Impact of pulmonary rehabilitation in sleep in COPD patients measured by actigraphy

Suman B Thapamagar; Kathleen Ellstrom; James D Anholm; Ramiz A Fargo; Nagamani Dandamudi

doi:10.1371/journal.pone.0248466

. 2021 Mar 16;16(3):e0248466. doi: 10.1371/journal.pone.0248466

Impact of pulmonary rehabilitation in sleep in COPD patients measured by actigraphy

Suman B Thapamagar ^1,^2,^3,^*, Kathleen Ellstrom ², James D Anholm ^1,², Ramiz A Fargo ^1,^2,³, Nagamani Dandamudi ^1,²

Editor: Federica Provini⁴

PMCID: PMC7963048 PMID: 33724995

Abstract

Introduction

Chronic obstructive pulmonary disease (COPD) patients have poor sleep quality, longer time to sleep onset and frequent nocturnal awakenings. Poor sleep quality in COPD is associated with poor quality of life (QoL), increased exacerbations and increased mortality. Pulmonary rehabilitation (PR) improves functional status and QoL in COPD but effects on sleep are unclear. PR improves subjective sleep quality but there is paucity of objective actigraphy data. We hypothesized that actigraphy would demonstrate subjective and objective improvement in sleep following PR. Paired comparisons (t-test or Wilcoxon-signed-rank test) were performed before and after PR data on all variables.

Methods

This retrospective study of COPD patients undergoing PR utilized actigraphy watch recordings before and after 8-weeks of PR to assess changes in sleep variables including total time in bed (TBT), total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), wakefulness after sleep onset (WASO) and total nocturnal awakenings. A change in Pittsburg Sleep Quality Index (PSQI) was a secondary outcome. PSQI was performed before and after PR.

Results

Sixty-nine patients were included in the final analysis. Most participants were male (97%), non-obese (median BMI 27.5, IQR 24.3 to 32.4 kg/m²) with an average age of 69 ± 8 years and 71% had severe COPD (GOLD stage 3 or 4). Prevalence of poor sleep quality (PSQI ≥5) was 86%. Paired comparisons did not show improvement in actigraphic sleep parameters following 8-weeks PR despite improvements in 6-min-walk distance (6MWD, mean improvement 54 m, 95% CI 34 m to 74 m, p<0.0001) and St. George’s Respiratory Questionnaire scores (SGRQ, mean improvement 7.7 points, 95% CI 5.2 to 10.2, p<0.0001). Stratified analysis of all sleep variables by severity of COPD, BMI, mood, mental status, 6-MWD and SGRQ did not show significant improvement after PR. In Veterans with poor sleep quality (PSQI ≥ 5), PR improved subjective sleep quality (PSQI, mean difference 0.79, 95% CI 0.07 to 1.40, p = 0.03).

Conclusions

Pulmonary rehabilitation improved subjective sleep quality in Veterans who had poor sleep quality at the beginning of the PR but did not improve objective sleep parameters by actigraphy. Our findings highlight the complex interactions among COPD, sleep and exercise.

Background

Adults with Chronic obstructive pulmonary disease (COPD) have poor sleep quality [1–3]. There is an increased prevalence of sleep symptoms such as difficulty of initiating and maintaining sleep or excessive daytime sleepiness among people with COPD [4]. People with severe COPD also have longer time to sleep onset and fragmented sleep due to frequent arousals [5]. Severity of COPD is also associated with poor sleep quality [6]. Additionally, poor sleep quality in people with COPD is associated with poor health related quality of life [1, 2], increased frequency of COPD exacerbations and mortality [7]. Poor sleep may also alter immune function and increase likelihood of COPD exacerbations [8].

Several factors, such as cough and dyspnea, affect sleep in people with COPD [7]. Daytime hypoxemia is independently associated with poor sleep efficiency [5, 9]. Nocturnal desaturation, however, does not have a clear relationship with poor sleep quality [10]. Pharmaceuticals used in the management of COPD such as corticosteroids and beta-agonists can also disrupt sleep and cause poor sleep quality [11].

Pulmonary rehabilitation (PR) has been proven to be beneficial in the management of COPD. It decreases dyspnea, increases exercise tolerance and improves quality of life (QoL) [12–14]. PR may provide short-term mortality benefit as well, if done early after acute exacerbation of COPD [15]. However, there are only sparse data on the impact of PR on sleep. A prospective study by McDonnell and colleagues showed that PR did not improve sleep quality as measured by Pittsburgh Sleep Quality Index (PSQI) despite improvement in QoL, exercise capacity, anxiety and depression [1]. Another study done in the chronic lung disease population by Soler et al. showed significant improvement in sleep quality after PR, even in the sub-group of COPD population [16]. There is also evidence that COPD patients with better sleep measures, such as non-fragmented sleep, good sleep efficiency, long bouts of sleep and short wakefulness after sleep onset, have increased activity during daytime and spent more time in the daylight [6]. If PR can improve sleep measures, improved sleep may, in turn, improve PR related outcomes.

All studies evaluating effects of PR in improving sleep quality in COPD have used subjective measures of sleep quality such as the PSQI. There is paucity of published studies measuring objective sleep measures such as sleep duration, sleep efficiency, nighttime awakening and wake after sleep onset. Therefore, we designed this retrospective, in-group, before-and-after study to evaluate effect of pulmonary rehabilitation in the quality of sleep in people with COPD using both subjective sleep quality (PSQI) and actigraphy data.

Methods

Study design and setting

We performed a retrospective “pre-and-post” study of prospectively maintained cohort data of people with COPD who underwent eight weeks of an outpatient center-based PR. This was a single-center study evaluating the Veteran population in Southern California. The study was approved by the Loma Linda Healthcare Systems institutional review board (IRB– 605, Protocol # 1219). The IRB waived consent requirement since the study was retrospective in design and data was analyzed anonymously.

Study participants and enrollment criteria

We reviewed charts of all Veterans who participated in PR at the VA Loma Linda Healthcare System from January 1, 2012 through December 31, 2018; and completed before-and-after rehabilitation watch actigraphy for sleep assessment. Only Veterans (older than 18 years of age) who underwent PR for COPD were included in the study. Veterans who did not complete the entire 8-weeks of the rehabilitation program (drop-outs) or had less than three days of actigraphy data, both before and after PR, were excluded from the study. We did not exclude current smoker in the study. Our PR program at one point allowed current smokers to participate. This exception was subsequently stopped due to high dropout rates among smokers. Since then only current non-smokers are allowed to participate in the PR program.

Pulmonary rehabilitation program

The PR program at VA Loma Linda Healthcare System is a comprehensive American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) certified program for Veterans. The program involves exercise training and extensive self-management educational programs including education on COPD symptoms, symptoms management, inhaler techniques, nutritional assessments and interventions and psychosocial evaluations. Participants meet three-days-a-week for eight weeks. Each PR session comprises of 30–60 minutes of educational sessions and 2 to 2.5 hours of exercise sessions with at least 30 minutes session of treadmill exercise tailored to each individual’s tolerance to exercise. As part of the PR program each participant completes an extensive list of questionnaires including demographics, medical history, medications, general health survey and various instruments assessing depression, mental status, dyspnea and sleep both before and after the PR.

All participants of the PR program at our center are asked to wear an Actiwatch 2® (Respironics Inc., Murrysville, PA) on the wrist 24-hour a day for at least a week before the program start and after completion of 8-weeks of the PR for a maximum of two weeks. At each time interval, the data is downloaded onto a computer via the Actiwatch 2® communication dock system. The Actiwatch2® software analyses data and a summary output including total time in bed (TBT), total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), wakefulness after sleep onset (WASO) and number of nightly awakenings is recorded for each of participant.

Assessments, data collection and outcomes

An actigraph is small simple device typically worn on the wrist like a watch. It can, however, be worn on an ankle or waist. This device is a sophisticated movement sensor that continuously records movement and integrates it over time. Mathematical algorithms are then utilized to estimate sleep and wakefulness time [17]. Use of actigraphy to monitor nocturnal sleep-wake parameters is feasible and simple. It is an accepted method to measure sleep parameters in clinical practice and is used in research as well [18, 19]. It has been studied in both the COPD and non-COPD populations; and has acceptable validity and sensitivity to detect sleep patterns associated with sleep disorders and medications [6, 19, 20].

Sleep quality was measured using the PSQI which was collected pre- and- post PR. PSQI measures sleep disturbances and sleep habits during last one month period. The questionnaire has 19 individual items and includes open ended questions and Likert-like items. It generates seven clinically derived domains or components of scores which includes: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. The global PSQI score is calculated by adding scores from all seven domains [21]. PSQI is a self-administered questionnaire with high test-retest reliability. It has been well validated to assess quality of sleep subjectively [21–23]. A global PSQI score of ≥ 5 reliably distinguishes “poor” quality sleepers from “good” quality sleepers (diagnostic sensitivity 89.6% and specificity 86.5%) [21].

