsy, EBUS-TBNA: Endobronchial ultrasound-guided transbronchial needle aspiration, TBB: transbronchial biopsy, TBLB: transbronchial lung biopsy, Data presented as mean ± standard deviation.

a: Mann–Whitney U test

b: t-test.

c: Fisher’s exact test

d:χ2 test.

Multivariate analysis to identify predictors of strong cough groups

Logistic regression analysis to identify predictors of the strong cough groups, among the variables that showed significance in the univariate analysis, female sex, sarcoidosis as an indication for bronchoscopy, BAL, TBLB, EBUS-TBNA, non-performed GS-TBB, non-performed observation and examination time (≥ 36 min), demonstrated independent associations between female sex (OR = 2.57; 95%CI: 1.27–5.21; p = 0.009), EBUS-TBNA (OR = 2.95; 95% CI: 1.40–6.18; p = 0.004), and examination time (≥36 min) (OR = 2.32; 95% CI: 1.13–4.76; p = 0.022) (Table 7).

Table 7

Multivariate analysis for strong cough.

	Odds ratio	95%CI	p value
Female	2.57	1.27–5.21	0.009
EBUS-TBNA	2.95	1.40–6.18	0.004
Examination time ≧ 36min	2.32	1.13–4.76	0.022

EBUS-TBNA, Endobronchial ultrasound-guided trasbronchial needle aspiration; 95%CI, 95% confidence interval.

Discussion

This study demonstrated that younger age, less-experienced bronchoscopist, and elevation of cough score per 1point were associated with discomfort. Importantly, with special reference to the severity of cough assessed using a cough score, we provide the first evidence that female sex, EBUS-TBNA, and prolonged examination time (≥36 min) are predictive factors for strong cough in bronchoscopy.

Regarding discomfort during bronchoscopy, previous reports suggested that female sex, unexpected pain [7], severe anxiety before bronchoscopy, bronchoscopist’s experience [3], nasal insertion, and examination time [4] affect patient discomfort. Among the predictive factors that were significant in our multivariate analysis, less-experienced bronchoscopists had already been published in a previous report [3], but younger age and cough severity have not been widely reported. Previous studies enrolled relative younger patients (i.e., aged 64.7 ± 12.4 years [mean ± standard deviation] [7], 59.9 ± 15.1 years [3], and 56.5 ± 13.7 years [4]) compared to those enrolled in ours (67.83 ± 13.44 years), which might emphasize that younger age itself can be a predictive factor for discomfort, especially in an aging society like that of Japan. Interestingly, this study demonstrated that “cough severity” was another predictive factor for discomfort, but the relationship between cough and patient discomfort has been scarcely reported. In this regard, the severity of cough was assessed by physicians after reaching a consensus, and the probability of being in the discomfort group increased (OR = 1.69) per 1point elevation of cough score.

Furthermore, predictive factors for strong cough included female sex (OR = 2.57), EBUS-TBNA (OR = 2.95), and prolonged examination time (≥36 min) (OR = 2.32). In general, women are more vulnerable to chronic cough than men in the clinic setting [8], while it is not known whether female sex itself can affect cough severity, even in the setting of bronchoscopy. Therefore, this study clearly demonstrated that female sex has a clear association with strong cough from the physician’s viewpoint. We also discovered that EBUS-TBNA is another predictive factor for strong cough. Even when sedated, cough can occur in 93% of patients during bronchoscopy [9], which is probably exaggerated by direct attachment of the EBUS probe to the main tracheal lumen or bronchus and the longer time required for completion of the procedure than the other bronchial examinations, as was seen in our study. Of note, this study clearly demonstrated that examination time over 36 min can predict strong cough regardless of whether EBUS-TBNA is performed.

This study has some limitations in that it was conducted in a single center; therefore, a multicenter prospective study with more cases is required. Furthermore, evaluation of cough severity only depended on the physicians’ consensus but not on quantitative methods, such as counting the absolute number of coughs [10]. In addition, during EBUS-TBNA, bronchoscopists specifically focus on the position of the probe in the trachea, which might lead to overestimation of the severity of cough.

