Active Coping, Resilience, Post-Traumatic Growth, and Psychiatric Symptoms Among Early and Late Liver Transplant Survivors

Abstract

Background:

Understanding survivorship experiences at different stages post-liver transplantation (LT) is essential to improving care. Patient-reported concepts including coping, resilience, post-traumatic growth (PTG), and anxiety/depression, have been implicated as important predictors of quality of life and health behaviors after LT. We aimed to descriptively characterize these concepts at different post-LT survivorship stages.

Methods:

This cross-sectional study featured self-reported surveys measuring sociodemographic, clinical characteristics, and patient-reported concepts including coping, resilience, PTG, anxiety, and depression. Survivorship periods were categorized as early (≤1 year), mid (1–5 years), late (5–10 years), and advanced (≥10 years). Univariable and multivariable logistic and linear regression modeling examined factors associated with patient-reported concepts.

Results:

Among 191 adult LT survivors, the median survivorship stage was 7.7 years (IQR 3.1–14.4) and median age was 63 years (range 28–83); most were male (64.2%) and Caucasian (84.0%). High PTG was more prevalent in the early survivorship period (85.0%) than late survivorship (15.2%). High trait resilience was only reported by 33% of survivors and associated with higher income. Lower resilience was seen among patients with longer LT hospitalization stays and late survivorship stages. About 25% of survivors had clinically significant anxiety and depression, which was more frequent among early survivors and females with pre-LT mental health disorders. In multivariable analysis, factors associated with lower active coping included survivors ≥65 years, non-Caucasian race, lower levels of education, and non-viral liver disease.

Conclusions:

In a heterogeneous cohort including early and late LT survivors, there was variation in levels of PTG, resilience, anxiety, and depression at different survivorship stage. Factors associated with positive psychological traits were identified. Understanding determinants of LT survivorship has important implications for how we should monitor and support LT survivors.

INTRODUCTION

Liver transplantation (LT) provides a chance of cure for patients with decompensated cirrhosis or early-stage hepatocellular carcinoma (HCC) and is associated with >70% 5-year survival.¹ However, LT often requires an arduous recovery filled with physical, emotional, and psychological challenges.^2,3 LT survivors must adapt to a new life that includes strict medication adherence, frequent clinical monitoring, and unanticipated complications. Understanding the patient perspective of LT recovery is essential to improving post-LT care. LT survivorship is more than patient and graft mortality—it encompasses the patient journey of experiences and symptoms that influence global functioning.⁴ The ways in which LT recipients adjust and adapt to their lives after LT over time is not fully understood. Patient-reported surveys can evaluate patients’ lived experiences to understand post-LT survivorship outcomes that are unattainable from traditional clinical sources.

Psychological symptoms such as anxiety, depression, and post-traumatic stress are well-known to influence post-transplant outcomes (e.g., worse immunosuppression adherence and quality of life).^5–9 Other psychological concepts have been investigated to assess how individuals react, change, and adapt in response to stressful life events. These include coping style^10–12, resilience^13–15, and post-traumatic growth (PTG),^16–19 which have been suggested as important predictors of quality of life and health behaviors in other chronic diseases including LT recipients. These psychological concepts may influence post-transplant recovery by playing a role in active self-management²⁰ and self-efficacy (confidence) to perform various health behaviors.^21–23 These concepts may also have implications for global functioning after LT, including ability to go back to work, engage in daily activities, and overall quality of life.^24–27 However, what remains unclear is whether concepts such as coping, resilience, and PTG vary based on survivorship stage, and if there are patient factors associated with higher levels of positive coping, resilience, and growth among transplant survivors at different stages in their recovery.

The aims of this study were to characterize under-studied patient-reported concepts using patient reported outcome measures (PROMs) at various stages of LT survivorship including early vs. late survivors. Of particular interest were assessments of novel concepts including resilience, PTG, the role of religion in controlling one’s health, and religious coping at different stages of recovery. Moreover, we aimed to identify factors associated with higher scores of positive coping, resilience, PTG and psychological symptoms. Understanding these patient traits, experiences, and symptoms may shed light on how LT survivors experience their recovery at various stages post-LT. Assuming that these psychological concepts have important implications for clinical outcomes, identifying factors associated with these concepts may identify at-risk survivors struggling with certain aspects of their post-LT recovery. Ultimately, this patient-centered approach can inform what resources and strategies are used to support LT recipients at different stages in their recovery.

METHODS

Patient Population

This cross-sectional study featured the administration of several surveys to adult (age > 18 years) LT recipients (transplanted between January 1990 to November 2019), who were actively followed at the University of North Carolina (UNC) Liver Transplant Center (Figure 1). Eligible patients were identified using a prospectively maintained registry of patients who underwent liver transplantation. We excluded patients who were no longer being followed in the Liver Transplant clinic at UNC or those who did not speak English. Eligible patients were recruited to complete email or paper-based surveys between 3/16/2020 and 6/11/2020. All research was conducted in accordance with both the Declarations of Helsinki and Istanbul and was approved by the UNC Institutional Review Board.

Figure 1. Flow Chart Including Participant Identification, Selection, and Response Rate.

Flow diagram representing potential liver transplant (LT) survivors who participated and provided survey responses.