We also collected data on COPD related QoL and symptom burden measurements with the COPD assessment test (CAT) [24], Modified Medical Council Research (mMRC) dyspnea scale [25], visual analogue scale part of Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ) [26] and St. George’s respiratory questionnaire (SGRQ) [27]; exercise capacity assessment using 6-minute walk test (6-MWT) [28]; mental status and depression assessments using St. Louis University Mental Status Examination scale (SLUMS) [29] and 30-points Geriatric Depression Scale (GDS) [30]; and daytime sleepiness using the Epworth Sleepiness Scale (ESS) [31]. These measurements were collected both before and after PR.

Data abstraction was done by clinicians involved in the care of the study participants. Most of the data abstracted were from pulmonary rehabilitation chart. In case of missing data, study participants clinical chart was accessed by clinicians directly involved in their care.

The primary outcome measure for this study was changes in sleep variables measured by actigraphy after 8-weeks of PR. Change in PSQI score was a secondary outcome measure.

Statistical analysis

All subjects who completed 8-weeks of PR program and have at least three days of both pre-PR and post-PR actigraphy data, were included in the final analysis. Shapiro-Wilk tests were performed to assess the normality of the data. Descriptive statistics are presented as mean (± SD) and median (Interquartile range, IQR) where applicable. Paired comparisons with paired t-test and Wilcoxon signed rank test were performed where applicable. Stratification of each of the variables (COPD severity, BMI categories, GDS, SLUMS, 6MWT, SGQR) based on clinically significant difference and paired comparisons were performed. Stratified analyses of all actigraphy sleep variables were performed based on severity of COPD, BMI, mood, mental status, 6-MWT, SGRQ scores and quality of sleep by PSQI. For PSQI, the study groups were stratified into normal quality sleepers (PSQI score of <5) and poor-quality sleepers (PSQI score of ≥5). Stata v15.0 (StataCorp, College Station, TX) was used for statistical analysis. A p-value < 0.05 was considered statistically significant.

Results

We reviewed medical charts of 90 Veterans who underwent PR to screen for the study. Thirteen participants were excluded because the indication for PR was other than COPD (Fig 1). Seventy-seven participants were identified who underwent PR for COPD. Eight more participants were excluded from the final analysis due to missing pre- or post- rehabilitation actigraphy data. Overall, 69 participants were included in the final analysis. Median number of days of actigraphy use before PR was 5 days (IQR 4–7) and 4 days (IQR 4–5) after PR.

Demographics and baseline clinical characteristic

The baseline characteristics of the study population are summarized in Table 1. The study population was predominantly male (97%) with mean age of 69 ± 8 years. More than half of the Veterans were not obese (62.3% had BMI less than 30 kg/m²). More than two-thirds (69.5%) of the Veterans had severe or very severe COPD (GOLD stage III or IV) and the impact of COPD in their lives as measured by COPD Assessment Test (mean CAT score 24.8 ± 7.1) was very high. Moreover, 75% of the study population had a high or very high impact of COPD on their daily lives. The SGRQ score was also moderately high (median 61.1, IQR 48.4 to 72.5) indicating high burden of COPD. The average dyspnea score (mMRC) was 2.4 ± 1.1. The six-minute walk distance (6-MWD) was relatively preserved (median 373m, IQR 300m – 432m).

Table 1. Baseline characteristics of the study population.

Demographics
Age, (mean ± SD), years	69 ± 8
Male, n (%)	67 (97)
BMI, kg/m², median (IQR)	27.5 (24.3–32.4)
Non-obese (BMI <30), n (%)	43 (62.3)
Obese (BMI 30–39.9), n (%)	20 (29.0)
Morbidly obese (BMI ≥ 40), n (%)	6 (8.7)
GOLD stages, n (%)
GOLD II	21(30.4)
GOLD III	33(47.8)
GOLD IV	15(21.7)
FEV₁% predicted, mean ± SD	47.4 ± 14.9
Impact of COPD
CAT score, n = 52, mean ± SD	24.8 ± 7.1
Medium impact—CAT score >10 - ≤ 20, n (%)	13 (25)
High impact—CAT score >20–30, n (%)	39 (75)
mMRC Dyspnea Scale, n = 63, mean ± SD	2.4 ± 1.1
SGRQ score, n = 67, median (IQR)	61.1 (48.8–72.5)
6-min walk test (meters), n = 69, median (IQR)	373 (300–432)
Prevalence of co-morbidities, n (%)
Hypertension	43 (62)
Dyslipidemia	40 (58)
Coronary artery disease	24 (35)
Diabetes mellitus	24 (35)
Prevalence of co-morbidities potential effect on sleep, n (%)
Chronic pain syndrome	36(52)
Psychiatric conditions	33 (48)
Home oxygen	18(26)
Medications with potential effect on sleep, n (%)
Analgesics	12 (17.4)
Psychoactive medications	16 (23.3)
Sleep aids	16 (23.2)
Sleep Burden of COPD
Prevalence of Poor Sleep Quality, n = 64, PSQI score ≥ 5, n (%)	55 (86)
Epworth’s Sleep Scale, n = 64, mean ± SD	8.0 ± 5.1
Neurocognitive Burden of COPD
Geriatric Depression Scale, n = 66, mean ± SD	12.9 ± 7.6
Normal (GDS score 0–10), n (%)	21 (31.8)
Mild depression (GDS score 11–20), n(%)	35 (53.0)
Severe depression (GDS score 21–30), n(%)	10 (15.2)
SLUMS Examination, n = 67, median (IQR)	25 (23–27)
Normal (Score 27–30), n (%)	18 (26.9)
Mild Cognitive Impairment (Score 21–26), n (%)	40 (59.7)
Dementia (Score <21), n (%)	9 (13.4)

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Abbreviations: SD–Standard deviation, IQR–Interquartile range, BMI–Body mass index, FEV1%—Forced Expiratory Volume in first second (% of expected), GOLD–Global initiative for Obstructive lung disease, CAT score–COPD assessment test score, mMRC–modified Medical research council, SGRQ–St. Georges Respiratory Questionnaire, SLUMS–St. Luis University Mental State Examination.

Sleep quality and factors impacting sleep

Poor sleep quality was highly prevalent in our study population. Eighty-six percent of the study population had poor sleep quality, defined by PSQI score of ≥ 5 and all participants had less than 90% of sleep efficiency. Co-morbidities affecting sleep were also prevalent in our study population. Nearly 7 in 10 Veterans (68.2%) had depressive symptoms (GDS score >10). Similarly, 59.7% of the Veterans had mild cognitive impairments and 13.4% met SLUMS criteria for dementia. Both depression and cognitive impairments can affect sleep health. One quarters of the Veterans had diagnosed sleep apnea (17 of 69) and related disorder and all were treated. ESS, which measures general sleepiness, was 8.0 ± 5.1 (mean ± SD) slightly higher than expected in normal individuals at baseline (ESS in normal individuals, 5.9±2.2, range 2–10) [31].

Chronic pain was present in 52% and psychiatric conditions including PTSD were present in 48% of our study population. Despite the high prevalence of pain and psychiatric conditions, only 17.4% of our Veterans were taking pain medications including narcotics and only 23.3% were taking psychoactive medications including antipsychotics. About one-quarter (23.2%) were on sleep aids (either prescription or over-the-counter) and 26% were on home supplemental oxygen.

Effect of PR on COPD related outcomes

Summary of effects of PR on COPD and sleep related variables are presented in Table 2. PR improved dyspnea and COPD related functional status and symptoms burden. SGRQ score significantly improved after PR (p<0.0001). PR was moderately efficacious in reducing COPD related respiratory symptoms (improvement in SGRQ by at least 8 points) in 50% of the Veterans. Dyspnea measured by the VAS part of the PFSDQ improved as well. The mMRC score improved on average by 0.76 points (95% CI 0.4–1.0; p<0.0001). However, only 29% (18/63) of the Veterans had a 2-point or more improvement in the mMRC score. The impact of COPD measured by CAT, decreased on average by 4.5 points (95% CI 2.5 to 6.5, p<0.0001). But only Veterans with high or very high impact of COPD at baseline (CAT score of >20) showed significant benefit. The 6-MWT also improved significantly after PR. On average, 6-MWD improved by 54m (95% CI 34m – 74m).

Table 2. Effect of PR on COPD/respiratory, sleep and neurocognitive variables.

