Key words : Balance, Exercise capacity, Fatique, ICF

Introduction

Lung transplantation (LT) has become a standard treatment option for various end-stage lung diseases and has shown increased long-term survival rates.^1,2 One-year and 5-year survival rates in adult LT recipients have been reported as 85% and 59%, respectively.² Outcomes after LT are more promising with improvements in donor selection, organ protection, surgical techniques, peri- and postoperative management, and immunosup-pression regimens.^1,2

Lung transplant at an advanced age is a risk factor for increased mortality in the early period after transplant because of increased risk of infections, vascular events, and potential malignancies. Therefore, transplant age is an important criterion for LT, and age above 65 years is considered a relative contraindication to transplant.^1,3 Although data on kidney, liver, and heart transplant have shown that older high-risk recipients can successfully and safely undergo transplant,^3,4 the suitability and outcomes of LT at older ages remain controversial.⁵

The International Classification of Functioning, Disability, and Health (ICF) is a coding system that was developed to establish a common and standard language and framework to identify health-related conditions, guide interventions, set goals, and assess and monitor progression among clinicians.^6,7 The ICF describes human functioning at 3 levels: the impairment level (body functions and structures), the activity level (execution of task), and the participation level (involvement in life situations). The functioning and disability of a patient may be assessed by selecting the appropriate category and its corresponding code in these dimensions and then adding the numbers or qualifiers that specify the extent of the functioning or disability in the category. Classification of function is essential to all components of health, enhances the capacity of health professionals to achieve a broader and more meaningful picture of a patient’s health status, and can improve multiprofessional collabo-rations that optimize treatment outcomes.^8,9

Although a previous publication used ICF to evaluate outcomes in different types of transplant recipients,¹⁰ no study to our knowledge has specifically assessed LT recipients using the ICF framework in the long term. Therefore, the primary aim of this study was to evaluate the effects of LT surgery on body function, body structure, and activity and participation restrictions on recipients within the scope of ICF over time. The secondary aim was to investigate the relationships between age and comorbidity levels with ICF domains in LT recipients.

Materials and Methods

Patients
This cross-sectional study was performed between January 2021 and November 2021. Twenty-seven bilateral LT recipients who had follow-up visits at the Thoracic Surgery Clinic at the University of Health Sciences, Ankara City Hospital were included in our study. The patient inclusion criteria were as follows: at least 3 months posttransplant surgery, clinically stable, and age range of 18 to 65 years. Patients with orthopedic, neurological, or mental complications that might interfere with the evaluations and those who underwent a single LT or combined heart-lung transplant surgery were excluded from the study.
All patients were taking immunosuppressive treatment, including tacrolimus and cyclosporine, systemic steroids, and prophylactic antifungal, antibacterial, and antiviral treatment in accordance with the standard recommended medical treatment for LT recipients. All patients who agreed to participate in the study provided written informed consent. The study was approved by the Ethical Committee of Ankara City Hospital (approval number, E2-21-52; January 27, 2021). The trial is registered at ClinicalTrials.gov (registration number, NCT05376605).

Demographics and clinical findings and comorbidities
We obtained patient’ age, sex, weight, and height. We also recorded the patients’ underlying disease and prognosis, time elapsed since the diagnosis, wait time on the transplant wait list, timing of the LT surgery, length of stay in the intensive care unit and in the hospital posttransplant, number of lung infections in the last year, and current medications.