Patient-Reported Concepts and Surveys

Variables of interest were selected a priori and were suspected to influence survivorship experiences in post-LT recovery based on a conceptual model of post-LT survivorship.³ All variables were self-reported in anonymous surveys and included: 1) sociodemographic variables: age, sex, race and ethnicity, education level, income; 2) pre-LT characteristics: indication for LT, waitlist time, history of HCC, psychiatric comorbidities, history of psychiatric counseling, history of substance abuse counseling; and 3) post-LT characteristics: years post-LT, dual liver-kidney transplant, hospital length of stay after LT, discharge location, employment status, and active caregiver help. We divided the survivorship periods into early (≤1 year), mid (1–5 years), late (5–10 years), and advanced (≥10 years) a priori considering potential complications that develop at different stages of recovery, as well as known survival data. Given that in the first year, survivors face unique acute post-surgical or infectious complications, and standard quality metrics consider the first year as an important cut-off for clinical outcomes, we defined the <=1 year as the early survivorship period. The 5-year mark was determined to be an important cutoff in recovery given that >70% of LT recipients survive beyond 5 years. After 5 years, survivors may develop significant metabolic, renal complications, as well as potential recurrence of disease. Moreover, given that median post-LT survival exceeds 10 years, the ≥10-year survivorship period is an important time to consider risk for long-term complications including cardiovascular and malignant complications.^28–30

The main variables of interest included psychological traits and concepts (Table 1), which we suspect have important implications for survivorship but have not been well described in the literature for LT recipients. These included post-traumatic growth (PTG)^16,18,31,32, resilience^13,15,33,34, role of God/religion in controlling one’s health^35,36, and positive coping traits such as active coping.^{10,11,37–39} Additionally, we investigated anxiety and depressive symptoms, which are well described in the LT population as relating to important outcomes including medication adherence.^37,40,41 We also examined internal health locus of control (HLOC) (i.e., a stronger belief in an individual’s control over his/her health) and God HLOC (i.e., the role in which God controls one’s health), scored on a scale of 6–30 with the higher number reflecting more control (Table 1). In particular, we were interested in PTG, which captures the patient’s ability to overcome a lifechanging event and potentially thrive after hardship; this concept may be associated with other post-LT outcomes, such as health-related quality of life after LT.⁴² The concept of resilience was examined given its association with health-related outcomes; resilience has been negatively correlated with perceived stress, anxiety, depression, negative affect, and physical symptoms, and positively correlated with positive affect and health behaviors such as exercise in a cardiac rehabilitation population.⁴³

Table 1.

Description and Scoring of Instruments Used to Measure Patient-Reported Concepts Among Liver Transplant Survivors

INSTRUMENT NAME	DESCRIPTION / SCORING	ITEM #	SCALE PER ITEM	THRESHOLDS / FINAL SCORE	VALIDATION POPULATION / REFERENCE	CRONBACH ALPHA COEFFICIENT
Brief COPE Scale	contains 14 subscales (2 items per subscale), each corresponding to 14 different coping styles. This study focused on positive coping styles including:  - Active Coping  - Positive Reframing  - Use of Emotional Support  - Religious Cope  - Acceptance	28	1–4	Higher = Better Coping Sum of score (range 2–8 for each subtype) No specific cutoffs in the literature	Community sample recovering from Hurricane Andrew49 Liver transplant candidates41	α = 0.50–0.90
Brief Resilience Scale	Assess the ability to bounce back or recover from a stressful experience or situation.	6	1–5	Higher = Better Resilience Mean Cut-Offs50 Low = 1–2.99 Normal = 3–4.3 High = 4.31–5	Two student samples and samples with cardiac disease and chronic pain.51 Patient who underwent total hip arthroplasty50	α = 0.79
Medical Outcome Study Social Support Survey (MOS-SSS)	Assesses levels of Social Support. Instrument includes measure of overall Social Support, as well as 4 Subscales:  - Emotional/Information Support  - Tangible Support  - Affectionate Support  - Positive Social Interaction	19	1–5	Higher = Better Support Composite score = average of subsets Cut-Off Scores per Category52 Low emotional support: <23 Low instrumental/tangible <11 Low compassionate/affectionate <8 Low leisure and free time/positive social interaction <11	Patients who had one or more of four chronic diseases (hypertension, diabetes, coronary heart disease, and depression)53	α >0.91
Multidimensional Health Locus of Control (MHLC) (Form A)	Investigates a subject’s general health locus of control in relation to a particular chronic medical condition. Those with an internal HLOC have a stronger belief that they are in control of their health. Split into 3 subscales:  - Internality (6 questions; scale 6–30)  - Powerful others externality (6 questions)  - Chance externality (6 questions)	18	1–5	Sub-scale 6–30 for Internal HLOC Higher = Better No specific cutoffs in the literature	Persons over 16 years waiting at gates in a metropolitan airport54,55	α = 0.673–0.859
God Health Locus of Control (GHLC)	Examines the relationship between religious beliefs and health, typically added to the MHLC form above. GHLC the role in which God controls health outcomes.	6	1–5	Sub-scale 6–30 Higher = Better No specific cutoffs in the literature	Rheumatoid arthritis and systemic sclerosis56	α = 0.91, 0.87, and 0.94
Post Traumatic Growth Inventory – Short Form (PTG-SF)	Assesses the relationship between challenging life experiences and positive change (i.e., growth through adversity). The instrument provides an overall measure of PTG, as well as 5 subscales:  - Relating to Others  - New Possibilities  - Personal Strength  - Spiritual Change  - Appreciation of Life	10	0–5	Total score (sum)=0–50 / Higher = Better Mean cutoffs:16,57–59 No/Low: <3 (mean score) Moderate/High: >=3 Alternative Mean cutoffs:39 Low < 2.5 Moderate>= 2.5 and <3.5 High=> 3.5	First sample: Adults who completed the PTGI in previous studies (to help identify items)60 Second samples: college students (to verify psychometric properties)	α = 0.86–0.89
PROMIS Emotional Distress – Depression – Short Form 8B	Assesses depression symptoms. Each item corresponds to self-reported symptoms of depression. A higher score corresponds to greater severity of depression symptoms.	8	1–5	Total score (8–40) = Raw Score → T score (37.1–81.8) T Score Cutoff:43 None: <55 Depression: >=55 Alternative T Score Cutoffs:44 No Depression (PHQ 0–4): <52.5 Mild (PHQ 5–9): 52.5–58.5 Moderate (PHQ 10–14): 58.6–64.6 Severe (PHQ 15–24): >=64.7 Alternative T Score Cutoff:61 Depression diagnosis >= 63 (specificity 99%; sensitivity 25%)	Men and women 18 years and older. They were required to be within the first four months of outpatient treatment for major depressive disorder. Minimum score of 12 on the 17-item Hamilton Scale for Depression62 Cervical cancer patients63 Individuals with major depressive disorder, back pain, chronic obstructive pulmonary disease, chronic heart failure and cancer64	α = 0.95–0.96
PROMIS Emotional Distress – Anxiety – Short Form 7a	Assesses anxiety symptoms. Each item corresponds to self-reported symptoms of anxiety. A higher score corresponds to greater severity of anxiety.	7	1–5	Total score (7–35)= Raw Score → T score (36.3–82.7) T Score Cutoff:43 None: <55 Depression: >=55 Alternative T Score Cutoffs:44 No Anxiety (GAD 0–4): <52.6 Mild (GAD 5–9): 52.6–60.9 Moderate (GAD 10–14): 61.0–67.6 Severe (GAD 15–21): >=67.7 Alternative T Score Cut Off:45,47 Clinically Significant Anxiety =>62

