TELEHEALTH INTERVENTIONS TO IMPROVE OUTCOMES IN LUNG TRANSPLANT RECIPIENTS: Primary Results of the INSPIRE III Randomized Clinical Trial

Abstract

Background:

There is growing evidence that many patients undergoing lung transplantation report significant distress and low physical activity (PA), which might not improve despite lung transplantation and may be associated with worse clinical outcomes. Few studies have attempted to improve psychological outcomes and functional capacity and PA after transplant.

Methods:

INSPIRE-III is a single-site, randomized clinical trial in which 180 post-lung transplant patients, recruited between November 2019 and October 2023, completed a psychometric test battery to assess distress and functional capacity measured by the Six-Minute Walk Test and PA assessed by 7 consecutive days of continuous activity monitoring. Participants were then were randomly assigned to either a 12-week Coping Skills Training and Exercise intervention (CSTEX) or a Standard of Care and Education (SoC-ED) program delivered via telephone. Participants were then retested after completion of the telehealth interventions.

Results:

After 12 weeks, both intervention groups achieved small but similar improvements in distress and functional capacity. Although there were no between group differences overall, patients who were considered clinically depressed at baseline and received CSTEX achieved greater improvements in depression compared to depressed patients who received SoC-ED.

Conclusions:

Although patients in both CSTEX and SoC-ED showed only modest benefit from their respective interventions, a subgroup of patients in CSTEX who were depressed at study entry had greater reductions in depressive symptoms compared to SoC-ED. Depressive symptoms should be carefully monitored post-transplant and referred for treatment if symptoms persist.

Trial registry:

NCT04093869

INTRODUCTION

Lung transplantation is a widely accepted and effective treatment for individuals with end-stage pulmonary disease. More than 3026 lung transplants were performed in 2023 in the United States.¹ Moreover, lung transplantation is expected to become more common in the future because of the aging of the American population, improved surgical techniques, greater utilization of prospective donors, better medical management of lung transplant recipients, and increased awareness of transplant as a viable option for end-stage lung disease. Furthermore, there remains a paucity of available treatments to reverse the pathophysiologic processes responsible for end-stage lung diseases.² Therefore, lung transplantation is an increasingly viable treatment option for patients with advanced lung disease.

There also is growing evidence that many patients experience significant distress and poor psychological quality of life (QoL) following transplant, despite improvements in physical QoL.^3,4 It has been shown that lung transplant patients exhibit slower return to normal function compared to other solid organ transplant recipients,⁵ and that, surprisingly, mental health QoL fails to improve significantly following transplant.⁶ These data are important because elevated levels of psychological distress are associated with a variety of adverse events, including chronic rejection⁷ and all-cause mortality,⁸ even after accounting for other clinical predictors.^9,10 Most attention has been given to pre-transplant candidates; efforts to reduce distress and improve physical activity (PA) in post-lung transplant recipients have received little attention.^11,12 Coping skills training and aerobic exercise represent two strategies that reduce distress, improve QoL, and increase functional capacity in patients with other chronic diseases.^13,14 However, despite data showing that psychological distress and physical inactivity are common in post-transplant patients, and are independently predictive of worse clinical outcomes,¹⁵ few studies have sought to improve psychological and physical well-being in post-lung transplant patients and there is a paucity of evidence from clinical trials regarding the benefits of exercise in post-lung transplant recipients.^16,17 To address this unmet need, the INSPIRE-III randomized clinical trial was designed to evaluate a combined exercise and coping skills intervention hypothesized to reduce distress, improve functional capacity, and increase PA in post-lung transplant recipients.

METHODS

Eligibility and Trial Overview

Investigational Study of Psychological Interventions in Recipients of Lung Transplant-III (INSPIRE–III) was an efficacy trial examining the effects of coping skills training combined with an enhanced exercise intervention (CSTEX) on self-reported stress and functional capacity in post-lung transplant recipients. A detailed description of the background and methods has been published previously.¹⁸ Participants underwent baseline measurement of stress, functional capacity, and PA at the Behavioral Medicine laboratory at Duke University School of Medicine, and were randomly assigned in a 1:1 ratio to either the CSTEX condition delivered over the telephone or to a standard of care plus transplant education (SoC-ED) control condition. Participants were re-assessed at the completion of the 12-week program for the primary endpoint (a composite measure of psychological distress) and multiple secondary endpoints including measures of functional capacity and PA. Assessors were unaware of participants’ group assignments.

This study was supported by grant from the National Institute of Nursing Research; the sponsor was not involved in the design of the study, the collection, analysis, interpretation of the data, nor in the decision to approve publication of the finished manuscript. An independent Safety Monitoring Committee provided oversight of the trial.