Conclusions

The present study demonstrated that younger age, bronchoscopist experience, and cough were associated with discomfort during bronchoscopy, and female sex, EBUS-TBNA, and prolonged examination time can be predictive factors for strong cough.

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15 Jun 2020

PONE-D-20-07274

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis

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Reviewers' comments:

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper the authors studied risk factors of patient discomfort and severe cough during bronchoscopy using data from 172 patient who underwent bronchoscopy at Kyorin University Hospital.

My questions/comments are as below.

It looks like “subjective analysis” was used to refer to analysis with discomfort as the endpoint and “objective analysis” was used to refer to analysis with “strong cough” as the endpoint. I found the use of subjective and objective confusing. Probably better to describe the endpoints directly.

It’s mentioned in the statistical analysis section that Mann-Whitney U test or t-test was used to compare continuous variable. Please label in the relevant tables which test was used for each continuous variable.

What were the covariates included in the logistic regression models? Were variables with VAS scores included as continuous variables?

I’d recommend showing continuous variable as the mean and standard deviation since medians can be the same for two groups while the p-value is still significant (e.g. Table 4.w Anxiety).

How was “36 minutes” determined to be the cutoff for prolonged examination time?

What does VAS 1-5 mean for question 5 (How about the duration of the examination?)? 1 means too long? Just right? uncomfortable length?

Are data on the bronchoscopists who performed the procedures available? Presumably, they can influence the comfort levels and maybe the severity of cough.

Figure 3. It is interesting that 100% participants in group 4 had strong cough while they were all in the comfort group. Any explanation for this?

Reviewer #2: Comments to the Author

While it is widely recognized that severe cough cause patients’ discomfort during bronchoscopy, predictive factors for severe cough have not been reported. The present prospective study reported factors associated with patients’ discomfort and cough severity during bronchoscopy.

Major points

The setting of the present prospective study has several problems.

1. The authors grouped patients into discomfort group and comfort group by use of questionnaire after bronchoscopy. The authors described that the discomfort group included patients who answered VAS score 1 or 2 to the question about discomfort during bronchoscopy and the comfort group included those who answered VAS score 3 to 5, in the materials and methods session, page 6 line82-82. However, they described that the comfort group included VAS score 1 or 2 and discomfort group included VAS score 3 to 5 at Figure 1. These were inconsistent?

2. The authors grouped patients into strong cough group and weak cough group by use of cough score, which was the original score defined by the authors and assessed by bronchoscopists. The strong cough group included patients whose cough score was 0 or 1, and the weak cough group 2 or 3. However, the difference between cough score 1 (slight cough) and 2 (moderate cough, no need to interrupt procedure) was ill defined. The authors defined the cough score as objective score, but it depended on bronchoscopists’ subjectivity.

3. The present study reported examination time was one of the factors which affected severe cough. Additionally, it is described that the procedure time in EBUS-TBNA groups was significantly longer than that in non-EBUS-TBNA-groups. The EBUS-TBNA groups included group 10-14, but they did not include group 2 (EBUS-TBNA). Why did the authors sort group 2 into the non-EBUS-TBNA-group? It was likely that the examination time did not be depend on EBUS-TBNA, but depended on using two procedures.

Minor points

1. The present study showed that patients in comfort group received more midazolam than those in discomfort group. The deep sedation could be important to comfort during bronchoscopy. In this study, there were patients who did not receive pethidine. How did the authors decide which they administered　 pethidine patients?

2. The authors described that patients’ discomfort reported to be associated with bronchoscopists’ experience in the discussion session. In this study, bronchoscopy was performed by pulmonologists whose experience ranged from 1 to 18 years. How did bronchoscopists’ experience affect the outcome of this study?

Reviewer #3: This study is very interesting. However some of detail is lacked.

First, how did you measured procedural time ? Is it from vocal code passing ? Is it to the end of procedure ? Please show me how.

Second, the procedural time is too long comparing with standardized procedure, especially for EBUS-TBNA group, and this result may be a confounding factor.