Most instruments have been developed and validated in other chronic conditions, and not cirrhosis or LT. The Brief Coping Orientation to Problems Experienced (COPE) has been empirically validated in adult LT populations.⁴⁴ Patient Reported Outcomes Measurement Information System (PROMIS) instruments were used given their robust psychometric development and testing, as well as the ability to compare them with U.S. population norms and across patients with a diverse array of chronic conditions.⁴⁵ Clinically significant cutoffs for each survey instrument were used (if available) based on evidence from the literature, as described in Table 1. More specifically, low, moderate and high PTG scores were defined based on a study of LT recipients using the long form of this instrument.⁴² For PROMIS depression and anxiety, the threshold of a T score ≥55 was used based on recommended cut-offs for mild symptoms.⁴⁶ Alternative cutoffs for each instrument are presented in Table 1. For example, for PROMIS depression and anxiety, a T score of ≥52.5 has also been associated with clinical symptoms of depression and anxiety as determined by the PHQ-8 and GAD-7 scores.^47–51 Additionally, a composite social support score included the average of all subscale scores. The patient-reported survey data was created, distributed, and stored securely using Redcap.

Statistical Analysis

Descriptive statistics included frequencies for categorical variables and medians with interquartile range (IQR) for continuous variables given most scores of patient-reported concepts were skewed. Frequency of patient-reported scores were categorized based on cutoffs derived from the literature and stratified by survivorship period. Bivariate analyses were used to identify associations between sociodemographic and clinical characteristics and patient-reported construct. More specifically, T-Test and Wilcoxon Ran-Sum tests were performed for 2 group comparisons of parametric and non-parametric outcomes, respectively. ANOVA or Kruskal-Wallis equality-of-populations rank tests were performed for >2 group comparisons of parametric and non-parametric outcomes, respectively.

Multivariable logistic regression modeling explored relationships between sociodemographic/clinical characteristics with patient-reported concepts, adjusting for potential covariates. Covariates were selected if significant in bivariate analyses, or a priori if thought to be clinically significant (e.g., age, sex, race). For survey scores without defined cutoffs per the literature, responses were analyzed using multivariate linear regression modeling.⁵² For subscales of the Brief COPE, analyses were conducted primarily using linear regression modeling; however, we also performed logistic regression modeling using a threshold score of >5 (midpoint of the scale 2–8) to signify moderate/higher coping. Tests for collinearity were performed and collinear variables were removed from the model based on significance testing. Models were reduced and variables removed if non-significant based on F testing. All quantitative analyses were performed using STATA version 16.

RESULTS

Sample Sociodemographic & Clinical Variables

A total of 191 adult LT recipients provided survey responses (response rate 41.0%) as described in Figure 1. The median survivorship stage was late (7.74 [IQR 3.09, 14.39] years post-LT), although the population included survivors at all phases of recovery including early (11.9%), mid (23.8%), late (20.8%), and advanced (43.5%) stages of survivorship. Characteristics of LT recipients stratified by survivorship period are included in Table 2. For the total sample, the median age was 63 years (range 28–83 years). Males made up 64.2% of respondents, and 84.0% were Caucasian. There was an even distribution among income levels including <$35,000 (22.6%), $35,000–65,000 (30.1%), $65,000–100,000 (24.7%) and >$100,000 (22.6%). Regarding pre-LT characteristics, just under one-third (31.1%) had viral hepatitis as their LT indication, followed by non-alcohol associated fatty liver disease (16.2%) and alcohol-associated liver disease (7.4%). Just over one-quarter (25.7%) of the population had HCC. About 40.3% of LT survivors had been on the waitlist for ≤6 months, whereas 12.0% were waitlisted 6–12 months, 28.9% for 1–2 years, and 18.9% waited over 2 years. Just under half of LT survivors were unemployed (42.1%), which was similar across survivorship periods. A majority (62.5%) reported having active caregiver support at the time of survey assessment, although caregiver support was lower in late/advanced survivorship periods (28.8%) compared to early survivors (100%) (Table 2).

Table 2.

Self-Reported Sociodemographic and Clinical Characteristics of Adult LT Survivors Stratified by Survivorship Stage (N=191)