Variables		Pre-PR	Post-PR	Mean change (95% CI)	Significance (p-value)
St. George’s Respiratory Questionnaire (SGQR), n = 64
	SGQR score, mean ± SD	60.9 ± 16.3	53.2 ± 16.4	7.7 (5.2 to 10.2)	<0.0001^*
	SGQR score, median (IQR)	61.1 (48.8 to 72.52)	56.7 (40.9 to 64.8)		<0.0001^*
Pulmonary Functional Status & Dyspnea Questionnaire
“Indicate how you have felt most days during past year?”, n = 53
	VAS, mean ± SD	5.6 ± 1.6	5.3 ± 1.7	0.3 (-0.1 to 0.7)	0.15^*
	VAS score, median (IQR)	6 (5 to 7)	5 (4.2 to 6.2)		0.15^*
“Indicate how you feel today?”, n = 60
	VAS, mean ± SD	4.9 ± 2.2	4.0 ± 2.1	0.8 (0.2 to 1.5)	0.01^*
	VAS Score, median (IQR)	5 (4 to 6)	4 (2 to 5.5)		0.01^*
“Indicate how you feel with most day-to-day activities?”, n = 60
	VAS, mean ± SD	5.9 ± 2.0	5.0 ± 1.9	0.9 (0.4 to 1.4)	0.001^*
	VAS Score, median (IQR)	6 (5 to 7)	5 (4 to 6)		0.001^*
COPD Assessment Test, n = 46
	CAT score, mean ± SD	24.2 ± 7.0	17.5 ± 6.2	4.5 (2.5 to 6.5)	<0.0001^**
	CAT score, median (IQR)	25 (20.5 to 29.5)	21 (16 to 24)		<0.0001^**
mMRC dyspnea scale, n = 63
	mMRC score, mean ± SD	2.4 ± 1.1	1.6 ± 0.9	0.76 (0.4 to 1.0)	<0.0001^**
	mMRC score, median (IQR)	2 (2–4)	2 (1–2)		<0.0001^**
SLUMS score, n = 64
	SLUMS score, mean ± SD	24.5 ± 3.2	25.7 ± 2.8	1.2 (0.4 to 2.0)	0.010^*
	SLUMS score, median (IQR)	25 (23 to 27)	26 (24 to 27)		0.010^*
Geriatric Depression Scale, n = 66
	GDS score, mean ± SD	12.7 ± 7.6	11.6 ± 7.7	1.1 (-0.1 to 2.3)	0.051^*
	GDS score, median (IQR)	13.5 (6 to 18)	11 (5 to 16)		0.051^*
6-min Walk test, n = 66
	6-MWD, meters, mean ± SD	340 ± 114	394 ± 129	54 (34 to 74)	<0.0001^*
	6-MWD, meters, median (IQR)	373 (300.3 to 431.9)	407.3 (331.6 to 165.7)		<0.0001^*
Epworth Sleepiness Scale, n = 61
	ESS score, mean ± SD	7.7 ± 5.1	8.0 ± 4.5	-0.3 (-1.4 to 0.7)	0.54^**
	ESS score, median (IQR)	8 (4 to 11)	8 (5 to 11)		0.54^**

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Abbreviations: 95% CI (95% Confidence Interval); Statistics:

*Wilcoxson Signed rank test

**paired t-test.

We observed statistical improvement in cognitive function by SLUMS score but only a trend toward improvement in mood (GDS score, median difference of 2.5, p = 0.051). The ESS did not change after PR in the entire cohort as well as when stratified by presence of absence of sleep disorders (stratified data not presented in the manuscript).

Effect of PR on sleep

The effect of PR on sleep is summarized in Table 3. The TBT and TST decreased after PR although not significantly. The SOL, SE, WASO and nightly awakenings did not change following PR. Stratified analysis of all sleep variables by severity of COPD, BMI, mood, mental status, 6-MWD and SGRQ did not show significant improvement after PR. Overall, PR did not improve sleep when measured quantitatively by the actigraphy. Veterans who were not taking any psychoactive medications, however, had decrease in TBT (median, IQR: Pre-PR 532 min, 463–599 vs Post-PR 491 min, 426–544; p = 0.047) and TST (median, IQR: Pre-PR 418.5 min, 349–486 vs Post-PR 370 min, 314–465; p = 0.003) after PR. Similarly, Veterans who were not on any pain medications, TST decreased as well (median, IQR: Pre-PR 394 min, 337–459 vs 376 min, 322–439; p = 0.04).

Table 3. Sleep related primary and secondary outcomes after 8-weeks of pulmonary rehabilitation.

	Before Pulmonary Rehabilitation	After Pulmonary Rehabilitation
Primary outcomes
Actigraphy Sleep Variables, n = 69	Median (IQR)	Median (IQR)	Significance
Total Time in Bed, TBT (min)	499 (447 to 567)	491 (437 to 548)	0.40^*
Total Sleep Time, TST (min)	384 (331 to 425)	377 (321 to 448)	0.14^*
Sleep Onset Latency, SOL (min)	29.7 (15.4 to 38.1)	29.6 (11.8 to 43.4)	0.99^*
Sleep Efficiency, SE (%)	80.6 (73.0 to 84.9)	79.5 (72.5 to 85.9)	0.32^*
Wakefulness After Sleep Onset, WASO (min)	51.3 (37.2 to 70.6)	56.3 (33.5 to 75.6)	0.70^*
Number of nightly Awakenings	33.4 (25.3 to 45)	35.5 (22.3 to 46.5)	0.77^*
Secondary outcomes
Pittsburg Sleep Quality Index (PSQI)	Mean (SD)	Mean (SD)	Mean Difference (^95% CI)	Significance
PSQI score–all Veterans, n = 61	8.1 (3.4)	7.5 (3.2)	0.57 (-0.05 to 1.2)	0.07^**
PSQI score in Veterans with normal sleep quality at baseline (PQSI ≤5), n = 9	3.2 (0.97)	3.7 (2.0)	-0.44 (-2.3 to 1.4)	0.59^**
PSQI score in Veterans with poor sleep quality at baseline (PQSI >5), n = 52	8.9 (2.9)	8.2 (2.9)	0.79 (0.07 to 1.4)	0.03^**

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*Wilcoxson Signed rank test

**Paired t-test; ^95% CI– 95% Confidence Interval.

Sleep quality measured by PSQI in this population did not improve after 8-weeks of PR. The average improvement in PSQI score in the entire cohort was 0.57 points (p = 0.07). In Veterans with poor sleep quality at baseline (pre-PR PSQI score of ≥ 5), however, PSQI score improved significantly (mean difference 0.79; p = 0.03) (Fig 2).

Fig 2 — Data are presented in mean change in PSQI among veterans with good sleep quality and poor sleep quality before and after PR. The line (+++) shows mean change and the line (—) shows data dispersion with ±1 standard deviation (SD). Abbreviations: PSQI, Pittsburg Sleep Quality Index; CI, Confidence interval.

A post-hoc analysis of actigraphic measure of sleep by quality of sleep at baseline (normal vs poor sleepers) was performed as well. There was no difference in quantitative sleep parameters in poor sleepers as compared to Veterans with normal sleep quality by PSQI.

Discussion

In this retrospective study, the most important finding was a significant improvement in the subjective sleep quality after pulmonary rehabilitation in Veterans who had poor quality sleep before PR. We did not find improvements in objective measures of sleep by actigraphy despite improvements in dyspnea, CAT, SGRQ, and mood/cognitive scores along with improved exercise.

Our cohort consistent of only Veterans and almost entirely males. Both factors can influence sleep. Veterans have high prevalence of psychiatric conditions such as PTSD, depression and anxiety as compared to general population [32]. Directly or indirectly these factors increase the prevalence of insomnia and poor-quality sleep. Gender affects sleep as well. Females have reported poor quality of sleep, longer sleep latency and increased nighttime awakenings as compared to males [33], however, when measured by PSG, females have better sleep efficiency, more time spent sleeping and less awakening [34]. In elderly population, this gender difference may be very small or non-significant and females have better correlation between objective and subjective sleep qualities [35]. All these studies are done in healthy volunteers, therefore, gender effect in people with COPD has not been studied.

The prevalence of poor-quality sleep in our cohort (86%) was higher than reported in previous studies [1, 2]. Quantitatively, our study cohort had poor sleep as well. For example, median sleep efficiency was 80.6% (IQR 73.0 to 84.9%). Although, PSQI poorly correlates with objective measures of sleep such as polysomnography or actigraphy [23], our cohort had poor sleep both qualitatively and quantitatively. The PR program was highly effective in several outcomes that were expected to improve. In theory, as well as qualitative data from prior studies (PSQI data) and robust improvement in COPD related variables with PR in our study, we expected improvement in objective sleep outcomes by actigraphy. However, the trend in our data was for a decrease in total bedtime, total sleep time and increased restless sleep, albeit without statistical significance. Some of the data trends in our study are in disagreement with recently published data from Cox et al. [36] but statistically similar. TST and SE increased in Cox et al. study but either decreased or remained unchanged in our study. Sleep parameters of our cohort were also slightly different from Cox et al. cohort. Our study cohort had markedly high total number of awakenings (median 33.5 vs 9) and SOL (median 29.7 vs 20) as compared to Cox et al. On the other hand, WASO was markedly higher in the Cox et al. cohort (median 79 vs 51.3). The Cox et al. study included both home-based and center-based PR participants but not all participants completed 8-weeks of PR. They also did not report subjective sleep measures. In contrast, we included only center-based participants and all participants completed a full 8-weeks of PR. We also reported both objective sleep measures (actigraphy data) and subjective sleep quality measures (PSQI data). To our knowledge this is the largest cohort of COPD patient undergoing PR and sleep evaluation both objectively and subjectively.