Participants

Post-lung transplant outpatients considered clinically stable from medical record review (e.g., no active infection or rejection) were recruited with approval from their transplant pulmonologists and underwent medical screening examinations to confirm eligibility. Eligibility criteria included lung transplant recipients aged 18 years or older who were discharged from the hospital, were at least 6 weeks post-transplant, and had completed post-transplant pulmonary rehabilitation within the previous 18 months. Exclusion criteria included illness such as malignancies that were associated with a life-expectancy of <12 months, current pregnancy, multi-organ transplant or repeat lung transplant, or individuals who were unable to read or who could not provide written informed consent.

The protocol was approved by the Institutional Review Board at Duke University and written informed consent was obtained from all participants. The first patient was randomized on November 6, 2019 and the last date for completing the post-intervention assessments was February 21, 2024.

Assessment procedures

Psychological Distress

A global psychological ‘distress’ index served as the primary outcome¹⁹, which averaged the rankings of the change scores between baseline and 12 weeks, for five separate measures for each participant. The measures included the following instruments:

Beck Depression Inventory-II (BDI-II):²⁰

The 21-item BDI-II is a widely used measure of depression. Scores range from 0 to 63, with higher scores suggesting greater depressive symptoms; scores ≥ 14 are suggestive of clinically significant depressive symptoms.

State-Trait Anxiety Inventory (STAI):²¹

The 20-item STAI was used to assess levels of state anxiety. Scores range from 20 to 80 with higher scores indicating greater state anxiety; scores ≥ 40 suggest clinically significant anxiety in medical patients.²²

Patient-Reported Outcomes Measurement Information System (PROMIS) Anger:²³

The 8-item PROMIS Anger scale assesses several dimensions of anger with scores ranging from 8 to 40 with higher scores indicating greater anger.

General Health Questionnaire (GHQ):²⁴

The GHQ is a 12-item measure of general distress, with scores ranging from 0 to 36 and higher scores indicating greater emotional distress.

Perceived Stress Scale (PSS):²⁵

The 10-item PSS assesses general distress and perceived ability to adequately cope with current life stressors with scores ranging from 0 to 40; higher scores indicate greater perceived stress.

Functional Capacity and Physical Activity

6-Minute Walk Test (6MWT).²⁶

The 6MWT is a standard, self-paced, timed test of the total distance that a patient could walk in 6 minutes.

Accelerometry.

Physical activity (PA) during daily life was quantified by recording the number of daily steps averaged over a 1-week period using Actigraph GT9X Link (Actigraph Corp., Pensacola, FL).

Leisure-time Physical Activity.²⁷

Participants completed the Godin Leisure-Time Exercise Questionnaire in which they indicated the number of times they engaged in mild, moderate, and strenuous exercise for more than 15 minutes.

Interventions

Patients were randomized either to CSTEX or SoC-ED. Native lung disease (Cystic Fibrosis [CF] v non-CF) and Sex (Male v Female) were used as stratification variables. Participants were informed of their group assignment via a phone call from the principal investigator (JAB) using a stratified randomization list. All patients were followed medically by their transplant pulmonologists or primary care physicians, who were blinded to intervention condition and who managed any episodes of escalating symptoms or evidence of graft rejection.

Coping Skills Training and Exercise

Patients in CSTEX received a coping skills intervention adapted from our previous work,^28,29 which combined education and cognitive-behavior therapy; participants also received an exercise prescription and daily exercise was encouraged. Participants were given a Fitbit Inspire HR^™ (Fitbit Group Health, San Francisco, CA) fitness wristband activity and heart rate (HR) monitor, which they wore daily during the 12-week intervention. Their daily steps were monitored weekly by the interventionist, and participants were encouraged to meet weekly exercise goals. The intervention was delivered in 12 weekly 30-minute sessions delivered over the telephone by a trained respiratory therapist. A detailed manual served as a guide and included such topics as rest-activity cycling, progressive muscle relaxation training, cognitive restructuring, problem solving, improving communication, and relapse prevention. All sessions were audiotaped for review and weekly supervision was provided by a licensed clinical psychologist (DCM).