VARIABLE		FREQUENCY n (%)
		TOTAL (N=191)	≤1 YEAR (N=20)	1–5 YEARS (N=40)	5–10 YEARS (N=35)	>10 YEARS (N=73)
PATIENT CHARACTERISTICS
Age (yrs)	18 – 49	15 (7.8)	3 (15.0)	7 (17.5)	1 (2.9)	4 (5.5)
	50 – 64	49 (25.7)	10 (50.0)	11 (27.5)	9 (25.7)	16 (21.9)
	> 65	56 (29.3)	7 (35.0)	12 (30.0)	13 (37.1)	21 (28.8)
	Missing	71 (37.2)	0 (0)	10 (25.0)	12 (34.3)	32 (43.8)
Sex	Female	43 (22.5)	7 (35.0)	12 (30.0)	7 (20.0)	16 (21.9)
	Male	77 (40.3)	13 (65.0)	18 (45.0)	16 (45.7)	24 (34.3)
	Missing	71 (37.2)	0 (0)	10 (25.0)	12 (34.3)	32 (43.8)
Education Level	High School Graduate	19 (9.9)	8 (40.0)	3 (7.5)	4 (11.4)	2 (2.7)
	Some College	39 (20.4)	6 (30.0)	12 (30.0)	7 (20.0)	12 (16.5)
	College Graduate	41 (21.5)	5 (25.0)	7 (17.5)	8 (22.9)	19 (26.0)
	Graduate Degree	21 (11.0)	1 (5.0)	8 (20.0)	4 (11.4)	8 (11.0)
	Missing	71 (37.2)	0 (0)	10 (25.0)	12 (34.3)	32 (43.8)
Income ($)	< 35 K	21 (11.0)	0 (0)	10 (25.0)	3 (8.6)	8 (11.0)
	35 – 65 K	28 (14.7)	0 (0)	7 (17.5)	7 (20.0)	11 (15.1)
	65 – 100 K	23 (12.0)	1 (5.0)	10 (25.0)	5 (14.3)	6 (8.2)
	>100 K	21 (11.0)	0 (0)	1 (2.5)	8 (22.9)	10 (13.7)
	Unknown / Unanswered	98 (51.3)	19 (95.0)	12 (30.0)	12 (34.2)	38 (52.0)
Race	White	84 (44.0)	14 (70.0)	23 (57.5)	21 (60.0)	35 (48.0)
	Black	14 (7.3)	4 (20.0)	7 (17.5)	0 (0)	6 (8.2)
	Other	2 (1.1)	2 (10.0)	0 (0)	2 (5.7)	0 (0)
	Missing	91 (47.6)	0 (0)	10 (25.0)	12 (34.3)	32 (43.8)
PRE-TRANSPLANT CHARACTERISTICS
Indication for LT *	HBV/HCV	46 (24.1)	5 (25.0)	5 (12.5)	11 (31.4)	28 (38.4)
	Alcohol	11 (5.7)	2 (10.0)	5 (12.5)	3 (8.6)	3 (4.1)
	NAFLD	24 (12.6)	7 (35.0)	11 (27.5)	6 (17.1)	4 (5.5)
	Other	67 (35.1)	6 (30.0)	19 (47.5)	15 (42.9)	38 (52.0)
	Unknown / Unanswered	22 (11.5)	0 (0)	0 (0)	0 (0)	0 (0)
Waitlist Time (months)	<=6	71 (37.2)	7 (35.0)	18 (45.0)	14 (40.0)	29 (39.7)
	7 – 12	27 (14.1)	8 (40.0)	8 (20.0)	5 (14.3)	6 (8.2)
	13 – 24	47 (24.6)	1 (5.0)	8 (20.0)	8 (22.9)	25 (34.3)
	> 24	34 (17.8)	4 (20.0)	6 (15.0)	8 (22.9)	13 (17.8)
	Unknown / Unanswered	12 (6.3)	0 (0)	0 (0)	0 (0)	0 (0)
HCC	Yes	46 (24.1)	7 (35.0)	13 (32.5)	11 (31.4)	13 (17.8)
	No	133 (69.6)	13 (65.0)	27 (67.5)	24 (68.6)	60 (82.2)
	Unknown / Unanswered	12 (6.3)	0 (0)	0 (0)	0 (0)	0 (0)
History of Illicit Substance Use	Yes	10 (5.2)	8 (40.0)	1 (2.5)	0 (0)	1 (1.4)
	No	180 (94.2)	12 (60.0)	39 (97.5)	35 (100)	72 (98.6)
	Missing	1 (0.5)	0 (0)	0 (0)	0 (0)	0 (0)
History of Alcohol Use	Yes	15 (7.9)	6 (30.0)	3 (7.5)	3 (8.6)	3 (4.1)
	No	164 (85.9)	14 (70.0)	37 (92.5)	32 (91.4)	70 (95.9)
	Missing	1 (0.5)	0 (0)	0 (0)	0 (0)	0 (0)
History of Mental Health Disorder	Yes	26 (13.6)	6 (30.0)	7 (17.5)	6 (17.1)	6 (8.2)
	No	164 (85.9)	14 (70.0)	33 (82.5)	29 (82.9)	67 (91.8)
	Missing	1 (0.5)	0 (0)	0 (0)	0 (0)	0 (0)
History of Pain Disorder	Yes	28 (14.7)	6 (30.0)	8 (20.0)	4 (11.4)	8 (11.0)
	No	162 (84.8)	14 (70.0)	32 (80.0)	31 (88.6)	65 (89.0)
	Missing	1 (0.5)	0 (0)	0 (0)	0 (0)	0 (0)
Received Psychiatric Care / Counseling	Yes	28 (14.7)	0 (0)	10 (25.0)	6 (17.1)	11 (15.1)
	No	125 (65.4)	0 (0)	30 (75.0)	28 (80.0)	60 (82.2)
	Unknown / Unanswered	38 (19.9)	20 (100)	0 (0)	1 (2.9)	2 (2.7)
Received Substance Abuse Counseling	Yes	16 (8.4)	2 (10.0)	7 (17.5)	4 (11.4)	3 (4.1)
	No	157 (82.2)	18 (90.0)	33 (82.5)	30 (85.7)	68 (93.2)
	Unknown / Unanswered	38 (19.9)	0 (0)	0 (0)	1 (2.9)	2 (2.7)
POST-TRANSPLANT CHARACTERISTICS
Combined Liver and Kidney Transplant	Yes	10 (5.2)	3 (15.0)	1 (2.5)	4 (11.4)	1 (1.4)
	No	149 (78.0)	17 (85.0)	39 (97.5)	31 (88.6)	72 (98.6)
	Unknown / Unanswered	32 (16.8)	0 (0)	0 (0)	0 (0)	0 (0)
Hospital Length of Stay (weeks)	<= 3	94 (49.2)	0 (0)	22 (55.0)	23 (65.7)	43 (58.9)
	4 – 8	45 (23.6)	0 (0)	10 (25.0)	7 (20.0)	24 (32.9)
	> 8	20 (10.5)	0 (0)	8 (20.0)	5 (14.3)	6 (8.2)
	Unknown / Unanswered	32 (16.8)	20 (100)	0 (0)	0 (0)	0 (0)
Discharge Location After LT ^	Home	116 (60.7)	0 (0)	34 (85.0)	19 (54.3)	54 (74.0)
	Inpatient Rehabilitation Hospital	8 (4.2)	0 (0)	1 (2.5)	7 (20.0)	0 (0)
	Other	35 (18.3)	0 (0)	5 (12.5)	9 (25.7)	19 (26.0)
	Missing	32 (16.8)	20 (100)	0 (0)	0 (0)	0 (0)
Employment Status	Yes	37 (19.4)	8 (40.0)	9 (22.5)	8 (22.9)	11 (15.1)
	No	80 (41.9)	12 (60.0)	21 (52.5)	12 (34.3)	30 (41.1)
	Missing	74 (38.7)	0 (0)	10 (25.0)	15 (42.9)	32 (43.8)
Active Caregiver Help	Yes	75 (39.3)	20 (100)	19 (47.5)	11 (31.4)	21 (28.8)
	No	45 (23.6)	0 (0)	11 (27.5)	12 (34.3)	20 (27.4)
	Missing	71 (37.2)	0 (0)	10 (25.0)	12 (34.3)	32 (43.8)