Subjective measures of sleep quality by PSQI have previously been studied in peoples with COPD undergoing PR. The results of those studies are mixed [1, 16, 37]. McDonnell et al. [1], in his 28-patient cohort, reported a mean difference in the PSQI score of 0.79 (95% CI -0.35 to 1.93) after PR. Soler et al. [16] included patients with both restrictive and obstructive lung diseases. In his cohort of 48-COPD patients, he reported significant improvement in the global PSQI index (6.6 ± 3.9 to 5.5 ± 3.6, p = 0.01). In these 48 patients, the proportion of patients with poor sleep quality decreased from 58% to 47% (p<0.001) [16]. In another study, Lan et al. [37], showed a significant decrease in the PSQI score (mean difference of 1.89) after PR in COPD patients. The number of patients with PSQI >5 decreased by 20.6% in that cohort (n = 34). In comparison to the above studies, we only found significant improvement in sleep quality in the subgroup of our Veterans who had poor quality sleep before the beginning of PR. While our study and some other studies, as discussed above, have found statistically significant improvement in PSQI but none of the study reached minimal clinically important difference (MCID) for PSQI which is 3 points. This underlines the fact that PR alone may not be sufficient to improve sleep. Interventions such as formal sleep education and cognitive behavioral therapy if incorporated in the PR program, may have more impact on sleep.

COPD impairs sleep quality potentially by sleep fragmentation from increased arousals and sleep disruptions. A multitude of factors may be involved including symptoms such as cough and dyspnea and underlying disease pathology such as lung hyperinflation, hypercapnia and hypoxemia. Other factors may also contribute including COPD comorbidities of anxiety, depression, pain, and neuropsychiatric conditions. Lastly, the treatments of COPD including oxygen therapy, beta-agonist therapy and anticholinergic therapy likely disrupt sleep as well. The natural effect of sleep itself worsens symptoms of COPD by decreasing ventilation, increasing airflow obstruction leading to hypercapnia and hypoxemia. PR improves the overall symptom burden in COPD, improves QoL and also improves comorbid conditions such as anxiety, depression [38, 39] and cognitive status [40].

Exercise is one of the major components of PR, therefore, we expected improvement in sleep quality following PR. However, lack of significant improvement in sleep in COPD after 8-weeks of PR suggests a possible complex interaction between pathophysiology of COPD, COPD symptoms, associated comorbidities and sleep. We did not observe significant objective benefit in our cohort which may suggest that PR programs substantially longer than 8-weeks are required to demonstrate improvement in other measure of sleep quality and quantity. Lack of improvement in actigraphy measures may also be related to severity of COPD in our cohort.

Exercise affects sleep in several ways and these effects may vary depending on the duration and intensity of the exercise [41]. Acute exercise may improve total sleep time and slow wave sleep probably by affecting core body temperature, increasing growth hormone, decreasing insulin resistance and decreasing vagal tone. Regular exercise improves sleep by modulating inflammation, circadian rhythm and mood [41]. Data on the effects of sleep in the elderly population are limited and those studies mostly included healthy individuals. Available data suggest that at least 10 to 16 weeks of regular exercise in elderly population improves sleep quality, reduces sleep fragmentation and improve sleep efficiency [42–46]. Increased sleep continuity and sleep depth was noted in a polysomnography (PSG) study after 16 weeks of exercise [47]. But the same study failed to show improvement in sleep quality (PSQI), total sleep time and sleep efficiency. A systematic review by Yang et al. showed only improvement in sleep quality (PSQI and SOL) but not sleep duration, efficiency and disturbances [43]. Regular exercise over 12 months or more may be needed to observe objective sleep benefits [41].

Another notable finding in our cohort was that those Veterans who were not on any pain medications or psychoactive medications had decrease in sleep durations (TBT and TST) but no effect on sleep efficiency. This may illustrate the effect of pain and psychiatric condition as well as its treatment on sleep.

Objective measures of sleep such as actigraphy measure different aspects of sleep than the subjective PSQI. As such, actigraphy outcomes correlate poorly with PSQI [23, 48]. Aili et al. recommended at least six-nights of measurements as a reliable measure of sleep quality [48]. We discovered similar discrepancy between subjective and objective sleep measure.

Limitations of the study

There are several limitations to our study. Some of the limitations are inherent to the retrospective design of the study such as lack of randomization and lack of a control group. However, a “before-and-after intervention” study design has the benefit of decreasing inter-subject variability. Multiple comparisons for the stratified analyses were done which may have decreased the power of the study. We only included participants with complete pre-PR and post-PR actigraphy data eliminating the problems of missing data. Another potential limitation of the study is the measurement of sleep variables with actigraphy. Actigraphy has acceptable validity and reliability [19, 20, 49] but has several limitations as compared to PSG. Actigraphy is one dimensional measurement of sleep based on movements and PGS gathers sleep data from multiple inputs such as electroencephalogram, electro-oculogram and electromyogram [49]. Therefore, certain sleep variables such as SOL is more accurate in PSG [50]. More definitive measurement of sleep by PSG would have been inconvenient and more time consuming for the subjects. An overnight PSG would have given only one day of sleep data. On other hand, actigraphy is able to gather data for multiple days providing a more robust picture of sleep disturbances than would be obtained from one night only [49]. Daytime activities and naps also affect sleep. Daytime napping can decrease sleep efficiency and duration of nocturnal sleep [51, 52]. On the other hand, people with COPD with better sleep have increased daytime physical activities [6]. We did not collect data on daytime activities or nap in our study cohort.

The study population was entirely composed of Veterans and nearly all were male. As discussed earlier, Veterans have high prevalence of post-traumatic stress disorder and other related psychiatric disorders, which, in turn, may cause a higher prevalence of poor sleep quality. Our PR program excludes current smokers as well. Therefore, our findings may not be generalizable to current smokers, females with COPD or the non-Veteran COPD population.

Conclusions

In summary, we found a high prevalence of poor sleep quality in our study population undergoing PR. Quantitative measures of sleep by actigraphy did not improve after 8-weeks of PR. Qualitative measures of sleep by PSQI improved significantly in Veterans with poor sleep quality but the improvement was small and may not be clinically important. These findings suggest a complex relationship between COPD, sleep and exercise but also show benefit of PR in people with COPD with poor sleep quality.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the VA Loma Linda Healthcare System, Loma Linda, CA.

All authors reviewed and approved final version of the draft manuscript and vouch for the accountability, accuracy and integrity of any part of the work.

Data Availability

Data is saved in Loma Linda VA Healthcare Systems server. Data cannot be shared publicly because of the data is the property of VA Healthcare systems. Data are available from the senior authors or the VA Loma Linda Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. IRB Contact: Sunbeam Obomsawin E mail: Sunbeam.obomsawin@va.gov Phone: 909-825-7084 x2264 Senior Author Contact: Nagamani Dandamudi, MD Email: Nagamani.Dandamudi@va.gov.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0248466.r001

Decision Letter 0

Federica Provini

15 Oct 2020

PONE-D-20-23683

Impact of Pulmonary Rehabilitation in Sleep in COPD patients measured by Actigraphy.

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Reviewer #1: Thank you for the opportunity to review this work which presents both subjective and objective sleep quality findings in a group of veterans with COPD who have undertaken pulmonary rehabilitation. The authors report findings that are largely consistent with the literature in this area, albeit a limited field of literature.

I have a couple of key queries to raise; followed by some more general comments.

- In the abstract and introduction the authors suggest that this is the first study in COPD to undertake actigraphic assessment of sleep relative to pulmonary rehabilitation. They then contradict this in the discussion with reference to the paper by Cox et al (reference 27). In the discussion the authors do accurately highlight theirs is the first study to include both subjective and objective assessment of sleep quality. Please amend all earlier statements to accurately reflect the work under consideration is not the first to use actigraphy in assessing sleep quality relative to pulmonary rehabilitation in COPD; but rather the first to combine both subjective and objective assessment of sleep quality.

- There are a number of discrepancies between the data in tables, data in text and associated text wording that tell a conflicting message. Depending on what is the correct data this may actually change the findings of the paper.

Pg 15: The text indicates that TBT and TST increased for veterans taking psychoactive medications, however the data for TST does not support this (pre median 394 minutes, post median 376 minutes). Please amend as appropriate. Conversely, in the discussion it is indicated that there is a decrease in TST. Similarly, the data on page 15 for veterans not taking psycho active medications indicates a reduction in TST (pre 418mins, post 370mins) but the text indicates an increase in TST.

