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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Pretransplant frailty is associated with decreased survival after lung transplantation

Published:October 19, 2015DOI:https://doi.org/10.1016/j.healun.2015.10.014

      Background

      Frailty is a condition of increased vulnerability to adverse health outcomes. Although frailty is an important prognostic factor for many conditions, the effect of frailty on mortality in lung transplantation is unknown. Our objective was to assess the association of frailty with survival after lung transplantation.

      Methods

      We performed a retrospective cohort analysis of all adult lung transplant recipients at our institution between 2002 and 2013. Frailty was assessed using the frailty deficit index, a validated instrument that assesses cumulative deficits for up to 32 impairments and measures the proportion of deficits present (with frailty defined as >0.25). We examined the association between frailty and survival, adjusting for age, sex, and bilateral (vs single) lung transplant using Cox proportional hazard regression models.

      Results

      Among 144 lung transplant patients, 102 (71%) completed self-reported questionnaires necessary to assess the frailty deficit index within 1 year before lung transplantation. Frail patients (n = 46) had an increased risk of death, with an adjusted hazard ratio (HR) of 2.24 (95% confidence interval [CI], 1.22–4.19; p = 0.0089). Frailty was not associated with an increased duration of mechanical ventilation (median, 2 vs 2 days; p = 0.26), intensive care unit length of stay (median, 7.5 vs 6 days; p = 0.36) or hospital length of stay after transplantation (median, 14 vs 10.5 days; p = 0.26).

      Conclusions

      Pre-transplant frailty was independently associated with decreased survival after lung transplantation. Pre-transplant frailty may represent an important area for intervention to improve candidate selection and lung transplant outcomes.