^*Other LT Indications: additional self-reported included Alpha-1 Antitrypsin Deficiency, Biliary Atresia, Drug Induced Liver Injury, Hemochromatosis, Cryptogenic

^{^}Other discharge locations included a caregiver’s home, motel/hotel, temporary housing near the transplant called the State Employees' Credit Union (SECU) housing

Abbreviations: Liver Transplant (LT), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Non-Alcoholic Fatty Liver Disease (NAFLD), Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Hepatocellular Carcinoma (HCC)

Patient Reported Concepts

Figure 2 includes median scores for all patient reported concepts, and Figure 3 includes patient-reported concepts, using established cut-offs, stratified by survivorship period. Unadjusted bivariate associations of sociodemographic or clinical characteristics and patient-reported concepts are included in Supplemental Tables 1 and 2. Frequencies of high vs. low resilience, PTG, depression, and anxiety are discussed individually below and reported in Supplemental Table 3.

Figure 2. Median Patient-Reported Scores at Different Survivorship Stages After Liver Transplantation (N=191).

For different survivorship stages, median patient-reported scores are presented for: A) Brief COPE subscales including positive coping traits and resilience, and B) internal/God health locus of control (HLOC), post-traumatic growth (PTG), anxiety, and depression.

Figure 3. Frequency of High Patient-Reported Concepts at Different Survivorship Stages after LT.

For different survivorship stages, frequency (%) of high patient-reported resilience, post-traumatic growth (PTG), anxiety, and depression. High scores were defined based on cutoffs identified in Table 1.

Positive Coping

The Brief-COPE measures several positive coping traits of interest including active coping, use of emotional support, positive reframing, acceptance, and religious coping. Overall, most patients expressed high coping traits and median scores for positive coping traits were relatively consistent between early and late survivors (Figure 2a). Among the coping subtypes, acceptance scores were highest in late-advanced survivorship periods, whereas active coping, positive reframing, and religious coping were highest among early survivors (Figure 2a). In multivariate linear regression modeling, older age (≥65 years), non-White race, and non-viral indications for LT were significantly associated with lower active coping (Table 3), whereas higher levels of education were associated with higher active coping. Adjusted mean active coping scores are provided in Table 3 accounting for covariates included in the model. When active coping scores were dichotomized into high (>5) and low/normal (≤5), similar associations were seen in multivariate logistic regression modeling (Table 4). There were no significant associations between patient characteristics and other coping subsets including positive reframing, use of emotional support, acceptance, and religious coping on multivariate analyses.

Table 3:

Adjusted Comparisons Between Patient Characteristics and Active Coping—Multivariable Linear Regression Model (N=77)

VARIABLE		ACTIVE COPING (scale 2–8)
		BETA COEFFICIENT (P VALUE)	TOTAL N	ADJUSTED MEAN SCORES (95% CI)*	P VALUE
Age (years)	<65	referent	42	6.08 (5.59, 6.57)	0.002
	>=65	−1.30 (0.003)	35	4.79 (4.25, 5.33)
Sex	Male	referent	47	5.19 (4.74, 5.65)	0.06
	Female	0.78 (0.07)	30	5.97 (5.38, 6.55)
Race	White	referent	64	5.77 (5.39, 6.16)	0.003
	Black/Other	−1.86 (0.002)	13	4.13 (3.20, 5.06)
Income	<65K	referent	41	5.35 (4.85, 5.85)	0.43
	>=65K	0.43 (0.31)	36	5.66 (5.12, 6.20)
Education	Highschool/Some College	referent	34	4.91 (4.37, 5.46)	0.02
	All College	0.81 (0.07)	24	5.76 (5.11, 6.40)
	Grad School	1.33 (0.01)	19	6.20 (5.45, 6.95)
Indication for LT	HBV/HCV	referent	28	6.31 (5.67, 6.94)	0.03
	ETOH	−0.90 (0.31)	5	5.37 (3.88, 6.86)
	NAFLD	−1.49 (0.03)	12	4.80 (3.76, 5.85)
	Other	−1.25 (0.008)	32	5.06 (4.47, 5.65)
History of HCC	No	referent	59	5.62 (5.22, 6.02)	0.25
	Yes	−0.60 (0.22)	18	5.08 (4.30, 5.85)
Waitlist Time	<1 year	referent	43	5.54 (5.07, 6.01)	0.78
	>=1 year	−0.17 (0.67)	34	5.43 (4.90, 5.97)
Post-LT Hospital Length of Stay (Weeks)	<4	referent	60	5.53 (5.14, 5.92)	0.70
	>=4	−0.17 (0.71)	17	5.36 (4.61, 6.12)
Years Post-LT	<=5	referent	23	5.36 (4.70, 6.02)	0.64
	>5	−0.10 (0.83)	54	5.55 (5.13, 5.97)
Active Caregiver Help	Yes	referent	40	5.68 (5.18, 6.17)	0.31
	No	−0.40 (0.30)	37	5.30 (4.78, 5.81)

Bold results highlight significant results.