The comorbidity risk level was assessed using the Charlson Comorbidity Index (CCI). The CCI is the most widely validated and used comorbidity score that predicts 10-year mortality for patients. Higher scores indicate a higher risk of mortality; a CCI >5 is associated with nearly 100% risk of death within 1 year.11

International Classification of Functioning, Disability, and Health checklist
The Turkish version of the ICF-based checklist was used to determine items for the LT recipients’ body function and structure and their activity and participation levels.⁸ The items for each domain (body functions, body structures, and activity and participation) were carefully reviewed to select items related to the outcomes. The items selected from each domain and the evaluation methods corresponding to these parameters are shown in Table 1. The extent of impairment was scored between 0 (no impairment) and 4 (complete impairment) separately for each item in the domains. Two experienced physiotherapists in the field of cardiopulmonary rehabilitation selected and scored the relevant items. The total score for body function, body structure, and activity and participation were expressed as a percentage (%). Items with higher scores (%) indicated more impairment or limitations.^8,9

Body function and structure outcomes
Weight maintenance was assessed based on the body mass index (BMI; in kilograms divided by height in meters squared), and patients were classified as having a low (<20), normal (20-27), or high (>27) BMI.¹²

Respiratory functions were evaluated using the pulmonary function test, with measurements made using plethysmography (Cosmed Quark Q-Box Plethysmograph System) in accordance with American Thoracic Society/European Respiratory Society criteria. Recent pulmonary function test results from the last clinical visit were recorded from the patients’ medical records due to COVID-19 pandemic restrictions.¹³

Factors associated with respiratory function were assessed using the modified Medical Research Council (mMRC) dyspnea scale and fatigue severity scale (FSS). The mMRC is a categorical scale with a range from 0 to 4, and it determines the dyspnea level of patients during daily life.¹⁴ The FSS includes 9 questions with total scores that range from 0 and 7. Scores ?4 indicate that severe fatigue is present in daily life.¹⁵

We assessed exercise tolerance for both the upper and lower extremities. The patients’ functional exercise capacity and their changing basic body position were evaluated using the 1-minute sit-to-stand (STS) test. In the 1-minute STS test, the patient sits in a chair with a seat height of 46 cm without armrests. The maximum number of sit-to-stand repetitions within 1 minute are recorded, with results expressed as a percentage of the reference values.¹⁶ Arm exercise capacity and lifting and carrying objects were evaluated using the 6-minute pegboard and ring test (6PBRT). For the 6PBRT, the participant moves as many rings as possible from the lower pegs to the upper pegs that are placed 20 cm above the lower pegs and vice versa for 6 minutes. The 6PBRT score is recorded as the total number of rings that are moved during the test. A reference equation that was determined by age was used to interpret the 6PBRT score.¹⁷

Sleep function and quality were assessed with the Pittsburgh Sleep Quality Index, in which a total score ?5 indicated poor sleep quality.¹⁸ Emotional functions were assessed using the Hospital Anxiety and Depression Scale (HADS). The cut-off score of the Turkish version of the scale was determined as 8 for the anxiety and depression subscale.¹⁹ Fear of movement was assessed by the Tampa kinesiophobia scale (TKS), in which a score of 37 or above confirms the presence of kinesiophobia.²⁰

The trunk structure was assessed using a postural analysis form developed by Corbin and colleagues.21 The total posture score from the lateral and posterior view was classified as excellent (0-2), very good (3-4), good (5-7), moderate (8-11), or poor (?12).

Activity and participation outcomes
Ability to change the basic body position and walking were evaluated using the timed up and go test (TUG). The TUG is an objective, easy-to-use test that evaluates the patient’s dynamic balance and functional mobility. The time that the patient takes to rise from a chair, walk 3 m away from the chair, turn around 180 degrees, walk back to the chair, and sit back in the chair was recorded in seconds using a stopwatch. The age-based reference value versus the time that the patient reached (%) was used to interpret the test.²²

The physical activity (PA) level was assessed using the International Physical Activity Questionnaire (IPAQ) long form. The IPAQ long form contains the following 8 domains for PA: vigorous PA, moderate PA, walking PA, occupational PA, transportation PA, house-yard PA, leisure time PA, and sitting time. Total scores were presented as the metabolic equivalent (minutes/week). The patients were categorized as sedentary, minimally active, and active according to the IPAQ categorization for PA level.²³