      KeyWords

      Lung transplant survival remains sub-optimal, and listed lung transplant candidates exceed historical donor organ availability.
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report—2013; focus theme: age.
      • Van Raemdonck D.
      • Neyrinck A.
      • Verleden G.M.
      • et al.
      Lung donor selection and management.
      • Sayegh M.H.
      • Carpenter C.B.
      Transplantation 50 years later—progress, challenges, and promises.
      Lung transplant patients are also at high risk for other adverse outcomes such as renal failure, malignancy, infection, and poor quality of life.
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report—2013; focus theme: age.
      • Trulock E.P.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report—2007.
      Thus, recognizing factors that affect post-transplant morbidity and mortality are important for lung transplant informed consent, prognostication, and optimal candidate selection. One possible such factor that remains understudied in lung transplantation is frailty.
      Frailty is a term used to describe an increased risk of adverse outcomes in the setting of functional decline across multiple domains and reduced physiologic reserves.
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      Used by some to describe biologic age rather than the chronologic age, frailty has been demonstrated to serve as a prognostic marker for death and other health outcomes. One model commonly used to explain frailty is the frailty deficit index. Developed by Rockwood et al,
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      • Rockwood K.
      • Andrew M.
      • Mitnitski A.
      A comparison of two approaches to measuring frailty in elderly people.
      the deficit index model uses the assumption that frail patients accumulate functional and health-related “deficits” and defines frailty as the proportion of deficits present.
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      • Rockwood K.
      • Andrew M.
      • Mitnitski A.
      A comparison of two approaches to measuring frailty in elderly people.
      Various frailty deficit indices have been developed and include as many as 70 possible deficits.
      • Mitnitski A.B.
      • Mogilner A.J.
      • Rockwood K.
      Accumulation of deficits as a proxy measure of aging.
      • Searle S.D.
      • Mitnitski A.
      • Gahbauer E.A.
      • Gill T.M.
      • Rockwood K.
      A standard procedure for creating a frailty index.
      • McNallan S.M.
      • Chamberlain A.M.
      • Gerber Y.
      • et al.
      Measuring frailty in heart failure: a community perspective.
      The deficit index has been used to reliably identify frailty and was a better predictor of death than other measures of frailty in large cohorts such as the Framingham Cohort, the Cardiovascular Health Study, and others.
      • Kulminski A.M.
      • Ukraintseva S.V.
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      • Arbeev K.G.
      • Land K.
      • Yashin A.I.
      Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study.
      • Kulminski A.M.
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      • Culminskaya I.V.
      • et al.
      Cumulative deficits and physiological indices as predictors of mortality and long life.
      • Li G.
      • Thabane L.
      • Ioannidis G.
      • Kennedy C.
      • Papaioannou A.
      • Adachi J.D.
      Comparison between frailty index of deficit accumulation and phenotypic model to predict risk of falls: data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort.
      Frailty has been studied in many patient populations, including geriatric, chronic obstructive pulmonary disease (COPD), intensive care unit (ICU), surgical, end-stage renal disease, and heart failure patients.
      • Searle S.D.
      • Mitnitski A.
      • Gahbauer E.A.
      • Gill T.M.
      • Rockwood K.
      A standard procedure for creating a frailty index.
      • McNallan S.M.
      • Chamberlain A.M.
      • Gerber Y.
      • et al.
      Measuring frailty in heart failure: a community perspective.
      • Kulminski A.M.
      • Ukraintseva S.V.
      • Kulminskaya IV,
      • Arbeev K.G.
      • Land K.
      • Yashin A.I.
      Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study.
      • Li G.
      • Thabane L.
      • Ioannidis G.
      • Kennedy C.
      • Papaioannou A.
      • Adachi J.D.
      Comparison between frailty index of deficit accumulation and phenotypic model to predict risk of falls: data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort.
      • Le Maguet P.
      • Roquilly A.
      • Lasocki S.
      • et al.
      Prevalence and impact of frailty on mortality in elderly ICU patients: a prospective, multicenter, observational study.
      • Joseph B.
      • Pandit V.
      • Sadoun M.
      • et al.
      Frailty in surgery.
      • Bao Y.
      • Dalrymple L.
      • Chertow G.M.
      • Kaysen G.A.
      • Johansen K.L.
      Frailty, dialysis initiation, and mortality in end-stage renal disease.
      • Park S.K.
      • Richardson C.R.
      • Holleman R.G.
      • Larson J.L.
      Frailty in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006).
      • Galizia G.
      • Cacciatore F.
      • Testa G.
      • et al.
      Role of clinical frailty on long-term mortality of elderly subjects with and without chronic obstructive pulmonary disease.
      Frailty in these groups has been associated with adverse outcomes such as increased mortality, hospital length of stay, hospital readmissions, falls, and nursing home utilization. In solid-organ transplant patients, frailty has been associated with increased waiting list mortality in liver transplant and delayed kidney graft function in kidney transplant.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.
      • Garonzik-Wang J.M.
      • Govindan P.
      • Grinnan J.W.
      • et al.
      Frailty and delayed graft function in kidney transplant recipients.
      Data in lung transplant are currently limited to abstract form but suggest a possible association between frailty and 30-day mortality or quality of life.
      • Singer J.P.
      • Katz P.P.
      • Dean M.Y.
      • et al.
      Frailty is common in lung transplant candidates and associated with poorer health-related quality of life.
      • Lederer D.J.
      • Sonett J.R.
      • Philip N.A.
      • et al.
      Frailty and early mortality after lung transplantation: preliminary results.
      Our objective was to use the frailty deficit index to evaluate the effect of frailty on mortality in lung transplant patients.

      Methods

      Patient population

      All adults undergoing single or bilateral lung transplantation at Mayo Clinic, Rochester, Minnesota, from January 1, 2002, to December 31, 2013, were eligible for study inclusion. Heart-lung transplant or retransplant patients were excluded. The Mayo Clinic Institutional Board of Review approved the study protocol (IRB #150000767).