Third, Please tell me the use or not use of your additional lidocaine spraying. If not, you can reduce the cough level during procedure. And you'd better show the average dose of Midazolam and Petizine. Previously published report show that the usage of sedative drugs reduce the cough during BFS procedure. You should discuss about the appropriation of your sedation.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Takashi Niwa

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Submitted filename: PONE-D-20-07274 editor comments.docx

Click here for additional data file.

4 Aug 2020

[Date of submission] July, 24 2020

[Editor’s name] Atushi Miyamoto

PLOS ONE

Dear Editor:

We wish to re-submit the manuscript titled “Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis”. The manuscript ID is PONE-D-20-07274

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. I look forward to working with you and the reviewers to move this manuscript closer to publication in PLOS ONE.

The manuscript has been rechecked and the necessary changes have been made as per the reviewers’ suggestions. A point-by-point response to all comments has been prepared and given below.

Reviewers’ Comments to the Author

Reviewer #1: In this paper the authors studied risk factors of patient discomfort and severe cough during bronchoscopy using data from 172 patient who underwent bronchoscopy at Kyorin University Hospital.

My questions/comments are as below.

It looks like “subjective analysis” was used to refer to analysis with discomfort as the endpoint and “objective analysis” was used to refer to analysis with “strong cough” as the endpoint. I found the use of subjective and objective confusing. Probably better to describe the endpoints directly.

Response: Thank you for your suggestion. As for Fig 2, we revised the term from “subjective score” to “patient-based evaluation” as well as from “objective score” to “physician-based evaluation”.

We also revised the heading from “Subjective scores on the comfort of bronchoscopy evaluated by patients” to “Evaluation of the comfort or discomfort based on the questionnaire after bronchoscopy” as well as from “Objective score of cough severity on bronchoscopy as evaluated by physicians” to “Cough score evaluated by physicians”

It’s mentioned in the statistical analysis section that Mann-Whitney U test or t-test was used to compare continuous variable. Please label in the relevant tables which test was used for each continuous variable.

Response: Thank you for your comments. We labeled the data in Tables 3, 4, and 6. (Pages 13–14 and 16–17, Lines 201–205, 208–210 and 241–245)

Comment: What were the covariates included in the logistic regression models? Were variables with VAS scores included as continuous variables?

Response: Thank you for these important comments.

In the view of analysis, the cough score and VAS score of anxiety were included as continuous variables. We also added the following sentences:

Regarding discomfort,

We performed logistic regression analysis using the significant variables in the univariate analysis, such as age, sarcoidosis as the indication for bronchoscopy, BAL, less-experienced bronchoscopy, examination time, cough score, Δsystolic BP (mmHg), Δ Heart rate (/min), and VAS score of anxiety. Only three factors, younger age (odds ratio [OR] = 0.96; 95% confidence interval [CI]: 0.93–0.98; p < 0.01) less experienced bronchoscopy (OR = 2.08; 95%CI: 1.01–4.28; p < 0.05) and severe cough (OR = 1.69; 95% CI: 1.40–2.74; p < 0.001) (Table 5) were significantly associated with discomfort. (Pages 14–15, lines 212–218)

Similarly, regarding strong cough,

Logistic regression analysis to identify predictors of the strong cough groups, among the variables that showed significance in the univariate analysis, female sex, sarcoidosis as an indication for bronchoscopy, BAL, TBLB, EBUS-TBNA, non-performed GS-TBB, non-performed observation, and examination time (≥ 36 min), demonstrated independent associations between female sex (OR = 2.57; 95%CI: 1.27–5.21; p < 0.01), EBUS-TBNA (OR = 2.95; 95% CI: 1.40–6.18; p < 0.01), and examination time (≥36 min) (OR = 2.32; 95% CI: 1.13–4.76; p < 0.05). (Pages 17–18, line 247–253).

These covariates are all categorical variables.

I’d recommend showing continuous variable as the mean and standard deviation since medians can be the same for two groups while the p-value is still significant (e.g. Table 4.w Anxiety).