The activities of daily living (ADLs) were evaluated using the London Chest Activity of Daily Living Scale (LCADL) to assess the effect of dyspnea in daily life. The LCADL consists of 15 items within the following 4 domains: personal care, domestic, physical, and leisure. Each item is graded from 0 to 5, with higher scores indicating more difficulty in performing ADLs.²⁴

Health-related quality of life was determined using the St. George Respiratory Questionnaire (SGRQ). The SGRQ consists of the following 3 dimensions: symptoms, activity, and impact. The total score ranges from 0 to 100 points, where a score of 0 indicates a normal state and a score of 100 indicates a severe disability.²⁵

Statistical analyses
We used SPSS version 23.0 (IBM Corp) for the statistical analysis. Variables were descriptively expressed as the mean ± standard deviation, median (minimum to maximum), frequency, and percentage. We examined the normality of the evaluation parameter distribution using visual (histogram and probability graphs) and analytical methods (Shapiro-Wilks test). We used Spearman correlation analyses to evaluate the relationship between the patient’s age, age at LT, comorbidity level, and ICF domain items. To evaluate the relationship, we classified correlation coefficients into the following 4 groups: weak (0-0.24), moderate (0.25-0.49), strong (0.50-0.74), and very strong (0.75-1.00). The level of significance was set at P < .05.²⁶

Results

Our study enrolled 27 LT recipients (5 women and 22 men; mean age of 49.93 ± 12.88 years) (Figure 1). Demographic and clinical findings of LT recipients are shown in Table 2. The mean age at transplant was 45.67 ± 13.35 years. Educational status of patients was as follows: 25.9% of patients (n = 7) completed primary school, 29.6% of patients (n = 8) completed secondary school, 25.9% of patients (n = 7) completed high school, 11.1% of patients (n = 3) had a bachelor’s degree, and 7.4% of patients (n = 2) had a master’s degree. The patients’ mean CCI score was 1.19 ± 0.96. Comorbid diseases included chronic liver disease (3.7%), diabetes mellitus (22.2%), moderate renal disease (3.7%), heart failure (3.7%), gastric ulcer (3.7%), and cerebrovascular disease (3.7%). The mean total Corbin posture analysis score in the patients was 4.04 ± 2.41. Signs of scoliosis were observed in 12 patients (44.4%), lordosis in 11 patients (40.7%), kyphosis in 7 patients (25.9%), and head-forward tilt posture disorder in 9 patients (33.3%). The 1-minute STS and 6PBRT test results showed that patients reached 49.92 ± 12.42% and 49.16 ± 10.45% of the expected values, respectively.

The ICF code distribution for the LT recipients according to their impairment level scoring is shown in Table 3. The most affected ICF parameters in the LT recipients were sleep function and exercise tolerance in the body function domain, as well as acquiring, keeping, and terminating a job, remu-nerative employment, and recreation and leisure time in the activity and participation domain.

Relationship between lung transplant recipient age and International Classification of Functioning, Disability, and Health domains
The correlation analysis results are shown in Table 4. A strong, statistically significant correlation was found between the LT recipient age and sleep functions (r = 0.57, P = .02), peak expiratory flow (PEF) values (r = -0.55, P = .02), and PEF (%) values (r = -0.63, P < .001). There was a weak association between LT recipient age and the lateral posture score (r = 0.48, P = .01), change in heart rate (r = -0.41, P = .04), and leg fatigue perception (r = -0.45, P = 0.02) during the 1-minute STS test.

Relationship between age at lung transplant and International Classification of Functioning, Disability, and Health domains
There was a significantly strong correlation between the LT recipient age at LT and sleep functions (r = 0.62, P = .001), lateral posture score (r = 0.57, P = .002), PEF (%) values (r = -0.51, P = .04), and change in leg fatigue perception during the 1-minute STS test (r = -0.55, P = .005). Age at transplant was weakly correlated with the 1-minute STS test score (r = -0.42, P = .02), change in dyspnea during 6PBRT (r = 0.43, P = .03), and change in oxygen saturation (r = -0.47, P = .01) during the 1-minute STS test.