Standard of Care plus Education Group (SoC-ED)

Patients in the standard of care and lung transplant education condition (SoC-ED) received their usual medical care and, in addition, received twelve weekly calls for support and enhanced education about lung transplantation. Topics included educational information about post-transplant care, common complications following surgery, the importance of medication adherence, healthy eating, pulmonary function monitoring, and maintenance of PA. For the last session, an overview of the educational topics was offered or participants were encouraged to select one of three optional topics, including depression, urinary incontinence, or resuming sexual activity after transplant. Participants randomized to the SoC-ED intervention were provided with a Fitbit to self-monitor their PA. Pulmonary health care educators with expertise in lung transplantation delivered the education modules and assisted patients with self-management but did not provide instruction in coping strategies or provide PA feedback. All sessions were audiotaped and reviewed weekly to ensure adherence to the manual.

Statistical analysis

Descriptive statistics are reported by study arm, with categorical variables summarized as counts and percentages, and continuous variables summarized as means with standard deviations.

Analyses followed the intention to treat principle (ITT), with participants analyzed according to their arm assignment, regardless of their adherence to the assigned intervention. Multivariable linear regression models were used to compare outcomes between the two arms. Models included a term for intervention assignment as well as the following pre-specified covariates: age, gender, disease (CF or non-CF), transplant type (unilateral or bilateral), severe Primary Graft Dysfunction (PGD = 3 at 48 hours and/or 72 hours post-transplant), donor age, and baseline value of the outcome variable. Estimates of the intervention effect for each outcome are reported with 95% confidence intervals (CI). Models were assessed graphically (residual, quantile-quantile plots) and with appropriate tests to ensure the assumptions of linear regression were satisfied. Transformations were applied to variables if needed to address heteroscedasticity (BDI-II square root transformed, STAI and PROMIS log transformed). For missing data, if ≥ 20% of items were missing from a psychometric test the entire scale was treated as missing, and models were fit on complete cases.

It should be noted that the trial was originally powered for two co-primary endpoints: a composite psychometric measure of distress (global distress index) and functional capacity assessed by distance walked on the 6MWT.¹⁸ Because 39.4% of the sample was missing data for in-person 6MWT due to the COVID-19 pandemic, 6MWT distance was changed to a secondary outcome before unblinding intervention group assignments. For our primary endpoint, global distress, we estimated power using a correlation of 0.53 between covariates and the outcome, with an initial sample size of 150 participants, attrition of 15%, and an α of 0.025. Based on these assumptions, we estimated that we would have 80% power to detect a small-to-moderate treatment size difference (d = 0.44).

As exploratory post-hoc analyses, the effect of the intervention on each of the 5 components of the primary outcome was examined (BDI-II, STAI, PROMIS Anger, GHQ, and PSS). Exploratory subgroup analyses were also conducted, to examine the effectiveness of the intervention among the following subgroups: participants with baseline 6MWT distances in the lowest quartile, participants with baseline BDI-II scores above the clinical threshold for depression (≥14), and participants with STAI scores above the threshold for anxiety (≥ 40).

RESULTS

Participant Flow

Figure 1 displays the flow of participants during the trial. Of the 310 lung transplant recipients who were initially contacted, 205 met initial inclusion criteria, 193 were consented, and 180 were randomized: 90 to CSTEX and 90 to SoC-ED.

Figure 1: CONSORT Diagram.

Participant flow in the INSPIRE-III (Investigational Study of Psychological Interventions in Recipients of Lung Transplant-III) clinical trial. CSTEX = Coping Skills Training with Exercise; SoC-ED = Standard of Care plus Education; ITT = intention-to-treat.

Participant Characteristics

The demographic, background, and medical characteristics of the sample are displayed in Table 1. The mean age of the cohort was 60 years (SD: 12); over half were male and the majority were white, which is consistent with the demographics of the overall lung transplant population at our institution. The time interval from transplant to randomization was about one year for both intervention groups (CSTEX; 12.17 [2.46]; SoC-ED: 12.49 [2.64] months; range 5-19 months). Most patients had IPF or other interstitial lung disease, and received bilateral lung transplants. Intervention groups were similar in background, clinical, and demographic characteristics.

Table 1:

Demographic and Clinical Participant Characteristics.