^*Based on the beta estimates from a multiple linear regression model adjusting for the variables included in this table.

Table 4.

Unadjusted and Adjusted Associations Between Patient Characteristics and High Active Coping, Resilience, and Post-Traumatic Growt^{^}—Multivariate Logistic Regression Model (N=77)^*

VARIABLE		PATIENT REPORTED CONCEPT^
		ACTIVE COPING		RESILIENCE		POST-TRAUMATIC GROWTH
		UNADJUSTED OR (95% CI)	ADJUSTED OR (95% CI)	UNADJUSTED OR (95% CI)	ADJUSTED OR (95% CI)	UNADJUSTED OR (95% CI)	ADJUSTED OR (95% CI)
Age (years)	<65	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>=65	0.41 (0.18, 0.92)	0.14 (0.03, 0.67)	0.93 (0.44, 1.95)	0.71 (0.19, 2.62)	0.70 (0.31, 1.58)	0.24 (0.06, 0.94)
Sex	Male	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Female	2.00 (0.86, 4.67)	7.73 (1.46, 40.90)	1.04 (0.48, 2.25)	1.00 (0.29, 3.47)	0.76 (0.33, 1.74)	0.28 (0.07, 1.07)
Race	White	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Black/Other	0.56 (0.19, 1.63)	0.15 (0.02, 0.96)	0.67 (0.21, 2.10)	0.49 (0.08, 3.10)	1.94 (0.51, 7.40)	2.43 (0.39, 14.79)
Income ($)	<65K	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>=65K	2.29 (0.99, 5.32)	3.03 (0.68, 13.54)	1.43 (0.62, 3.30)	3.88 (1.02, 14.76)	1.45 (0.59, 3.60)	2.52 (0.65, 9.81)
Education	Highschool/ Some College	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	All College	2.02 (0.83, 4.95)	3.33 (0.74, 15.11)	1.28 (0.57, 2.89)	2.75 (0.69, 11.00)	1.44 (0.55, 3.80)	4.15 (0.91, 18.93)
	Grad School	8.19 (2.09, 32.10)	22.21 (3.42, 157.36)	0.39 (0.11, 1.29)	0.20 (0.03, 1.09)	0.47 (0.16, 1.32)	0.23 (0.05, 1.09)
Indication for LT	HBV/HCV	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	ETOH	0.98 (0.24, 4.00)	0.14 (0.01, 1.89)	2.27 (0.53, 9.65)	3.40 (0.32, 36.61)	0.78 (0.19, 3.26)	1.36 (0.08, 23.49)
	NAFLD	0.54 (0.19, 1.54)	0.11 (0.01, 0.95)	1.94 (0.63, 5.95)	0.56 (0.07, 4.30)	1.56 (0.46, 5.25)	0.63 (0.09, 4.39)
	Other	0.79 (0.35, 1.79)	0.20 (0.04, 0.98)	2.34 (0.96, 5.69)	3.26 (0.83, 12.76)	1.23 (0.49, 3.06)	0.71 (0.18, 2.78)
Post-LT Hospital Length of Stay (Weeks)	<=4	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>4	0.75 (0.34, 1.66)	0.37 (0.09, 1.53)	0.45 (0.18, 1.12)	0.19 (0.03, 0.91)	0.40 (0.17, 0.96)	0.76 (0.20, 2.96)
Years Post-LT	<=5	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>5	0.88 (0.42, 1.86)	0.53 (0.12, 2.37)	0.79 (0.39, 1.57)	0.16 (0.03, 0.80)	0.38 (0.17, 0.87)	0.33 (0.07,1.54)
Active Caregiver Support	Yes	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	No	0.50 (0.22, 1.11)	0.50 (0.14, 1.78)	2.30 (1.07, 4.96)	4.20 (1.17, 15.07)	0.70 (0.31, 1.59)	1.43 (0.46, 4.42)

Bold results highlight significant results.

^*N is for model adjusted for variables as indicated in the table.

^{^}High active coping score defined as >5 and low/normal <5 (based on midpoint of scale 2–8). As defined in Table 1, resilience dichotomous outcome was defined as high resilience (>4.31) and low/normal (<=4.3); moderate/high PTG (>=3) and low PTG (<3) based on cutoffs in the literature.

Resilience

Most survivors had low/normal self-reported resilience (68.2%), with only about one-third of patients (31.8%) having high (better) resilience (Supplemental Table 3; Figure 2a). High resilience scores were more frequently seen in mid-late survivorship periods (Figure 3). In multivariable analysis, higher resilience scores were significantly associated with higher income and the absence of an active caregiver (Table 4). Factors associated with worse resilience included a greater length of hospital stay at time of transplant and late survivorship.

Post-Traumatic Growth (PTG)

Overall, most LT recipients (71.2%) had high post-traumatic growth (PTG) scores (i.e., growth through adversity) (Figure 2b & 3). High PTG was more prevalent in the early survivorship period (85.0%) than the late survivorship period (15.2%) (Figure 3; Supplemental Table 3). In unadjusted analyses, factors associated with low PTG included longer LT hospitalization stay and late survivorship (Table 4); however, these factors were no longer significant in multivariable analysis. The only factor associated with low PTG in adjusted models was older age.

Anxiety and Depression

One quarter of survivors had clinically significant anxiety and depression, based on pre-defined thresholds (Supplemental Table 3). Higher anxiety and depression scores appeared more frequent in the early-mid survivorship period with 29.4% having anxiety and a 33.3% having depression <1-year post-LT, with lower frequency of anxiety/depression symptoms in later survivorship periods (Figure 3). In multivariate models, female sex was associated with anxiety, and a history of pre-LT mental health disorder was significantly associated with both anxiety and depression (Table 5); higher income was associated with lower odds of depression.