Response: Thank you for your important suggestions. We revised the data from the median (range) to mean ± SD in Tables 3, 4, and 6. (Pages 13–14 and 16–17, Lines 201–205, 208–210 and 241–245)

How was “36 minutes” determined to be the cutoff for prolonged examination time?

Response: Thank you for your comment. We added these sentences to the statistical analyses section.

Regarding the ROC curve for examination time, the cutoff point was determined as the minimum value of [(1-sensitivity) 2 + (1-specificity) 2]. (Page 9, lines 143–144)

What does VAS 1-5 mean for question 5 (How about the duration of the examination?)? 1 means too long? Just right? uncomfortable length?

Response: Thank you for your comments. We have added these sentences as follows:

A VAS score of 1 meant no anxiety at all, no discomfort during pharyngeal anesthesia or during and/or after bronchoscopy, and the examination time for bronchoscopy was very short or easily acceptable for performing repeat bronchoscopy. （Page 5, lines 71–73）

Are data on the bronchoscopists who performed the procedures available? Presumably, they can influence the comfort levels and maybe the severity of cough.

Response: Thank you for your valuable comment. As you pointed out, we re-analyzed the data for the bronchoscopists. In the first edition, we recorded the youngest physician when more than one bronchoscopist performed the bronchoscopy, but we decided to use the data of the bronchoscopist who performed the procedure the longest. Therefore, the results of the analysis for discomfort were highly variable, and both univariate and multivariate analyses showed that the experience of bronchoscopists had a significant impact on the patients’ discomfort. This means less-experienced bronchoscopists (less than 3 years) were identified as additional predictive factors for discomfort.

On the other hand, the bronchoscopist’s experience did not affect the cough during bronchoscopy.

We further added the following sentences in the material methods section; “Collection of the associated data” in the cases who were handled by more than one bronchoscopist.

Among all enrolled cases, more than half of them underwent bronchoscopy by two or three bronchoscopists. In such cases, the bronchoscopist experience was recorded as the one who mainly performed the procedure. (Page 8, lines 129 -131)

Figure 3. It is interesting that 100% participants in group 4 had strong cough while they were all in the comfort group. Any explanation for this?

Response: Thank you for your comments. In the original article, Groups 4 and 5, were TBLB (n=4) and TBB (n=3). However, we mistakenly labeled Fig 3. Therefore, we revised Fig 3, and group 4 (renamed as group 5) as TBB (n=3). (Page 10, line 154) We cannot precisely explain the reason for this dissociation; however, they were all elderly patients (mean age of 73.3 years), and they had some determining factors for the comfortable group by univariate analysis such as short examination time (average: 32.6 minutes), no BALF, and no suspicion of sarcoidosis. On the other hand, all procedures were performed by less-experienced bronchoscopists.

Reviewer #2: Comments to the Author

While it is widely recognized that severe cough cause patients’ discomfort during bronchoscopy, predictive factors for severe cough have not been reported. The present prospective study reported factors associated with patients’ discomfort and cough severity during bronchoscopy.

Major points

The setting of the present prospective study has several problems.

1. The authors grouped patients into discomfort group and comfort group by use of questionnaire after bronchoscopy. The authors described that the discomfort group included patients who answered VAS score 1 or 2 to the question about discomfort during bronchoscopy and the comfort group included those who answered VAS score 3 to 5, in the materials and methods session, page 6 line82-82. However, they described that the comfort group included VAS score 1 or 2 and discomfort group included VAS score 3 to 5 at Figure 1. These were inconsistent?

Response: Thank you for your valuable comments. We have revised this as follows.

…, which were defined as the comfort group (VAS score was 1 or 2) and discomfort group (VAS score was 3 to 5), and compared the two groups (Fig 1). (Page 5, lines 75–77)

2. The authors grouped patients into strong cough group and weak cough group by use of cough score, which was the original score defined by the authors and assessed by bronchoscopists. The strong cough group included patients whose cough score was 0 or 1, and the weak cough group 2 or 3. However, the difference between cough score 1 (slight cough) and 2 (moderate cough, no need to interrupt procedure) was ill defined. The authors defined the cough score as objective score, but it depended on bronchoscopists’ subjectivity.