Characteristic	SoC-ED, N = 90	CSTEX, N = 90	Overall, N = 180
Gender, n (%)
Male	53 (59%)	55 (61%)	108 (60%)
Female	37 (41%)	35 (39%)	72 (40%)
Race, n (%)
Asian or Pacific Islander	1 (1.1%)	1 (1.1%)	2 (1.1%)
Black, Non-Hispanic	14 (16%)	11 (12%)	25 (14%)
Hispanic	2 (2.2%)	1 (1.1%)	3 (1.7%)
Multiracial	1 (1.1%)	1 (1.1%)	2 (1.1%)
White, Non-Hispanic	72 (80%)	76 (84%)	148 (82%)
Age, Mean (SD)	60 (12)	60 (12)	60 (12)
Disease, n (%)
CF	6 (6.7%)	5 (5.6%)	11 (6.1%)
PH	3 (3.3%)	1 (1.1%)	4 (2.2%)
COPD	15 (17%)	13 (14%)	28 (16%)
IPF	36 (40%)	37 (41%)	73 (41%)
ILD	23 (26%)	22 (24%)	45 (25%)
Other	7 (7.8%)	12 (13%)	19 (11%)
Transplant type, n (%)
Bilateral	83 (92%)	81 (90%)	164 (91%)
Unilateral	7 (7.8%)	9 (10%)	16 (8.9%)
PGD = 3 at 48 or 72 hours post-transplant, n (%)	17 (19%)	16 (18%)	33 (18%)
Donor age (years), Mean (SD)	36 (14)	35 (14)	36 (14)
Days hospitalized post-transplant, Mean (SD)	23 (13)	26 (19)	25 (16)
Average rank, baseline global distress scores (T1), Mean (SD)	92 (41)	89 (42)	90 (42)
Missing	0	1	1
Baseline 6MWT distance (ft), Mean (SD)	1,428 (243)	1,442 (255)	1,435 (249)
Missing	18	20	38
Baseline steps per day, Mean (SD)	8,549 (2,728)	8,180 (3,292)	8,366 (3,019)
Missing	1	2	3

Note: CF: cystic fibrosis; PH: pulmonary hypertension; COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis; ILD: interstitial lung disease

Intervention Adherence

Adherence to the intervention protocol generally was excellent (see Table 2). Only two participants failed to complete the intervention (1 in CSTEX and 1 in SoC-ED); five participants required more than 16 weeks to complete the CSTEX intervention while all patients in SoC-ED completed the intervention within 16 weeks. CSTEX sessions were longer compared to SoC-ED (average: 35 min vs 15 min).

Table 2.

Intervention Adherence

Characteristic	SoC-ED, N = 90	CSTEX, N = 90
Intervention duration (weeks)
Mean (SD)	11.57 (1.03)	12.65 (2.48)
Median [IQR]	11.14 [10.86, 12.00]	12.00 [11.00, 13.57]
Range	9.57, 15.00	8.86, 25.86
Did not complete	1	1
Intervention duration greater than 16 weeks, n (%)	0 (0%)	5 (5.6%)
Did not complete	11	1

Note:

¹One participant died after completing 4 telephone sessions.

Self-reported medication adherence before and following the 12-week intervention was excellent. Adherence was high among participants in both intervention groups upon study entry; 94% of the sample indicated that they never or almost never forgot to take their medications as prescribed. Adherence was maintained over the 12 weeks, and there was no difference in self-reported adherence between the two groups following the interventions, with both groups reporting that they never or almost never missed a dose of their prescribed transplant medications (CSTEX = 95%; SoC-ED =96%)

Intervening Hospitalizations

Forty-three patients (23 CSTEX; 20 SoC-ED) experienced at least one unplanned hospitalization during the 12-week intervention (Table 3). Thirteen participants (6 CSTEX; 7 SoC-ED) experienced an additional 17 rehospitalizations, totaling 60 separate admissions. There were no differences in baseline psychometric test scores between those with and without a hospitalization.

Table 3.

Hospitalizations During 12-week Interventions

Reason for Hospitalization1	SoC-ED N=20	CSTEX N= 23	Overall N = 43
Infection	4 (2)	8 (3)	12 (5)
Treatment for rejection	4 (2)	4 (2)	8 (4)
Respiratory, not infection or rejection	3 (1)	5 (2)	8 (3)
GI related	5 (2)	2 (1)	7 (3)
Cancer related	1 (0)	1 (0)	2 (0)
Cardiac	1 (0)	1 (0)	2 (0)
Other2	2 (2)	2 (0)	4 (2)

¹Thirteen participants experienced more than one hospitalization. Numbers in parentheses represent the number of repeat hospitalizations. For example, 4 patients in SoC-ED were hospitalized for an infection and additionally there were 2 re-hospitalizations for an infection during the intervention.

²Includes renal, neurologic, anaphylaxis, sinus surgery, rotator cuff surgery, and suspected serum sickness as reasons for hospitalization

Effects of Interventions on Distress

The pre-intervention global distress ranks were comparable for CSTEX and SoC-ED groups (Baseline: CSTEX = 89 (42), SoC-ED = 92 (41)). Post-intervention global distress ranks also were not different from each other (CSTEX = 89 (39); SoC-ED = 90 (41)); the global distress outcome was 4.1 (95% CI: −6.0, 14.0, p = 0.4) ranks higher in the CSTEX arm compared to SoC-ED after adjusting for age, sex, transplant time, native disease type, PGD, donor age, and baseline global distress.