- Table 3: the mean difference for change in PSQI for veterans with poor sleep quality needs to be a negative number ie. a decline in PSQI which corresponds to an improvement. Similarly for Figure 2.

Conversely, PSQI for veterans who did not have poor sleep quality needs to be a positive number ie. an increase in PSQI score which corresponds to a decline in sleep quality. Similarly for Figure 2.

- Table 2: Data for 6MWD suggests there was a significant decline in 6MWD post PR greater than the clinically meaningful difference (54m decline). The mean difference in the table needs to be presented as a negative number. This is also inaccurately reported in the text of the results as an improvement in 6MWD. Can the authors please check the data entered into the table in the event the pre and post rehab data have been transposed? Or amend the findings as presented. If, indeed, there was a decline in 6MWD this might suggest that in these participants PR did not achieve the expected outcomes/benefits associated with exercise capacity, and could be a contributing factor to the findings ie. insufficient training dose to see potential changes in sleep parameters?

The above queries may well result in relevant amendments throughout all sections of the manuscript.

Abstract:

- I’m not sure that ‘before-and-after’ requires hyphenation?

Introduction:

- The authors might consider describing the participants as ‘people with COPD’ as opposed to ‘patients with COPD’ as the study was not conducted in inpatients.

Methods:

- It is unclear how this study did not exclude current smokers, when the PR program under consideration does not include current smokers. Can the authors please clarify this wording.

- It would be helpful to indicate the session duration for the 3x PR sessions each week, and ideally what proportion of each class comprised exercise training.

- Did participants in this study also keep a sleep diary? If yes, how does patient documented timing of factors such as bed time line up with that produced by actigraphy?

- Can the authors please provide brief additional details as to how the actigraph device in question determines sleep factors, particularly bed-time vs sleep onset vs wake time vs get up time.

Results

- The sub heading ‘Prevalence of sleep…..’ does not seem to accurately reflect the content in this section. The authors may consider amending this sub-heading, possibly ‘Sleep quality and impacts on sleep’.

Discussion:

- Sentence one – please specify ‘subjective’ sleep quality improvement (if this is accurate relative to results queries)

- Can the authors comment on their PSQI findings, relative to the literature, in the context of the minimal important difference for the PSQI? While this and some studies have identified statistically significant improvements in PSQI with PR, no studies have demonstrated an improvement that exceeds the MID.

- The final paragraph of the discussion prior to limitations is a largely a repeat of already presented text and could be amended or deleted.

- It would add depth to this report if the authors specifically articulated the ‘disagreement in trends’ that they note between their work and that published by Cox et al. On reviewing that paper, it would appear that both studies have similar findings in that both studies found no change in sleep parameters measured by actigraphy following PR; which would be useful to articulate in terms of placing this study within the context of other findings.

Typographical errors:

- Pg 10, line 1: Typographical error. ‘Out’ PR program, should read ‘Our’ PR program

- Pg 12: Typographical error. ‘St Louise’ mental status exam, should read ‘St Louis’

- Pg 12. Patients clinical chart was ‘accessed’ by… (currently reads access)

- Pg 13 line 2 amend to read ‘clinically significant difference’

- Pg 14 – 6MWD has not been previously defined in the text of the manuscript

Reviewer #2: PONE-D-20-23683

Comments to the authors;

The study of Thapamagar and collaborators entitled "Impact of Pulmonary Rehabilitation in Sleep in COPD patients" is relevant as patients with COPD have significant sleep disorders, including poor sleep quality (the focus of this manuscript), obstructive sleep apnea, and nocturnal oxygen desaturations among others.

Increasing awareness about such sleep disturbances is relevant. Non-pharmacological approaches, such as pulmonary rehabilitation programs can be considered. Objective measurements of sleep quality can provide a scientific rationale to implement such therapies.

In this particular work, the authors tested the hypothesis that actigraphy would demonstrate improvement in objective sleep quality in patients with COPD attending a VA pulmonary rehabilitation program.

I think the manuscript could benefit from a revision. My comments are as:

1. The authors state that they did a retrospective study. They analyzed a large dataset of subjects that attended the PR program at the VA system with COPD. My understanding is that the subjects had the actigraphy (all of them) for sleep assessment as a routine part of the program? Or to assess daily activity? Please explain. Was it planned initially as a research study? If not, please expand on why your program is using Actiwatch on a PR program.

2. Expanding the discussion about male predominance is essential. The difference in sleep patterns from the gender perspective may help understand some of the results, and not limit the comment on the limitation section (which it should also be described as the authors did).

3. There is some discrepancy about the severity of the disease (please include 'severe and very severe' when describing the population -2 and 3- and the reference to GOLD severity guidelines). Why the patients had relatively preserved exercise tolerance measured by 6MW but are mostly on the 'severe' to 'very severe' category? That could happen, but less likely with such a high CAT score (mean of 24.8 +/- 7).

4. As very briefly discussed by the authors, pharmacology may have played an essential role in this population. However, I didn't find the multivariate analysis considering this variable as a whole ('any meds that may affect sleep). The impact of such medications on sleep architecture, expanding the discussion, and running the analysis may help.

5. COPD and sleep quality have been assessed (objectively)with PSG, contrary to what the authors describe. Discussing differences/limitations on actigraphy on sleep assessment seems important, contributing to the negative results.

6. The factors on the background influencing poor sleep (second paragraph) could use seminal references. The pharmacological effects and the reference (11) presented is not optimal.

7. The PR described (please add exercise tolerance on the third paragraph) also need some of the seminal or best references (Ries et al. in Annals, ATS PR document, or alike).

8. The paragraph starting (background section) 'there is also evidence that COPD…….. outcomes' will fit better in the discussion section.

9. Do not abbreviate Loma Linda VA (VALL) as it is not standard.

10. Typo on the last paragraph on methods' Out' needs to be 'Our', I guess.

11. Subheading explaining the actigraphy assessment. Briefly, what does, and how you use it (already described). Rephrase the 'use of the actigraphy' paragraph and put on the discussion. Also, it is simple to set, but not as simple to analyze for research purposes. A brief discussion of the actigraphy limitations seems necessary. "Actigraphy is a validated method to assess sleep, etc.'. It could be from Ancoli-Israel paper cited or equivalent.

12. There is no clarity on the overweight group (BMI 25-<30). Please expand on the discussion as the mean was 29? Table result (27.5) and text do not match BMI; please correct with the right number.

13. In the results section, limit to describe the % found. Avoid as much as possible 'nearly', majority, three-quarters by the %, etc. Just write the results.

14. SGRQ has an error/typo; 31.1 or 61? See text/table discrepancy.

15. mMRC is not expected to change that much. The authors seemed surprised by the results. Personal comment.

16. The description of the cognitive findings can be on the table and expand on the discussion. Those are not the primary or secondary aim for the study.

17. I would recommend running the analysis excluding patients on oxygen -26%- (improves sleep) and or obstructive sleep apnea (I assume there will be some). Both can interfere with the results. Despite having fewer subjects, may help better understand the results. It is very briefly discussed in two lines but a very general approach, and it is relevant for this study.

18. The results for PR are not necessary on the results section but a table and the discussion briefly (to demonstrate the program was effective). Are well known. Perhaps shortly name the ones that improved (quality of life, exercise tolerance, etc.).

19. The discussion could benefit from more profound thoughts from the authors regarding the benefits on the more severe patients (CAT score >20) as well as the ones with already low sleep quality (PSQI >5). Also, about the effects/impact of medication on sleep.

20. Some brief discussion comparing objective measurements of sleep would help the reader not familiar with sleep medicine (PSG vs. Actigraphy).

21. The paragraph starting with 'Exercise is one of the ….' Has to be before the previous one 'exercise affects sleep.'

22. On the limitations, some paragraphs will be perhaps better to move up to the discussion section; 'Actigraphy has reasonable validity ….'. Also, the phrase is not too scientific; maybe it can be rephrased.

23. Discussion about the patient population. This is relevant. And then briefly can be said in the limitation section as well.

24. Nice tables. Perhaps the median doesn't add much to the study description. The dyspnea questionnaire expanded is not needed in much detail as it is beyond the study's intent. The Epworth was collected and had to be part of sleep discussion and assessment and not standing alone.

25. Perhaps the reader could benefit from a brief explanation of how sleep quality is measured. Many readers are not familiar with sleep variables.

**********

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Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Mar 16;16(3):e0248466. doi: 10.1371/journal.pone.0248466.r002

Author response to Decision Letter 0

8 Dec 2020

PONE-D-20-23683

Response to the Reviewer #1

Authors greatly appreciate the excellent review, comments, critics and recommendations by the reviewers. We have put forward our best effort to answer your concerns and comments and amended our manuscript as appropriate. We continue to value your critics and comments.