Response: Thank you for your comment. We revised the term from “subjective score” to “patient-based evaluation” as well as from “objective score” to “physician-based evaluation.”

3. The present study reported examination time was one of the factors which affected severe cough. Additionally, it is described that the procedure time in EBUS-TBNA groups was significantly longer than that in non-EBUS-TBNA-groups. The EBUS-TBNA groups included group 10-14, but they did not include group 2 (EBUS-TBNA). Why did the authors sort group 2 into the non-EBUS-TBNA-group? It was likely that the examination time did not be depend on EBUS-TBNA, but depended on using two procedures.

Response: Thank you for your important comments. We failed to show group 4 as a black column. The statistical analysis of examination time for the presence or absence of EBUS-TBNA in the original article was performed, including group 2. Thereby, we revised Figure 3A and demonstrated precisely the EBUS-TBNA group.

Minor points

1. The present study showed that patients in comfort group received more midazolam than those in discomfort group. The deep sedation could be important to comfort during bronchoscopy. In this study, there were patients who did not receive pethidine. How did the authors decide which they administered pethidine patients?

Response: Thank you for your important comments.

Two patients who underwent bronchoscopy with only midazolam were on maintenance hemodialysis. We prefer midazolam to pethidine in cases with chronic renal failure.

Therefore, we added the sentences in the sentences in the section of the “bronchoscopy procedure” section.

The initial use and additional dosages of midazolam and pethidine were at the discretion of the primary bronchoscopist. Some patients on dialysis did not receive pethidine. (Page 7, line 105-107).

2. The authors described that patients’ discomfort reported to be associated with bronchoscopists’ experience in the discussion session. In this study, bronchoscopy was performed by pulmonologists whose experience ranged from 1 to 18 years. How did bronchoscopists’ experience affect the outcome of this study?

Response:

Thank you for your important comments. As you pointed out, we re-analyzed the data for the bronchoscopists. In the first edition, we recorded the youngest physician when more than one bronchoscopist performed the bronchoscopy, but we decided to use the data of the bronchoscopist who performed the procedure the longest. Therefore, the results of the analysis for discomfort were highly variable, and both univariate and multivariate analyses showed that the experience of bronchoscopists had a significant impact on the patients’ discomfort. This means less-experienced bronchoscopists (less than 3 years) were identified as additional predictive factors for discomfort.

On the other hand, the bronchoscopist’s experience did not affect the cough during bronchoscopy.

We further added the sentences in the material and methods section as follows: “Collection of the associated data”; for the cases which were handled by more than one bronchoscopist.

Among all enrolled cases, more than half of them underwent bronchoscopy by two or three bronchoscopists. In such cases, the bronchoscopist experience was recorded as the one who mainly performed the procedure. (Page 8, lines 129-131)

Reviewer #3: This study is very interesting. However some of detail is lacked.

First, how did you measured procedural time ? Is it from vocal code passing ? Is it to the end of procedure ? Please show me how.

Response: Thank you for your important comments. We added these sentences in the section of “Collection of the associated data”

bronchoscopy examination time; the time from insertion of the tip of the bronchoscope into the oral cavity to remove from the mouth (page 8, lines 120–121)

Second, the procedural time is too long comparing with standardized procedure, especially for EBUS-TBNA group, and this result may be a confounding factor.

Response: Thank you for your important comments. Exactly, EBUS-TBNA requires much time (median: 39 minutes), even if it is performed as a sole procedure (Fig 3A, group 2). Moreover, previous reports described that EBUS-TBNA needs 29 (PMID: 28967732) to 30 minutes (PMID: 28435314). In addition, our results suggest that EBUS-TBNA, examination time, and female sex were associated with strong cough independently on multivariate analysis.

Third, Please tell me the use or not use of your additional lidocaine spraying. If not, you can reduce the cough level during procedure. And you'd better show the average dose of Midazolam and pethidine. Previously published report show that the usage of sedative drugs reduce the cough during BFS procedure. You should discuss about the appropriation of your sedation.