Post hoc examination of individual stress measures, adjusted for each pretreatment (baseline) score and predefined covariates, showed no significant difference by intervention group. Group differences in post-intervention scores were generally small and not statistically or clinically significant (Table 4).

Table 4.

Individual Psychological Components of Global Distress Before and After the Interventions

	SoC-ED			CSTEX
Variable2	Baseline Mean (SD)	Post-Intervention Marginal Mean [95% CI]	T2-T1 [95% CI]	Baseline Mean (SD)	Post-Intervention Marginal Mean [95% CI]	T2-T1 [95% CI]	Effect estimate * [95% CI]
Beck Depression Inventory-II	7.68 (6.28)	5.75 [4.85, 6.73]	−1.18 [−2, −0.35]	6.99 (5.25)	6.00 [5.07, 7.01]	−0.67 [−1.86, 0.51]	0.053 [−0.22, 0.32]
Spielberger Anxiety Inventory-State	31.57 (10.00)	31.13 [29.88, 32.44]	−0.1 [−1.51, 1.31]	31.64 (8.36)	31.75 [30.47, 33.07]	0.45 [−1.06, 1.95]	0.023 [−0.04, 0.08]
General Health Questionnaire	14.08 (5.58)	13.66 [12.55, 14.77]	−0.01 [−1.29, 1.27]	12.50 (5.84)	12.81 [11.70, 13.92]	−0.11 [−1.53, 1.32]	−0.85 [−2.43, 0.73]
PROMIS Anger Questionnaire	14.36 (5.08)	13.97 [13.17, 14.82]	0.2 [−0.81, 1.2]	13.85 (4.67)	14.37 [13.54, 15.26]	0.69 [−0.28, 1.66]	0.033 [−0.05, 0.11]
Perceived Stress Scale	11.67 (6.71)	11.46 [10.40, 12.51]	−0.16 [−1.36, 1.05]	11.62 (5.81)	11.23 [10.17, 12.29]	−0.44 [−1.51, 0.62]	−0.23 [−1.72, 1.27]

Note: Baseline scores and standard deviations (SD) for CSTEX and SoC-ED, as well as Post-intervention marginal mean scores and 95% CIs for individual components of global distress measure, and change scores (T2-T1) and 95% t-distribution CIs. Treatment effects (and 95% CI) on individual distress measures after adjustment for the pretreatment level of each outcome and pre-determined variables¹ are presented.

¹Adjusted for Age, Sex, Bilateral vs Unilateral Transplant, CF vs non-CF, PGD 3 at 48 or 72 hours post-transplant, Donor Age, and pretreatment level of stress measure.

²For BDI-II and PSS, data was missing for one patient in the SOC-ED group and for two patients in the CSTEX group. For the other scales, data was missing for one patient in each arm.

³The Beck Depression Inventory-II estimate is square-root transformed; the Spielberger Anxiety Inventory-State estimate and the PROMIS Anger estimate are log-transformed (to satisfy regression model assumptions).

Of note, 26 individuals (14%; 12 in CSTEX and 14 in SOC-ED) exhibited clinically elevated levels of depression before the interventions (i.e., BDI-II ≥ 14) and 34 individuals (19%; 19 in CSTEX and 15 in SOC-ED) reported clinically significant levels of anxiety (STAI ≥ 40). Analysis of the depressed subgroup revealed that individuals in the CSTEX group exhibited a 10.1-point reduction (5.8) on the BDI-II, compared with reductions of 2.5 (4.1) points in the SoC-ED group. In this post-hoc subgroup analysis, after adjusting for pre-intervention BDI-II and predefined covariates, the CSTEX group had a lower post-intervention BDI-II score on average by 8.5 points (95% CI: 3.0, 14.0, p=0.005) which was significantly different than the BDI-II < 14 group (p-interaction <0.001) (Figure 2).

Figure 2: Intervention-related Changes in Depression Among Subgroup of Depressed Patients.

Mean BDI-II scores (± 1 SE error bars) at baseline (T1) and post-intervention (T2) among subgroup of 26 depressed participants (baseline BDI-II scores ≥14) for CSTEX (N =12) and SoC-ED (N =14) groups plotted separately

We performed a similar post-hoc analysis for individuals with high anxiety at baseline. Participants in the CSTEX reported a 3.7 (8.5)-point reduction compared to a 4.3 (7.7)-point reduction in SoC-ED. Adjusting for pre-intervention STAI scores and other covariates, we found there was no significant difference by intervention group in the post-intervention STAI scores (estimate: 0.1, 95% CI: [−7.5, 7.6], p=0.987, p-interaction 0.699).