Table 5.

Unadjusted and Adjusted Associations Between Patient Characteristics and Clinical Symptoms of Depression and Anxiet^{^}—Multivariate Logistic Regression Model

VARIABLE		PATIENT REPORTED OUTCOME (PRO)
		ANXIETY (N=94)*		DEPRESSION (N=86)*
		UNADJUSTED OR (95% CI)	ADJUSTED OR (95% CI)	UNADJUSTED OR (95% CI)	ADJUSTED OR (95% CI)
Age (years)	<65	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>=65	0.32 (0.10, 1.10)	0.42 (0.07, 2.36)	0.41 (0.13, 1.29)	0.89 (0.17, 4.63)
Sex	Male	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Female	4.54 (1.41, 14.60)	5.85 (1.19, 28.69)	3.72 (1.22, 11.31)	3.80 (0.78, 18.51)
Race	White	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Black/Other	2.21 (0.60, 8.09)	1.51 (0.34, 6.71)	0.71 (0.15, 3.50)	0.26 (0.04, 1.81)
Income ($)	<65K	--	--	1.00 (referent)	1.00 (referent)
	>=65K	--	--	0.14 (0.03, 0.64)	0.09 (0.01, 0.68)
Education	Highschool/ Some College	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	All College	1.53 (0.46, 5.04)	2.20 (0.52, 13.51)	0.63 (0.19, 2.07)	1.12 (0.19, 6.61)
	Grad School	0.70 (0.13, 3.84)	1.67 (0.22, 12.41)	0.43 (0.08, 2.21)	1.96 (0.25, 15.27)
HCC	No	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Yes	0.74 (0.25, 2.19)	3.43 (0.61, 19.38)	0.57 (0.17, 1.84)	0.60 (0.11, 3.37)
Pre-LT Mental Health Disorder	No	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	Yes	4.23 (1.40, 12.72)	9.47 (1.85, 48.53)	4.60 (1.51, 13.98)	8.48 (1.71, 42.0)
Years Post-LT	<=5	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	>5	1.01 (0.36, 2.89)	0.85 (0.20, 3.56)	0.93 (0.32, 2.67)	0.61 (0.14, 2.70)
Active Caregiver Support	Yes	1.00 (referent)	1.00 (referent)	1.00 (referent)	1.00 (referent)
	No	0.26 (0.07, 0.97)	0.19 (0.36, 0.97)	0.69 (0.23, 2.08)	0.48 (0.11, 2.18)

^*N is for model adjusted for variables as indicated in the table.

^{^}As described in Table 1, clinical symptoms of depression or anxiety were defined as occurring at T values >=55.

-Omitted in the model given too few observations or non-significant.

Internal and God Health Locus of Control (HLOC)

Overall, internal and God HLOC were high among survivors and consistent across survivorship stages (Figure 2b). In multivariate linear regression modeling, there were no significant predictors of increased internal HLOC. Factors associated with significantly lower God HLOC included a history of HCC and lack of caregiver support adjusting for age, sex, race, education, indication for LT, survivorship stage, and hospitalization length of stay at time of LT (data not shown).

Social Support

Social support scores were high among LT recipients across all stages of survivorship (median score 4.47; IQR 2–5). Factors associated with a significantly higher composite social support score included female sex (beta=0.58; p=0.04) and higher income ≥$65K (beta=0.53; p=0.04) adjusting for age, race, education, LT indication, survivorship stage, time on waitlist, and presence of an active caregiver. On analyses of domains of social support, female sex was associated with significantly higher emotional support (beta=0.68; p=0.02) and tangible support (beta=0.62, p=0.04). Higher income was associated with higher positive social interaction scores (beta=0.71; p=0.02).

DISCUSSION

In a heterogeneous cohort extending from early to advanced stages of survivorship post-LT, we investigated patient-reported constructs including active coping, post-traumatic growth (PTG), resilience, anxiety and depression symptoms. We uncovered several interesting findings and associations. While over two-thirds of survivors had high PTG, this sense of growth through adversity dwindled in later stages of survivorship. Only one-third of survivors had high trait resilience, yet over half reported high active coping skills. About 25% of survivors had clinically significant anxiety and depressive symptoms, which were more frequently seen in early survivors within the first year post-LT.

Results from our study highlight important disparities that may exist and social determinants of post-LT survivorship. We found that older adults had significantly lower active coping and PTG than younger patients, whereas patients with higher levels of education and income had higher coping skills, higher resilience, and lower depression. One potential explanation of these findings is that higher socioeconomic status may afford LT survivors better access to resources and support to facilitate positive coping strategies and resilience. Understanding these relationships has important implications for identifying who and how we should support individuals after LT—resources may need to be allocated to assist those individuals who are less resilient, have less adaptive coping skills, and are experiencing anxiety and depression after LT.

LT recipients at different survivorship stages may have variable life experiences and require different types of support at different stages of their post-LT survivorship trajectory. We found that early survivors had higher active coping, PTG, and resilience compared to late survivors. This difference in scores may be because the immediate benefits of LT are felt more readily early post-LT and survivors are highly motivated to care for their graft. By comparison, in later stages of survivorship, patients have adjusted to post-LT life and may face other struggles (e.g., financial, social, other comorbidities) and the psychological growth encountered early after LT may feel less salient years later. Interestingly, anxiety and depression were highest in the early to mid-stages of survivorship and were less prevalent among later stages of recovery. These findings suggest that while early survivors may have high PTG, they also experience psychological distress during the same timeframe, suggesting that these constructs are not mutually exclusive. Some of the discrepancies in early vs. late survivor experiences persisted on multivariable analysis adjusting for confounders.