      Definition of frailty

      Frailty was defined using a validated frailty deficit index measurement tool, with a score of 0.25 or greater defined as “frail,” as previously described by Rockwood et al (Appendix, available on the jhltonline.org Web site).
      • Rockwood K.
      • Andrew M.
      • Mitnitski A.
      A comparison of two approaches to measuring frailty in elderly people.
      • McNallan S.M.
      • Chamberlain A.M.
      • Gerber Y.
      • et al.
      Measuring frailty in heart failure: a community perspective.
      • Dunlay S.M.
      • Park S.J.
      • Joyce L.D.
      • et al.
      Frailty and outcomes after implantation of left ventricular assist device as destination therapy.
      This cumulative frailty deficit index score is calculated by dividing the number of deficits present by the total deficits possible. The index score ranges from 0 to 1, with 0 representing no deficits and 1 representing 32 of 32 possible deficits.
      The first 14 items of the frailty deficit index represent activities of daily living. These variables were collected using a prospective questionnaire completed by patients every 12 months at pre-transplant appointments. Patients were included in the study if they answered 13 of the 14 questions (>90%) and the questionnaire was completed less than 12 months before lung transplantation. The denominator of the deficit index calculation was adjusted if 1 question was not answered. The remaining 18 variables were collected using a manual medical record review.

      Medical record abstraction and definitions

      Some variables were collected prospectively and available in our electronic transplant database. Other variables were obtained by manual medical record abstraction, which was performed by 2 assessors. Lung transplant diagnosis was separated into obstructive lung diseases, restrictive lung diseases, cystic fibrosis, pulmonary hypertension, and other. All test measures were taken from pre-transplant testing as close to lung transplant as possible. Moderate and severe renal insufficiency was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2 using the Modification of Diet in Renal Disease equation. Body mass index (BMI) at transplantation was calculated using the weight in kilograms as measured at the time of transplantation divided by the height in meters squared. Underweight was defined as a BMI of less than 18.5 kg/m2, overweight was defined as a BMI between 25 and 30 kg/m2, and obesity was defined as a BMI of ≥ 30 kg/m2. Anemia was defined as a hemoglobin concentration of < 12.0 g/dl in women and < 13.0 g/dl in men. The other comorbidities were defined by documentation of diagnosis.
      Primary graft dysfunction was defined according to published guidelines using a grading system of grade 0 to 3 derived from the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (Pao2/Fio2) and the presence of radiographic infiltrates at 24, 48, and 72 hours, with time 0 being time of patient arrival to the ICU.
      • Christie J.D.
      • Carby M.
      • Bag R.
      • Corris P.
      • Hertz M.
      • Weill D.
      Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation.
      Patients without Pao2/Fio2 measurements at one of the measured time points were considered to have grade 0 at that time point, because post-transplant patients in our institution without measured Pao2/Fio2 ratios typically are extubated and on room air without respiratory compromise. Length of mechanical ventilation after transplantation was defined as the number of days from transplantation to the date of initial extubation. ICU and hospital lengths of stay were from the time of transplantation to the time of discharge from the ICU or hospital, respectively. The lung allocation score (LAS) was abstracted as calculated at the time of transplant for patients who received a transplant in 2005 and later.

      Outcomes

      The primary outcome was all-cause mortality during the first 3 years after transplant. Secondary outcomes focused on peri-operative events, including primary graft dysfunction, cardiopulmonary bypass during transplant surgery, duration of mechanical ventilation, and ICU and hospital lengths of stay after transplant.

      Statistical analysis

      Baseline characteristics are summarized using counts and percentages for categoric variables and as medians and interquartile ranges (IQR) for continuous variables. Characteristics and secondary outcomes were assessed using 2-sample t-tests for continuous variables, the chi-square test for categoric variables, and the Wilcoxon sign rank for non-parametric variables. Time to last follow-up or death among frail and non-frail patients was analyzed using Kaplan-Meier and Cox proportional hazard model methods considering the first 3 years after transplant. Hazard ratios (HR) for death were adjusted for potential confounders. A κ statistic was used to calculate inter-rater agreement for record abstraction. Statistical analysis was performed using JMP 10 software (SAS Institute Inc, Cary, NC). P-values < 0.05 were considered statistically significant.