Functional Capacity and Daily Physical Activity

Both CSTEX (n = 52) and SoC-ED (n = 57) groups achieved small improvements in 6MWD after 12-weeks with large variability across patients (change in 6MWTD distance: CSTEX: 46(148); SoC-ED: 30 (177)).

In terms of daily PA, the average number of daily steps for both groups was about the same after 12 weeks compared to baseline and there were no between group differences at 12-weeks (Table 5). Similarly, scores on the Godin, a self-report measure of PA revealed small incremental changes in self-reported PA after 12 weeks, with no differences between intervention arms (Table 5).

Table 5.

Functional Status and Physical Activity.

	SoC-ED			CSTEX
Variable	Baseline Mean (SD)	Post-intervention Marginal Mean [95% CI]	T2-T1 [95% CI]	Baseline Mean (SD)	Post-intervention Marginal Mean [95% CI]	T2-T1 [95% CI]	Effect estimate (95% CI)
6MWD (ft)	1428 (243)	1468 [1423, 1512]	29.76 [−17.2, 76.72]	1442 (255)	1488 [1442, 1535]	45.9 [4.67, 87.13]	21 [−44, 85]
Average steps per day	8549 (2728)	8512 [8047, 8978]	71.75 [−372.35, 515.84]	8180 (3292)	8196 [7728, 8664]	−134.95 [−685.5, 415.6]	−316 [−979, 346]
Godin score	30 (22)	35 [31, 40]	4.55 [−0.67, 9.77]	32 (27)	36 [32, 41]	4.09 [−1.33, 9.5]	1.1 [−5.1, 7.2]

Treatment effects (and 95% CIs) for functional status and physical activity measures after adjustment for the pretreatment level of each outcome and pre-determined variables are presented.¹

¹Adjusted for Age, Sex, Bilateral vs Unilateral Transplant, CF vs non-CF, PGD = 3 at 48 or 72 hours post-transplant, Donor Age, and pretreatment level of functional capacity/physical activity measure.

^**Missing data for 71 patients for 6MWT (33 in SoC-ED, 38 in CSTEX), 5 patients for average steps per day (2 in SoC-ED, 3 in CSTEX), and 13 patients for Godin score (5 in SoC-ED, 8 IN CSTEX).

Perception of Changes Following Interventions

At the conclusion of the interventions, participants completed a post-intervention survey that asked about their experience over the 12-week intervention. Participants in both groups-77% in CSTEX and 43% in SOC-ED reported they were able to cope with stress either ‘somewhat’ or ‘much better’ after the intervention period. Concerning physical activity, 32% of participants in CSTEX reported that they were ‘much better’ at getting regular exercise after the intervention compared to only 17% of those participants in SoC-ED (Table 6).

Table 6.