Here are our responses:

Comment by the reviewer:

Response:

We really appreciate you pointing out this oversight. The matter of the fact is that when we conceived this study and during initial write up, there were no published studies which used actigraphy to assess sleep relative to pulmonary rehabilitation. While we were working on our data analyses, Cox et al. published their data. As suggested by the reviewer, we will amend our statement in the abstract and introduction section to reflect use of both subjective and objective assessment of sleep quality.

Comment by the reviewer:

Response:

Authors greatly appreciate reviewer pointing out this discrepancy. In fact, TBT and TST data among Veterans not taking pain medications or psychoactive agents were inadvertently swapped and the same data was erroneously interpreted as increased rather than decreased. The data crossed checked and error was corrected.

This segment of the manuscript reads as below before correction: (errors in red)

“Veterans who were not taking any pain medications, however, had an increase in TBT (median, IQR: Pre-PR - 481 min , 456-554 vs. Post-PR 491 min, 439 – 541; p=0.047) and TST (median, IQR: Pre-PR: 394 min, 337-459 vs Post-PR 376 min, 322 – 439; p=0.042) after PR. Similarly, Veterans who were not on any psychoactive medications, TST increased as well (median, IQR: Pre-PR: 418.5 min, 349-486 vs. Post-PR 370 min, 314 – 465; p=0.003)”

The updated/corrected paragraph will read as below: (corrections in blue)

“Veteran who were not taking any psychoactive medications, however, had decrease in TBT(median, IQR: Pre-PR 532 min, 463-599 vs Post-PR 491 min, 426-544; p=0.047) and TST (median, IQR” Pre-PR 418.5 min, 349 – 486 vs Post-PR 370 min, 314 – 465; p=0.003) after PR. Similarly, Veteran who were not on any pain medications, TST decreased as well (median, IQR: Pre-PR 394 min, 337 – 459 vs 376 min, 322 – 439; p=0.04).”

This portion of the data was not presented in the tables. If editorial team and reviewers think it will be useful, the authors are open to add to the table or authors will submit this section of data as a supplemental table.

Changes were made in the discussion section to reflect above mentioned changes.

- Table 3: the mean difference for change in PSQI for veterans with poor sleep quality needs to be a negative number ie. a decline in PSQI which corresponds to an improvement. Similarly for Figure 2.

Conversely, PSQI for veterans who did not have poor sleep quality needs to be a positive number ie. an increase in PSQI score which corresponds to a decline in sleep quality. Similarly for Figure 2.

Response: We appreciate this discussion. It is reasonable to think that change in PSQI is negative in the language of numbers (ie PSQI decreased and therefore it should be marked as negative). However, the construction of the PSQI is such that a lower number represents less severe symptoms and improvement from prior. Since, we calculated all variables as difference from Pre-PR to Post-PR values, we adopted positive change for PSQI as improvement. If reviewers strongly feels that the convention is otherwise please advise. Authors are be happy to reconsider.

- Table 2: Data for 6MWD suggests there was a significant decline in 6MWD post PR greater than the clinically meaningful difference (54m decline). The mean difference in the table needs to be presented as a negative number. This is also inaccurately reported in the text of the results as an improvement in 6MWD. Can the authors please check the data entered into the table in the event the pre and post rehab data have been transposed? Or amend the findings as presented. If, indeed, there was a decline in 6MWD this might suggest that in these participants PR did not achieve the expected outcomes/benefits associated with exercise capacity, and could be a contributing factor to the findings ie. Insufficient training dose to see potential changes in sleep parameters?

The above queries may well result in relevant amendments throughout all sections of the manuscript.

Response: We again appreciate catching this by our reviewer. In fact, the mean+/-SD data was transposition during the construction of the table. It has been re-checked and verified from the main data output sheet. No changes in the manuscript was needed except correction of the transposition of mean+/-SD values.

Abstract:

- I’m not sure that ‘before-and-after’ requires hyphenation?

Response: Authors agree that it does not improve the sentence. Hence, we’ll remove the hyphenation.

Introduction:

- The authors might consider describing the participants as ‘people with COPD’ as opposed to ‘patients with COPD’ as the study was not conducted in inpatients.

Response: We agree with describing the participants as “people with COPD”. It reads better as well. “Patients” in most places were replaced by “people with COPD” as appropriate. In some places, where another article was referenced or the flow of the sentence was impeded by the phrase “people with COPD”, it was not changed.

Methods:

- It is unclear how this study did not exclude current smokers, when the PR program under consideration does not include current smokers. Can the authors please clarify this wording.

Response: Our PR program excludes people with COPD who is a current smoker. As a pilot project, however, few people with COPD who were currently smoker were allowed. The pilot project was quickly discontinued due to high drop-out rate among smokers in the program. Since the number of participants who smoke were small, we decided to include them in our study.

Method section has been amended to reflect the explanation.

- It would be helpful to indicate the session duration for the 3x PR sessions each week, and ideally what proportion of each class comprised exercise training.

Response: Each PR session comprised of 30-60 min of educational session and 2-2.5 hours of exercise session with at-east 30 min of treadmill session tailored to each individual’s tolerance to exercise.

A paragraph detailing this has been added to the manuscript.

- Did participants in this study also keep a sleep diary? If yes, how does patient documented timing of factors such as bed time line up with that produced by actigraphy?

Response: Since this study was retrospective in design, the participants were not expected to keep a sleep diary.

- Can the authors please provide brief additional details as to how the actigraph device in question determines sleep factors, particularly bed-time vs sleep onset vs wake time vs get up time.

Response: Actigraphy continuously monitors movement and activities of subjects when worn. By analyzing these movements using an algorithm, sleep variables can be estimated. We have added 2 lines with a new reference to summarize the actigraphy under “Assessments, Data Collection and Outcomes” section of the manuscript.

Results

Response: Our intention was to describe and report Sleep quality and condition affecting sleep. We agree that “Prevalence of sleep” may not describe the section well. We made changes as suggested with some modification.

Discussion:

- Sentence one – please specify ‘subjective’ sleep quality improvement (if this is accurate relative to results queries)

Response: This is accurate information and ‘subjective” has been added to the sentences. Thank you again.

Response: Authors agree that studies have not found significant effect of PR on sleep quality by PSQI (at least MCID or better). Plausible explanation of this could be that multitude of factors affect sleep, especially in conditions like COPD. As discussed in the manuscript, several of factors affect sleep in COPD and impact of only PR in improving sleep may be small. Therefore, additional measures which may help to improve may be needed and incorporated in the PR to improve sleep in such population. Measures such as cognitive behavioral therapy for insomnia (CBT-i) could be beneficial.

Change in manuscript: the following was added to the paragraph discussing PSQI in the discussion section.

“While our study and some other studies, as discussed above, have found statistically significant improvement in PSQI but none of the study reached minimal clinically important difference (MCID) for PSQI which is 3. This underlines the fact that PR alone may not be sufficient to improve sleep. Interventions such as formal sleep education and cognitive behavioral therapy if incorporated in the PR program, may have more impact on sleep.”

- The final paragraph of the discussion prior to limitations is a largely a repeat of already presented text and could be amended or deleted.

Response: The sentence, which was similar from prior paragraph has been deleted.

There are no studies assessing sleep in both objective and subjective methods in a COPD cohort. Our study is the first to report such data.

Response: Authors agree with your statement that the findings are similar statistically. However, there are some differences in the actigraphic sleep architecture and change following PR between Cox et al. cohort and ours. For example, TST increased in Cox et al but decreased in ours. SOL and Awakenings were low in Cox et al. study but WASO was higher than ours.

Few sentences detailing similarities and differences has been added to the paragraph.

Typographical errors:

- Pg 10, line 1: Typographical error. ‘Out’ PR program, should read ‘Our’ PR program

- Pg 12: Typographical error. ‘St Louise’ mental status exam, should read ‘St Louis’

- Pg 12. Patients clinical chart was ‘accessed’ by… (currently reads access)

- Pg 13 line 2 amend to read ‘clinically significant difference’

- Pg 14 – 6MWD has not been previously defined in the text of the manuscript

Response: Thank you again for spotting all these typographical errors.

Page 10, Line 1: Changed to ‘Our’

Page 12: Changed to ‘St Louis’

Page 12: Changed to ‘accessed’

Page 13: Changed to ‘clinically significant difference’

Page 14: We agree that 6-MWD was not previously defined in the manuscript. Added six minute walk distance before 6-MWD.

PONE-D-20-23683

Response to Reviewer # 2

Here are our responses:

Response: During early days of PR program at Loma Linda VA, a pilot study was done to incorporate activity tracker to track activity and sleep. The study included only few patients. An abstract was presented to ATS. However, the practice to use activity tracker continued as a standard of care for PR program at our institution.

No changes in manuscript made in response to this comment. Please advise if it is absolutely necessary amend the manuscript.