Response: Thank you for your comments. Regarding lidocaine spraying, we described the following:

When the bronchoscope was passed through the larynx and trachea or coughing occurred during the procedure, 2% lidocaine was administered through the bronchoscopy channel. (Page 7, lines 108-109).

For midazolam and pethidine, the total doses of midazolam and pethidine are shown in Table 3. The total dosages of midazolam and pethidine between discomfort and comfort were comparable. However, the total dosage of midazolam in the strong cough group was significantly higher than that in the weak cough group (Table 6), which seemed not to be the cause but the result of the strong cough.

We would like to thank the reviewers for their time and valuable comments, which have resulted in a significantly improved manuscript. We feel that the revised manuscript reflects suitable responses to the reviewers' comments, and we hope that revisions are completed to the Editor's satisfaction and it is now deemed suitable for publication in your journal.

Thank you for your consideration. We look forward to hearing from you.

Sincerely,

Takeshi Saraya MD, PhD

Department of Respiratory Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

Address: 6-20-2, Shinkawa, Kyorin University School of Medicine

Post code:181-8611

City: Mitaka

Country: Japan

e-mail: sara@yd5.so-net.ne.jp

Submitted filename: Response_to_the_reviewers_20200720.docx

Click here for additional data file.

8 Sep 2020

PONE-D-20-07274R1

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis

PLOS ONE

Dear Dr. Saraya,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

According to the reviewers' new comments, please refine the manuscript before publication.

==============================

Please submit your revised manuscript by Oct 23 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Atsushi Miyamoto

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed the reviewers' comments in this revision. I only have one more comment. Please update the p-values in Tables 3-7 with more accurate p-values rather than a range, e.g., <0.05.

Reviewer #2: The manuscript has been improved by the authors.

However, the problem has been remaining that the difference between cough score 1 (slight cough) and 2 (moderate cough, no need to interrupt procedure) was ill defined. How did the bronchoscopists decide which patients had slight cough or moderate cough?

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

17 Sep 2020

Dear Reviewers

Thank you for your kindness to review our manuscript.

We revised the manuscript according to the reviewer's comments point by point.

We are very grateful to your great effort.

Thank you again.

Reviewer #1: The authors have addressed the reviewers' comments in this revision. I only have one more comment. Please update the p-values in Tables 3-7 with more accurate p-values rather than a range, e.g., <0.05.

R: Thank you for your comments. We revised them.

Reviewer #2: The manuscript has been improved by the authors.

However, the problem has been remaining that the difference between cough score 1 (slight cough) and 2 (moderate cough, no need to interrupt procedure) was ill defined. How did the bronchoscopists decide which patients had slight cough or moderate cough?

R: Thank you for your thoughtful comments. We revised them (Fig.2 and Table2) more precisely as follows.

Score Cough severity

0 No cough

1 A slight cough：go ahead the procedure

2 Moderate cough: transient interruption of the procedure in the trachea

3 Severe cough: removal of the bronchoscope from the trachea

Submitted filename: to reviewer revise2.docx

Click here for additional data file.

22 Sep 2020

PONE-D-20-07274R2

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis

PLOS ONE

Dear Dr. Saraya,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

Before acceptance, please confirm the inquiry from Reviewer1 as soon as possible.

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Please submit your revised manuscript by Nov 06 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Atsushi Miyamoto

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In Table 3, there seems to be a typo. The numbers for Gender under Discomfort column should be 51/33 not 51/44.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

22 Sep 2020

Dear Reviewer1

Thank you for your kindness to review our manuscript.

We revised the Table3 as follows.

Thank you for your comments.

We are very grateful to your great effort.

Thank you again.

Submitted filename: Response to Reviewer.docx

Click here for additional data file.

28 Sep 2020

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis

PONE-D-20-07274R3

Dear Dr. Saraya,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Atsushi Miyamoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

6 Oct 2020

PONE-D-20-07274R3

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: a prospective questionnaire analysis

Dear Dr. Saraya:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Atsushi Miyamoto

Academic Editor

PLOS ONE