Perceived Changes Post-intervention

Survey Item	SoC-ED, N = 90	CSTEX, N = 90
My ability to cope with stress, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	1 (1.3%)	0 (0%)
About the same	42 (55%)	18 (23%)
Somewhat better	18 (24%)	39 (50%)
Much better	15 (20%)	21 (27%)
Missing	14	12
My adherence in taking my medications as prescribed by my doctor, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	0 (0%)	0 (0%)
About the same	47 (62%)	55 (71%)
Somewhat better	6 (7.9%)	3 (3.8%)
Much better	23 (30%)	20 (26%)
Missing	14	12
My feelings of anxiety and depression, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	2 (2.6%)	1 (1.3%)
About the same	43 (57%)	33 (43%)
Somewhat better	12 (16%)	25 (32%)
Much better	19 (25%)	18 (23%)
Missing	14	13
My getting regular exercise, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	4 (5.3%)	1 (1.3%)
About the same	30 (40%)	23 (29%)
Somewhat better	28 (37%)	29 (37%)
Much better	13 (17%)	25 (32%)
Missing	15	12
My sleep at night, n (%)
Much worse	2 (2.6%)	0 (0%)
Somewhat worse	3 (3.9%)	6 (7.7%)
About the same	44 (58%)	43 (55%)
Somewhat better	16 (21%)	21 (27%)
Much better	11 (14%)	8 (10%)
Missing	14	12
My ability to bounce back from health setbacks, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	4 (5.3%)	0 (0%)
About the same	42 (55%)	41 (53%)
Somewhat better	17 (22%)	23 (30%)
Much better	13 (17%)	13 (17%)
Missing	14	13
My ability to breathe, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	2 (2.7%)	0 (0%)
About the same	42 (56%)	42 (54%)
Somewhat better	11 (15%)	10 (13%)
Much better	20 (27%)	26 (33%)
Missing	15	12
My nutritional/dietary habits, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	2 (2.6%)	8 (10%)
About the same	42 (55%)	40 (51%)
Somewhat better	21 (28%)	21 (27%)
Much better	11 (14%)	9 (12%)
Missing	14	12
My ability to regularly monitor my lung function, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	1 (1.3%)	2 (2.6%)
About the same	46 (61%)	39 (50%)
Somewhat better	15 (20%)	21 (27%)
Much better	13 (17%)	16 (21%)
Missing	15	12
My overall quality of life, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	1 (1.3%)	1 (1.3%)
About the same	39 (51%)	20 (26%)
Somewhat better	21 (28%)	36 (47%)
Much better	15 (20%)	20 (26%)
Missing	14	13
My ability to solve problems, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	1 (1.3%)	1 (1.3%)
About the same	51 (67%)	27 (35%)
Somewhat better	14 (18%)	30 (38%)
Much better	10 (13%)	20 (26%)
Missing	14	12
My ability to communicate with others, n (%)
Much worse	0 (0%)	0 (0%)
Somewhat worse	1 (1.3%)	1 (1.3%)
About the same	49 (64%)	27 (36%)
Somewhat better	12 (16%)	26 (34%)
Much better	14 (18%)	22 (29%)
Missing	14	14
How beneficial were the 12 weekly INSPIRE calls?, n (%)
Not at all helpful	3 (3.9%)	1 (1.3%)
Neutral (Neither helpful or not helpful)	7 (9.2%)	1 (1.3%)
Somewhat helpful	18 (24%)	9 (12%)
Mostly helpful	26 (34%)	27 (35%)
Very helpful	22 (29%)	40 (51%)
Missing	14	12
*Perceived Changes Mean Response* (1-5 scale, with higher better), Median (IQR)	3.35 (3.08, 4.08)	3.69 (3.46, 4.08)
Missing	14	12

DISCUSSION

INSPIRE-III was a randomized clinical trial to evaluate the efficacy of a cognitive-behavioral intervention combining coping skills training and exercise on psychological distress and functional capacity compared to standard of care plus a post-lung transplant education program. Although we hypothesized that the CSTEX intervention would result in greater reductions in distress, better 6MWT performance, and increased PA, results indicated that there were only small and clinically insignificant differences between the groups at the end of the 12-week intervention. We note that participants generally had low levels of distress at baseline, and, as a group, were relatively physically active, so that it may have been difficult to show meaningful, clinically significant improvements. The average pre-intervention score on the BDI-II was around 7 points and the average STAI score was 32 points; the cutoffs for these instruments for depression and anxiety are 14 and 40 points, respectively. At the conclusion of the interventions, participants in both groups dropped about one point on the BDI-II and scores on the STAI were unchanged. Also, the sample averaged approximately 8300 steps per day over 7 days prior to the intervention, which is considered average for healthy older adults; there was only a small improvement for both groups in daily PA. All participants underwent pulmonary rehabilitation before and after undergoing lung transplantation at our center prior to study enrollment, which in and of itself has been shown to improve exercise capacity and reduce distress,¹⁶ and likely contributed to participants’ high levels of psychological and physical function prior to the start of the intervention.³⁰ Further, it should be noted that the comparison group for INSPIRE-III was not a placebo control group, but rather an active comparison group in which the SoC-ED intervention provided important educational information that the participants found beneficial and the effectiveness of the SoC-ED intervention may have further diminished between-group differences. In the absence of a usual care control condition with no telehealth contact, it cannot be determined whether any phone contact during the 12-week intervention may have been beneficial and comparable to the CSTEX intervention.

Although there were no between-group differences in either psychological distress or functional capacity across all participants, in an exploratory analysis we observed important differences in a subset of participants who were depressed at study entry. We noted that 14% of our sample obtained significantly elevated scores on the BDI-II at baseline (i.e., ≥14), albeit somewhat lower than the prevalence reported in other surveys of transplant patients.³¹ De Vito Dabbs, Dew et al. have suggested that careful monitoring of patient distress is important and that and that timely identification and treatment of distressed patients has the potential to improve their overall QoL.⁵ Indeed, among the subgroup of participants with elevated BDI-II scores at baseline, those randomized to CSTEX obtained a 10-point reduction in BDI-II scores compared to only a 2.5-point reduction for those who received SoC-ED. Although this advantage is clinically meaningful, the clinical benefits of this improvement are unknown; however, previous studies suggest that patients exhibiting clinically elevated levels of depression following transplant are nearly twice as likely to experience chronic rejection or die compared to their nondepressed counterparts.^7,8 Thus, the improvement seen in this subgroup of patients may not only benefit their quality of life but could also have a positive impact on their long-term survival. Although interventions to reduce distress in pre-transplant patients have failed to improve long term survival,³² in part because pre-transplant distress is not predictive of adverse clinical outcomes after transplant,^33,34 the longer-term impact of reduced depression is not known and warrants further investigation.