Relationship between comorbidity level and International Classification of Functioning, Disability, and Health domains
A strong, statistically significant correlation was found between the comorbidity level in LT recipients, the 1-minute STS test score (r = -0.73, P < .001) (Figure 2), and 1-minute STS test (r = -0.52, P = .05). Otherwise, the comorbidity level was weakly related with lateral posture score (r = 0.46, P = .01), TUG test score (r = 0.40, P = .03), 6PBRT score (r = -0.42, P = .04), IPAQ domestic and gardening activities (r = -0.48, P = .01), IPAQ leisure time PA score (r = -0.41, P = .04), and SGRQ score (r = 0.41, P = .04).

In our LT recipients, 58.33% (n = 14) had kinesiophobia (TKS score ?37). The TKS score was also significantly moderately related with mMRC dyspnea score (r = 0.45, P = .02) and HADS anxiety score (r = 0.44, P = .03) and strongly correlated with FSS score (r = 0.65, P < .001) and HADS depression score (r = 0.66, P < .001)

Discussion

The main findings in this study were that the most affected ICF dimensions for LT recipients were sleep functions; exercise tolerance functions; acquiring, keeping, and terminating a job; remunerative employment; and recreation and leisure time. There was a relationship between both the age of LT recipients and age at transplant and the body function domains, but there was no association with activity or participation level domains. Additionally, comorbidity level in LT recipients was related to both body function and level of activity and participation.

According to the current International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation report (2019), the most common indication for LT is chronic obstructive pulmonary disease (COPD).²⁷ Most of our patients (55.6%) required transplant because of COPD. The level of comorbidity is an important survival indicator for LT recipients along with other factors. Immunosuppressive drugs are used for a longer period of time and at higher levels after LT compared with other solid-organ transplant procedures. Therefore, the susceptibilities to infection and malignancy are higher, resulting in a high risk level for comorbidities.²⁸ The most common comorbid condition after LT is diabetes mellitus with a 20% to 40% incidence rate.²⁹ Almost 26% of the patients in our study had diabetes mellitus as a comorbidity, which is in agreement with the literature.

Body functions and structures
Voth and colleagues showed a high frequency of obstructive sleep apnea syndrome in both LT recipients and candidates, especially in patients with sleep problems in the pretransplant period.³⁰ Poor subjective sleep quality was reported to be a common symptom after LT, and the most common problem was initiating and maintaining sleep. Nonrespiratory problems, including immunosuppressive therapy, have significant effects on sleep quality deterioration along with respiratory problems in LT recipients.³¹ In our study, 67% of LT recipients had impaired sleep quality. A moderately positive association was also shown between sleep disturbances and both the age of LT recipients and the age at surgery. We suggest that sleep disturbances increase with age because the effect of LT on respiratory mechanics increases over time and there is a longer duration of immunosup-pressive therapy.

In LT recipients, PEF measurements can reflect lung function.³² Decreases in the PEF values with age is a normal physiological adaptation associated with pathological conditions affecting cardiopulmonary status and expiratory function.³³ A moderately negative correlation was demonstrated between respiration function in LT recipients and age, which is in agreement with the literature.