Response: added a paragraph:

Gender affects sleep as well. Females have reported poor quality of sleep, longer sleep latency and increased nighttime awakenings as compared to males[32], however, when measured by PSG, females have better sleep efficiency, more time spent sleeping and less awakening[33]. In elderly population, this gender difference may be very small or non-significant and females have better correlation between objective and subjective sleep qualities[34]. All these studies are done in healthy volunteers, therefore, gender effect in people with COPD has not been studied.

Response: Thank for pointing out the discrepancy. We added “very severe” in the sentence to reflect the accurate description of the severity of the disease.

We were also intrigued by the finding that exercise capacity was relatively preserved in our study population with severe or very severe COPD with very high CAT score. In my clinical practice, I obtain mMRC and CAT score on every patient on every visit. I also get 6MWT if there is any decline in functioning. For some reason, I have seen large discrepancy in mMRC and CAT score. I do not have large sample to cross validate this discrepancy with 6MWT in my practice. However, we know that there is a very good correlation between mMRC and CAT score (r=0.788, p<0.0001; Kaltsakas, ERJ 2013). We also know that dyspnea scales correlate with 6MWT. If I have to guess, I would suspect that it has to do something about discrepancy between various components of CAT score vs mMRC, especially components of CAT score asking about dyspnea. This is something I intend to pursue in a separate project. It is also difficult to evaluate the relative preservation of exercise in our population from this data set because of the nature of the study (we are studying 6MWT in a population who is expected to or are exercising).

Response: This is very interesting aspect of COPD and sleep management and an intriguing question as well. We did consider COPD medications as a factor in our protocol and data analysis. We collected data on each category of the medications including short acting bronchodilators, LABA, LAMA and ICS. We also included other drugs affecting sleep such as sleep aids, psychoactive medications as well as pain medications. Nearly all participants were on short-acting bronchodilators (SABD) and nearly all were in some combination of LABA, LAMA or both. The difference in the pattern of SABD, LABA, LAMA and combination of those would be very small. Therefore, to isolate the effect of those medications on sleep on during and after PR, we would have required much larger sample. We did not track changes in COPD medication use pattern. Our PR program only admits patients after their medications were optimized and therefore, we do not expect large changes in COPD medications. To answer the effect of COPD medications on sleep and PR, a well-designed prospective study may be needed. For this reason, we did not even present data on COPD medications. In regards to all medications affecting sleep, we presented data on psychoactive medications and pain medications. Small proportions of participants were taking medications affecting sleep (less than 25% in all medication group affecting sleep).

No changes were made in response to this comment.

5. COPD and sleep quality have been assessed (objectively) with PSG, contrary to what the authors describe. Discussing differences/limitations on actigraphy on sleep assessment seems important, contributing to the negative results.

Response: We agree that Sleep in people with COPD has been objectively assessed by PSG. If the reviewer’s comment arise from the last paragraph of the “introduction” segment, we merely wanted to point out that there are paucity of data objectively evaluating effect of PR in sleep in people with COPD not in COPD population as such.

No changes were made to the manuscript in response to this comment.

6. The factors on the background influencing poor sleep (second paragraph) could use seminal references. The pharmacological effects and the reference (11) presented is not optimal.

Response: We agree seminal references would help the paper. We have added a reference to improve this.

McCarthy, B., et al., Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews, 2015(2).

Spruit, M.A., et al., An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med, 2013. 188(8): p. e13-64.

Ries, A.L., et al., Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest, 2007. 131(5 Suppl): p. 4S-42S.

We retained ref#11 for pharmacological effects since adding reference for individual agents would have been long.

7. The PR described (please add exercise tolerance on the third paragraph) also need some of the seminal or best references (Ries et al. in Annals, ATS PR document, or alike).

Response: Added exercise tolerance as recommended. Also added the following reference:

Ries, A.L., et al., Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest, 2007. 131(5 Suppl): p. 4S-42S.

8. The paragraph starting (background section) 'there is also evidence that COPD…….. outcomes' will fit better in the discussion section.

Response: Thank you for your careful review. If it is not prohibit, authors would like to keep the paragraph where it is. We believe it support the rationale why we wanted to do the study. We agree that it can fit well in the discussion section as well.

9. Do not abbreviate Loma Linda VA (VALL) as it is not standard.

Response: VALL has been removed and replaced with ‘VA Loma Lima Healthcare system’ or ‘our’ in the appropriate

10. Typo on the last paragraph on methods' Out' needs to be 'Our', I guess.

Response: Thank you for spotting the typographical error. I hunted down all “out” masquerading as “our”

Response: Added few sentences divided between method section and limitations. Hopefully it suffices.

“Actigraphy has acceptable validity and reliability [19, 20, 49] but has several limitations as compared to PSG. Actigraphy is one dimensional measurement of sleep based on movements and PGS gathers sleep data from multiple inputs such as electroencephalogram, electro-oculogram and electromyogram[49]. Therefore, certain sleep variables such as SOL is more accurate in PSG[50].”

12. There is no clarity on the overweight group (BMI 25-<30). Please expand on the discussion as the mean was 29? Table result (27.5) and text do not match BMI; please correct with the right number.

Response: BMI group of less than 30, 30 to 39 and 40 or more was chosen for simplicity since half of the subjects in less than 30 BMI group had normal BMI. There was no significant difference between 3 BMI group (as above) or 4 BMI group (including normal, overweight, obese and morbidly obese) in regards to outcomes.

The mean BMI was 29 and median BMI was 27.5. Mean+/-SD presented in the abstract was changed to median BMI with IQR.

13. In the results section, limit to describe the % found. Avoid as much as possible 'nearly', majority, three-quarters by the %, etc. Just write the results.

Response: Those phrase were replaced by numbers/data where appropriate.

14. SGRQ has an error/typo; 31.1 or 61? See text/table discrepancy.

Response: Thank you for spotting this typographical error as well. I cross-checked and verified that the true value is 61.1. It was changed in the manuscript.

15. mMRC is not expected to change that much. The authors seemed surprised by the results. Personal comment.

Response: Thank you for sharing your experience and fact about mMRC. The truth is that I was surprised by the degree of change in mMRC.

16. The description of the cognitive findings can be on the table and expand on the discussion. Those are not the primary or secondary aim for the study.

Response: Stratified analysis by cognitive function and depression did not show any significant change in both objective and subjective sleep measures. Intuitively we expected some effect of mood or memory on sleep but we found none. Hence, we did not discuss futher. We have been collecting further data on short term and long term cognitive change after PR. We plan to discuss this issue further on next paper.

Response: We did perform stratified analysis based on oxygen use. Among people who were not using supplemental oxygen for chronic respiratory failure, there was no significant effect of PR on sleep (Actigraphy variables as well as PSQI).

Among people who used supplemental oxygen (n=18), total sleep time (TST) decreased marginally (pre-PR TST: 376±71 minutes, mean±SD, vs post-PR 321±100 minutes; p=0.02). Also, sleep efficiency improved marginally (pre-PR sleep efficiency: 76.0±8.4% vs post-PR sleep efficiency: 70.7±11.8%; p=0.03). Since the sample size was small, we did not report in the manuscript. Should the editor or reviewer believe that this information is significant for the manuscript, authors are ready to include and discuss in the full manuscript.

Similarly, stratified analysis of sleep variables (PSQI as well as actigraphy parameters) among people with or without sleep disorder, did not show any significant differences.

Response: Authors belief that it improves the flow of reading. If it not prohibiti, authors would like to keep the paragraph in the Effect of PR on COPD related outcomes subheading.

Response: In theory, we expected robust improvement in sleep variables in severe COPD patients (CAT score >20) and PSQI> 5. Stratified analysis did not show any benefit in sleep variables despite significant improvement in CAT score (among severe patient, CAT score >20: mean change – 6.32 points, 95% CI -4.4 to -8.3, p<0.001; not presented in the manuscript) after PR. Therefore, we did not want to speculate the effect or propose a theory based on our retrospective data.

20. Some brief discussion comparing objective measurements of sleep would help the reader not familiar with sleep medicine (PSG vs. Actigraphy).

Response: Added few sentences on Actigraphy in the method section and comparison in the limitation section. Details on PSG would have been long and confusing since none of our outcomes are based on PSG data.

21. The paragraph starting with 'Exercise is one of the ….' Has to be before the previous one 'exercise affects sleep.'

Response: Moved as recommended.

Response: Thank you for picking that up as well. I agree “reasonable” may be less scientific. However, society practice guidelines has described actigraphy as “acceptable”. Hence, will change to “acceptable” from “reasonable”

Morgenthaler, T., et al., Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep, 2007. 30(4): p. 519-29.

Recommendations: Actigraphy provides an acceptably accurate estimate of sleep patterns in normal, healthy adult populations and inpatients suspected of certain sleep disorders.

23. Discussion about the patient population. This is relevant. And then briefly can be said in the limitation section as well.