The importance of patient-reported experiences is becoming more apparent in the transplant literature, including their implication for clinical outcomes after transplant. The negative impact of anxiety and depression on immunosuppression adherence, increased stress, and lower ability to engage in self-care has been well established in lung and heart transplant recipients.^5,6 Similar to our findings in this study, many LT survivors grapple with anxiety and depression^8,53,54, as well as post-traumatic stress symptoms⁷ which have been shown to be significantly associated with poor physical and mental health-related quality of life.⁷ Consistent with our findings, about 25% of LT recipients reported persistent symptoms of anxiety and depression, which have been associated with medication non-adherence and worse quality of life.^8,54

Active coping, resilience, and PTG have also been shown to be important in chronic conditions including solid organ transplant populations. Positive coping traits, including active coping, have been associated with higher mental and physical quality of life domains in post-LT patients⁵⁵, and specifically predict higher levels of quality of life related to physical and mental functioning.¹⁰ Similarly, higher levels of resilience have been associated with lower levels of depression/anxiety and improved quality of life in kidney transplant recipients and cancer populations.^56–58 Coping encompasses a variety of forms, may change over time, and some coping strategies have been associated with more positive health outcomes in LT recipients.^12,39 Specifically, active coping (i.e., taking action and focused effort when facing a particular situation) has been positively associated with treatment adherence and higher quality of life after LT.^59,60,61 Thus, exploring what specific coping strategies LT recipients utilize in the post-LT period, and which factors may be associated with active coping, may provide valuable insight into how to improve outcomes. Others have investigated the role of social support and factors related to coping, showing that active coping and higher perceived social support were positively associated with resilience after LT.³⁹

The concept of growth through adversity (i.e., PTG) is emerging as an important concept in transplantation.^{17,18,32,62,63} In a systematic review of PTG among cancer survivors, PTG was positively associated with optimism, spirituality, and positive coping styles.⁶⁴ Among lung transplant recipients, factors associated with higher PTG included female sex, lower education, post-transplant panic disorder, greater friend support, and better perceived health.⁶³ It remains unclear what the effect of higher PTG is on post-LT outcomes. In the few studies of PTG in LT recipients, an interaction was observed between PTG and active coping strategies, such that an interaction was observed between PTG and active coping strategies. Perez San-Gregorio et al. found that higher PTG in LT recipients was associated with higher usage of healthy coping strategies, including active coping, instrumental support, and emotional support.¹¹ In a Spanish population of 240 LT recipients, higher PTG scores were associated with higher vitality scores on a quality of life measure.¹⁸ The authors conclude that higher PTG may have a protective role after LT given its association with lower bodily pain, and higher vitality and mental health. However, predictors of high PTG remain unclear. In this study, we found that older age was associated with low PTG adjusting for potential confounders. Interestingly, we also found that early-stage survivors had higher frequency of high PTG scores as compared to late/advanced survivorship stages.

The results of this study shed light on potential variability in experiences among early and late survivors, as well as identify patient characteristics associated with higher risk for struggling including lower active coping, resilience, PTG, and higher anxiety/depression symptoms. By identifying those individuals who have higher positive coping strategies or resilience, we may be able to leverage strategies that are used by these individuals to enhance post-LT recovery. For example, cognitive-behavioral treatment can improve active coping, positive reframing, and resilience, which in turn, may improve quality of life and self-management skills among survivors. Moreover, early interventions for those at risk (e.g., monitoring of females with history of pre-LT mental health disorders) may reduce the likelihood of developing disabling psychiatric symptoms post-LT.

Limitations of this study include its cross-sectional, single center design, which limits generalizability of the findings. Moreover, we were not able to capture how psychological traits, experiences and symptoms change over time in the same cohort. While our survey response rate may have contributed to potential biases, the average response rate for survey research is typically around 30–40%.^65–67 More frequent follow-up contact with the research team and providing renumeration for survey completion are strategies that would likely enhance retention and survey completion in future studies of post-transplant populations.⁶⁸ Furthermore, there may have been a recall bias especially for late and advanced LT survivors who were asked to report on aspects of their pre- and post-LT experiences years later. Some indications for LT were not well captured in our population including alcohol associated liver disease and hence we were not powered to evaluate certain associations based on indication for transplant. Despite this, we tried to investigate multiple dimensions of health including former substance use and mental health disorders. We can only report on potential relationships between patient characteristics and patient-reported constructs, acknowledging that these associations do not reflect causation; in fact, reverse causation could explain these relationships as well (e.g., individuals with higher resilience are more successful at making money and garnering support). While the anonymous nature of survey completion circumvented our assessment of other outcomes such as graft function and survival, this study provides novel data on the prevalence of survivorship constructs at various stages of recovery post-LT. This preliminary data can inform future studies that investigate the relationship between patient-reported constructs and clinical outcomes. Finally, most of the instruments used in this study were not developed in LT populations nor have they been empirically validated in LT population. Therefore, there is a need for both qualitative studies to establish content validity and quantitative methods to examine the psychometric properties of these instruments in LT populations so that future studies can evaluate novel survivorship constructs in addition to quality of life. In the future, we need large multi-center studies including a diverse population of survivors to further investigate these relationships longitudinally to evaluate how they change over time and relate to other important outcomes including graft/patient survival and health behaviors.

Despite these limitations, this study features a large population of early and late survivors, who reported on novel patient-reported constructs that are not well described in the transplant literature. By capturing traits, attitudes, and psychological symptoms through patient-reported instruments, we provide an important lens on post-transplant survivorship at different stages of recovery. Beyond differences between early and late survivors, there were sociodemographic and racial disparities in patient-reported experiences highlighting potential disparities in post-LT recovery. Future steps include investigating the relationship between these psychological constructs and post-LT outcomes including health behaviors and survival, as well as further examining characteristics of survivors who have improved global functioning after LT. Ultimately, gaining a patient-centered perspective on LT survivorship can inform how we improve our care for those patients at-risk for worse outcomes.

Abbreviations:

Brief COPE

Brief Coping Orientation to Problems Experienced

HCC

Hepatocellular carcinoma

HLOC

Internal Health Locus of Control

IQR

Interquartile Range

LT

Liver Transplantation

NAFLD

Non-Alcoholic Fatty Liver Disease

PROMs

Patient Reported Outcome Measures

PROMIS

Patient Reported Outcomes Measure Information System

PTG

Post-traumatic growth

UNC

University of North Carolina