Long-term hospitalization in the intensive care unit and use of immunosuppressive drugs in addition to respiratory and cardiac factors could negatively affect the recovery of exercise capacity after LT.³⁴ The exercise capacity in LT recipients remained at 40% to 60% of the expected value 2 years after transplant. This is thought to occur from a combination of preoperative lung disease, chronic deconditioning, and postoperative factors (such as prolonged hospitalization, effects of immunosup-pressive medication).^35,36 The main reason for decreased exercise capacity has been shown to be due to muscular limitations (problems in skeletal muscle oxygen delivery, uptake, and use) in lower extremities, upper extremities, and trunk.³⁶  Decreased muscle mass and strength, type 1 muscle fiber ratio, calcium intake and release, mitochondrial enzyme activity, early decline in muscle pH, and impaired oxidative capacity of peripheral muscles have been shown in LT recipients posttransplant.^37,38 We evaluated the exercise capacity of our patients using a 1-minute STS test, which is a reliable test for LT recipients.³⁹  In our study, the mean 1-minute STS score in LT patients was only 49.1% of the expected value, and there was a significant decrease in exercise capacity, which is in agreement with the literature. Leung and colleagues demonstrated a negative correlation between maximum oxygen consumption and patient age at LT.⁴⁰ Transplant age and posttransplant exercise capacity in LT recipients were also negatively correlated in another study in which exercise capacity was evaluated using the 6-minute walk test from Mejia-Downs and colleagues.³⁶ We confirmed the findings from both of these studies. We suggest that recipients with an advanced transplant age are more affected by posttransplant complications than younger recipients. The progression of age and disease can decrease the heart rate variability response in exercise tests because of deterioration of the autonomic nervous system.⁴¹ Sympathetic nervous system activity could also decrease with age.⁴² A negative relationship between the age of LT recipients and a change in heart rate and leg fatigue during the 1-minute STS in our study are consistent with published results.

In addition to the leg exercise capacity, arm exercise capacity could also be affected in patients with lung diseases.^43,44 Our study showed that functional arm exercise capacity in LT recipients decreased after LT (49% of the expected values). In addition, as the age at LT increases, dyspnea during the 6PBRT also increased. We suggest that the increase in dyspnea in the functional arm activities with advanced age could be due to a decrease in inspiratory muscle strength, with changes related to the aging process and respiratory sarcopenia.⁴⁵

Comorbidities reduce exercise capacity in patients with COPD and interstitial lung diseases.^46,47 In a review, LT recipients with comorbidities did not reach the expected maximum exercise capacity.³⁸ Our study was the first to examine the relationship between the comorbidity level and exercise capacity in LT recipients. We showed that comorbidity levels in LT recipients were strongly related to exercise tolerance functions and movement performance. The increased level of comorbidity negatively affected both upper and lower extremity performance in LT recipients. Therefore, we observed that both upper and lower extremity exercise capacities were reduced in LT recipients as a result of muscular dysfunction, metabolic abnormalities, comorbidity levels, and other posttransplant factors.

Postural abnormalities increased in patients with obstructive lung disease compared with healthy controls.48 However, as age increases, respiratory functions decrease and kyphosis increases in healthy individuals.49 In our study, we showed a positive relationship between the age of LT recipients, their age at transplant, and lateral posture impairments. Lateral posture disorders that were observed in our patients could be due to the effects of thoracic surgery and increased accessory respiratory muscle activity caused by decreased respiratory function. Because these postural alterations increase with age, we suggest that lateral postural disorders increase with advanced age.

Lung transplant recipients experience psychosocial problems due to potential complications and risks associated with organ transplant.⁵⁰ In a study sample that included 50 lung and heart-lung transplant patients, 27% had clinically significant depressive symptoms and 30% had anxiety symptoms.^50,51 In our study, LT recipients similarly displayed anxiety (25.9%) and depression (29.6%). We observed a close relationship between physical symptoms and limitations and significant anxiety and depressive symptoms in LT patients. Lower educational levels can also lead to poor adherence of patients to the complex transplant regimen, resulting in worse health outcomes and psychosocial problems.⁵⁰ Vardar-Yagli and colleagues demonstrated fear of movement associated with increased perception of dyspnea, fatigue, and higher comorbidity level in COPD patients.⁵² Nearly 60% of our LT recipients had kinesiophobia and kinesiophobia levels related to dyspnea and fatigue perceptions during daily life and anxiety and depression levels. Although we did not make any correlations between educational status, kinesiophobia level, and psychosocial status, <20% of our patients had an education level above high school degree. This could have led to high anxiety and depression and fear of movement in LT recipients.