Response: Added a paragraph:

Our cohort consistent of only Veterans and almost entirely males. Both of these factors can influence sleep. Veterans have high prevalence of psychiatric conditions such as PTSD, depression and anxiety as compared to general population [31]. Directly or indirectly these factors increase the prevalence of insomnia and poor quality sleep.

Response: Nearly half of the variable were normally distributed and rest were not. Representing data in both means+/-SD and median+/-IQR provides some symmetry. Also, expanded PFSDQ VAS score provides an additional measure for dyspnea. Authors would like to keep those measure if acceptable to the reviewers. If the reviewers truly believe that those should be truncated or removed, we will be happy to make changes.

In regards to ESS, added few sentences in the result section

ESS, which measures general sleepiness, was 8.0±5.1 (mean±SD) slightly higher than expected in normal individuals at baseline (ESS in normal individuals, 5.9±2.2, range 2-10)

The ESS did not change after PR in the entire cohort as well as when stratified by presence of absence of sleep disorders (stratified data not presented in the manuscript).

Since ESS was slightly above normal range and did not change in the overall cohort and in stratified analysis, we decided not to discuss it further.

Also, correction was made to the SD values for ESS in table 2 (the table contained SE not SD)

25. Perhaps the reader could benefit from a brief explanation of how sleep quality is measured. Many readers are not familiar with sleep variables.

Response: I did not quite understand how to respond to this comment. I added a small paragraph on PSQI in the method section. Discussion of all sleep variables would be too lengthy. I hope this suffices.

The added paragraph reads as below:

PSQI measures sleep disturbances and sleep habits during last one month period. The questionnaire has 19 individual items and includes open ended questions and Likert-like items. It generates seven clinically derived domains or components of scores which includes: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. The global PSQI score is calculated by adding scores from all seven domains {Buysse, 1989}.

Attachment

Submitted filename: Response to Reviewr # 2.docx

Click here for additional data file.^{(31.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0248466.r003

Decision Letter 1

Federica Provini

13 Jan 2021

PONE-D-20-23683R1

Impact of Pulmonary Rehabilitation in Sleep in COPD patients measured by Actigraphy.

PLOS ONE

Dear Dr. Thapamagar,

Please submit your revised manuscript by March 1st. 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'.

We look forward to receiving your revised manuscript.

Kind regards,

Federica Provini

Academic Editor

PLOS ONE

There are a number of discrepancies between data in tables and data in text.

For example

1) in the text: ”Seventy five percentage of the study population had a high or very high impact of COPD on their daily lives with a mean CAT score of 24.4 ± 7.1

2) in the table: CAT score, n=52, mean ± SD 24.8 ± 7.1

If you want to report data on different subgroups, please clarify in the text or in the tables

Please, carefully check and resubmit again

PLoS One. 2021 Mar 16;16(3):e0248466. doi: 10.1371/journal.pone.0248466.r004

Author response to Decision Letter 1

23 Jan 2021

PONE-D-20-23683

Response to the reviewer

Comment from the reviewer:

There are a number of discrepancies between data in tables and data in text.

For example

1) in the text: ”Seventy five percentage of the study population had a high or very high impact of COPD on their daily lives with a mean CAT score of 24.4 ± 7.1

2) in the table: CAT score, n=52, mean ± SD 24.8 ± 7.1

Response:

Thank you very much for spotting the typographical error. The value should be 24.8 ± 7.1 in the text as well (as in the table).

After re-reading the text again, I felt that the construct of the sentence was confusing. It was suggesting as if the mean CAT score presented in the text was for “High and Very high impact” group, which was not the intention. Therefore, we decided to make changes to 2 sentences in the baseline characteristic paragraph.

Before change:

Nearly 80% of the Veterans had severe or very severe COPD (GOLD stage 3 or 4). Seventy five percentage of the study population had a high or very high impact of COPD on their daily lives with a mean CAT score of 24.4 ± 7.1.

The new sentences read as below:

Nearly 80% of the Veterans had severe or very severe COPD (GOLD stage 3 or 4) and the impact of COPD in their lives as measured by COPD Assessment Test (mean CAT score 24.8 ± 7.1) was very high. Moreover, 75% of the study population had a high or very high impact of COPD on their daily lives.

The break down for CAT score groups was as follows:

Medium impact group (CAT score >10 to 20)

n=13, mean ± SD, 15.5 ± 3.0

High or very high impact group (CAT score of > 20)

n=39, mean ± SD: 27.9 ± 4.9

Proportional break down of the CAT score provides a good insight into the data. Adding additional piece of data would have cluttered the table more (in our opinion). Therefore, we decided not to add anything more to the table.

Attachment

Submitted filename: Response to the reviewer_2.docx

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PLoS One. doi: 10.1371/journal.pone.0248466.r005

Decision Letter 2

Federica Provini

1 Feb 2021

PONE-D-20-23683R2

Impact of Pulmonary Rehabilitation in Sleep in COPD patients measured by Actigraphy.

PLOS ONE

Dear Dr. Thapamagar,

Please check carefully again the data in the text and in the tables because some disagreeents are still present.

For example- Non-obese pts: 52.3 % in the text and 62.3% in the table.

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'.

We look forward to receiving your revised manuscript.

Kind regards,

Federica Provini

Academic Editor

PLOS ONE

PLoS One. 2021 Mar 16;16(3):e0248466. doi: 10.1371/journal.pone.0248466.r006

Author response to Decision Letter 2

26 Feb 2021

PONE-D-20-23683

Response to the reviewer

Comment from the reviewer:

Please check carefully again the data in the text and in the tables because some disagreements are still present.

For example- Non-obese pts: 52.3 % in the text and 62.3% in the table.

Response:

Thank you very much for spotting the typographical error. The value in the table (62.3%) is accurate. This was crossed check with data output and corrected in the updated manuscript.

We also carefully checked the entire manuscript for other typographical and formatting errors as well as grammatical errors. We found few and have made changes as below:

1) Results/Demographics: “80%” should have been “70%”

Used to read: “Nearly 80% of the Veterans”

Now reads: More than two-thirds (69.5%) of the Veterans

2) “GOLD stages 3 or 4” were changed to “GOLD stages III or IV”

3) Table 1: “%” signs inside the parentheses in the second column were removed since it was already indicated in the first column. For example:

Used to read as: 43 (62.3%)

Now reads: 43 (62.3)

4) Table 1: Minimal cognitive impairment was changed to Mild cognitive impairment since SLUMS does not have minimal cognitive impairment in the scale.

5) All sentences with “veterans” were changed with “Veterans”

6) Result/Sleep quality and factors affecting sleep:

- Chronic pain prevalence was 52% not 42%. It was cross checked and corrected in the edited manuscript.

7) Results/Effect of PR on COPD related outcomes:

-p value for change in CAT score was <0.0001 not <0.001.

8) Punctuations and grammatical errors were corrected as appropriate.

Attachment

Submitted filename: Response to the reviewer_3.docx

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PLoS One. doi: 10.1371/journal.pone.0248466.r007

Decision Letter 3

Federica Provini

1 Mar 2021

Impact of Pulmonary Rehabilitation in Sleep in COPD patients measured by Actigraphy.

PONE-D-20-23683R3

Dear Dr. Thapamagar,

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.

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PLoS One. doi: 10.1371/journal.pone.0248466.r008

Acceptance letter

Federica Provini

5 Mar 2021

PONE-D-20-23683R3

Impact of pulmonary rehabilitation in sleep in COPD patients measured by actigraphy

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Data Availability Statement

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PERMALINK

Impact of pulmonary rehabilitation in sleep in COPD patients measured by actigraphy

Suman B Thapamagar

Kathleen Ellstrom

James D Anholm

Ramiz A Fargo

Nagamani Dandamudi

Roles

Abstract

Introduction

Methods

Results

Conclusions

Background

Methods

Study design and setting

Study participants and enrollment criteria

Pulmonary rehabilitation program

Assessments, data collection and outcomes

Statistical analysis

Results

Fig 1. Study flow chart.

Demographics and baseline clinical characteristic

Table 1. Baseline characteristics of the study population.

Sleep quality and factors impacting sleep

Effect of PR on COPD related outcomes

Table 2. Effect of PR on COPD/respiratory, sleep and neurocognitive variables.

Effect of PR on sleep

Table 3. Sleep related primary and secondary outcomes after 8-weeks of pulmonary rehabilitation.

Fig 2. Effect of PR in PSQI score in veterans with good sleep quality (PSQI <5) and poor sleep quality (PSQI ≥5).

Discussion

Limitations of the study

Conclusions

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Federica Provini

Roles

Author response to Decision Letter 0

Decision Letter 1

Federica Provini

Roles

Author response to Decision Letter 1

Decision Letter 2

Federica Provini

Roles

Author response to Decision Letter 2

Decision Letter 3

Federica Provini

Roles

Acceptance letter

Federica Provini

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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