Anxiety is common both before and following lung transplantation. In the present study, the average baseline score on the STAI was 32, well below the cutoff for significant anxiety. Only 19% of patients reported clinically significant anxiety (STAI ≥40), which is considerably less prevalent than has been reported in some studies following lung transplantation.^4,35 The subgroup of patients with STAI scores ≥40 randomized to CSTEX achieved lower scores following the 12-week interventions (CSTEX = 40; SoC-ED = 44), although the difference between groups was not statistically significant. Anxiety disorders are typically resistant to routine medical care and exercise alone appears to have limited effectiveness,³⁶ suggesting that psychiatric treatment may be necessary if symptoms persist or worsen.

The relatively small improvement in exercise capacity and daily PA among both intervention groups was unexpected. All participants engaged in pulmonary rehabilitation prior to study entry and appear to have maintained, but not improved, their functional capacity. Exercise training has been shown to improve cardiopulmonary function and reduce depression in older adults and patients with clinical depression.^37,38 Exercise also has been shown to be beneficial for patients before and after lung transplantation; however, the evidence for direct causation is limited by the lack of randomized controlled trials.³⁹ Well-designed randomized controlled trials are needed, as well as further research into the effect of exercise training on important post-transplant clinical outcomes, such as time to discharge, rejection, infection, survival and re-hospitalization.

The INSPIRE-III trial has a number of strengths including a relatively large sample of well-characterized patients who had undergone a lung transplant within 18-months from study enrollment and completed standard post-transplant pulmonary rehabilitation. We had a very high rate of study acceptance, with 87% of eligible lung transplant recipients volunteering to participate. The demographic and clinical characteristics of our sample were similar to those of patients routinely transplanted at Duke and other transplant centers suggesting that our findings are likely to be generalizable to other large transplant centers. Moreover, adherence to the protocol was excellent, with a 99% completion rate. However, we also recognize the single center nature of the study and center specific practices may limit some of the generalizability of the study results. It should be noted that the challenges in working with this post-transplant population should not be underestimated. Despite a healthy, medically stable sample of post-lung transplant recipients, almost a quarter of the sample required in-patient hospitalization during the 12-week intervention. In addition, most patients experienced a variety of somatic symptoms including injuries from falls, gastrointestinal distress, various bacterial and fungal infections, side effects from medications, excessive fatigue, and general malaise, all of which undoubtedly affected their participation in the interventions and limited their daily PA. These medical events while not unexpected and non-study related, were certainly disruptive and serve as a reminder that these patients remain highly vulnerable to untoward clinical events and require ongoing monitoring of their pulmonary condition and general health.

Summary.

Taken together the data from the INSPIRE-III randomized clinical trial suggest that emotional distress may not be as common as previously reported. Most lung transplant recipients cope well post-transplant and maintain their medication adherence. However, 15-20% of patients may experience significant depression or anxiety that may need additional treatment over and above routine medical care. Patients with clinical depression who received the CSTEX intervention had significant reductions in depressive symptoms that may not only improve their QoL but could also improve their long-term survival. Studies with longer follow-up are needed to evaluate the effects of reduced depression on clinical outcomes.

Abbreviations

BDI

Beck Depression Inventory

BOS

Bronchiolitis obliterans syndrome

CI

Confidence interval

CSTEX

Coping Skills and Exercise

CF

Cystic fibrosis

COPD

Chronic obstructive pulmonary disease

GHQ

General Health Questionnaire

INSPIRE

Investigational Study of Psychological Interventions in Recipients of Lung Transplantation

IPF

Idiopathic pulmonary fibrosis

ITT

Intention to treat

PA

Physical activity

PSS

Perceived Stress Scale

PROMIS

Patient-Reported Outcomes Measurement Information System

SoC-ED

Standard of Care plusEducation

QoL

Quality of life

SD

Standard deviation

STAI

Spielberger State-Trait Anxiety Inventory

6MWT

Six minute walk test

SE

Standard error

Data Availability

The data on which this manuscript was based will be made available upon request after all follow-up data for the study have been collected.