Activity and participation
Wickerson and colleagues demonstrated that LT candidates have low PA levels after surgery, and they continue their lives with a lower PA level compared with the general population at 6 months without further improvement.⁵³ We found that 45.8% of the LT recipients were inactive, 54.2% were minimally active, and none of the recipients were in the very active category, which is consistent with the literature. As the comorbidity level of LT recipients increased, there was also a significant decrease in ICF items of walking and moving around in various places and situations. This could occur in parallel with the decreased exercise capacity and increased comorbidity level in LT recipients.

Functional mobility and balance are impaired in patients with obstructive lung diseases. Trunk muscles contribute to balance due to increased accessory respiratory muscle activity, with impaired muscles leading to impaired balance, especially in the mediolateral direction.^48,54 Our study also demonstrated balance impairment in LT recipients, and this balance disorder was positively related to the increased dyspnea perception during daily life, the comorbidity level, and impaired exercise capacity. We suggest that decreased balance and increased risk of falling in LT recipients could be a result of impaired exercise capacity, lower extremity muscle strength, an increased perception of dyspnea during daily life, postural changes in the lateral plane, and current comorbidities. Health-related quality of life is significantly reduced in people with advanced lung diseases and LT candidates.⁵⁵ Smeritschnig and colleagues reported that side effects of immunosuppressive therapy are an important factor that can affect the quality of life in LT recipients.⁵⁶ Cardoso and colleagues reported a moderately positive relationship between the LCADL score and complications and physical limitations in self-care for LT recipients.⁵⁷ In our study, the comorbidity level in LT recipients was moderately positively associated with the SGRQ total score. We suggest that the high comorbidity level caused negative changes in the functional status (eg, decreased exercise capacity, balance impairment), leading to deterioration in the ADLs and quality of life in LT recipients.

Ding and colleagues assessed cardiopulmonary components in the early posttransplant period using the ICF cardiopulmonary core set.¹⁰ However, this study included all the following transplant recipient groups: liver, heart, kidney, pancreas, and lung. In a study of 40 pediatric patients with or without cystic fibrosis, the ICF framework was easy to apply and useful for evaluating body function and structure disorders such as muscle weakness, postural abnormalities, and limitations to activity and participation in daily life, and it was helpful in creating a treatment plan.⁵⁸ Jácome and colleagues reported that assessment within the scope of ICF makes rehabilitation planning easier and more effective in patients with COPD.⁵⁹ Vitacca and colleagues also showed that ICF assessment is useful because it provides additional general information on rehabilitation outcomes and creates a common perspective for COPD patients.⁶⁰ The strength of our study was that this was the first study, to our knowledge, to show that ICF is useful and beneficial for long-term follow-up of LT recipients.

This study had some limitations. Only a limited number of recipients could be contacted, resulting in a distribution that may have been biased. Another limitation of this study was that exercise capacity could not be evaluated using the gold standard cardiopulmonary exercise test.

Conclusions

In our examination of body functions and structures and activity/participation levels of LT recipients and relationships between these dimensions of ICF, we found that, as age and age at LT increase, sleep functions, respiratory functions, exercise tolerance function, and trunk structure are negatively affected. As the comorbidity level in recipients increases, we also found that sensations related to muscles and movement functions, trunk structure, changing the basic body position, lifting and carrying objects, walking, moving around in different locations and situations, and community life were negatively impacted. The most adversely affected ICF dimensions in LT recipients were sleep functions; exercise tolerance functions; acquiring, keeping, and terminating a job; remunerative employment; and recreation and leisure time. Therefore, medical treatments and pulmonary rehabilitation programs given by a multidisciplinary team should focus on these parameters in LT recipients. This study also showed that the ICF evaluation model is applicable in LT recipients in the long term, and it can increase awareness for rehabilitation professionals in terms of body function and structure disorders and activity and participation restrictions in LT recipients. Using ICF for assessment and treatment planning can create a common language among all health professionals, enabling them to design better interventions for this patient group. However, ICF core tests need to be established in future studies with LT recipients.

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