      Results

      Population

      Of 144 patients who underwent lung transplantation from January 1, 2002, to December 31, 2013. 102 (71%) completed the questionnaires necessary to calculate the frailty deficit index and were included in the analysis (Table 1). Self-reported questionnaires were completed independently by patients 90% of the time and with the assistance of a family member 10% of the time. Inter-rater agreement for record abstraction was excellent (κ = 0.8). Patients were a median age of 57 years (IQR, 51–62.3 years) and 51 (50%) were women. Bilateral transplantation was performed in 70 patients (67%) . There were no statistically significant differences between the 102 patients included in the study and the 42 who were excluded in age (median, 57.0 [IQR, 51.7–63.2] years vs 56.4 [IQR, 44.7–61.5] years, p = 0.055), pre-transplant BMI (median, 25.2 [IQR, 21.2–28.4] kg/m2 vs 23.0 [IQR, 21.3–27.1] kg/m2, p = 0.34), female sex (50% vs 58%, p = 0.45), bilateral lung transplant (69% vs 58%, p = 0.24), or LAS score (median, 38.2 [IQR, 34.5–51.0] vs 37.0 [IQR, 33.3–45.0], p = 0.38).
      Table 1Baseline Demographics and Perioperative Characteristics
      Baseline demographics and perioperative characteristics are presented for 102 single and bilateral lung transplant recipients divided into all patients, frail (frailty deficit index score >0.25) patients, or non-frail patients (frailty deficit score ≤ 0.25).
      Characteristic
      Continuous data are presented as the median (interquartile range) and categoric data as number (%).
      TotalNot frailFrailp-value
      (N = 102)(n = 56)(n = 46)
      Age, years57 (51–62.3)57.5 (51–62.8)56.5 (51.8–61.5)0.95
      Female gender51 (50)22 (39)29 (63)0.02
      Statistically significant (p < 0.05).
      Non-Caucasian race12 (12)8 (14)4 (9)0.38
      Transplant diagnosis0.22
       Obstructive lung disease41 (40)20 (36)21 (46)
       Restrictive lung disease46 (45)29 (52)17 (37)
       Cystic fibrosis2 (2)2 (4)0 (0)
       Primary pulmonary hypertension8 (8)3 (5)5 (11)
       Other5 (5)2 (4)3 (7)
      Secondary pulmonary hypertension49 (48)22 (40)27 (59)0.06
      Daily steroid use
       At time of transplant41 (40)23 (41)18 (39)0.78
       Pre-transplant steroid dose (prednisone equivalent), mg10 (5–10)10 (7.5–10)10 (5–11.3)0.68
      Pre-transplant 6-minute walk distance, meters267.0 (192.0–347.0)296.4 (218.8–378.7)241.6 (177.2–321.6)0.01
      Statistically significant (p < 0.05).
      Lung allocation score38.2 (34.5–50.5)37.1 (34.4–44.5)42.0 (34.6–59.1)0.03
      Statistically significant (p < 0.05).
      Body mass index at transplant, kg/m225.2 (21.2–28.4)24.5 (20.8–27.6)26.2 (22.4–29.8)0.14
      Bilateral transplant70 (69)34 (61)36 (78)0.05
      Total ischemic time, minutes233.5 (203.3–258.3)233 (207–268.5)234 (199.3–252.5)0.19
      Days on transplant waiting list133 (41.5–398.5)101 (45–247)169.5 (26.3–568)0.02
      Statistically significant (p < 0.05).
      a Baseline demographics and perioperative characteristics are presented for 102 single and bilateral lung transplant recipients divided into all patients, frail (frailty deficit index score >0.25) patients, or non-frail patients (frailty deficit score ≤ 0.25).
      b Continuous data are presented as the median (interquartile range) and categoric data as number (%).
      c Statistically significant (p < 0.05).

      Frailty prevalence

      Forty-six patients were frail, with an overall prevalence of frailty of 45%. The median frailty deficit index for the total transplant population was 0.22 (IQR, 0.17-0.31). The prevalence of frailty did not differ by lung transplant diagnosis (Table 1). Frail patients were more likely to be female (63% vs 39%, p = 0.02) and have longer transplant waiting list times (169.5 [IQR, 26.3–568] days vs 101 [IQR, 45–247] days, p = 0.02). As expected, frail patients had a higher median LAS (42.0 [IQR, 34.6–59.1] vs 37.1 [IQR, 34.4–44.5], p = 0.03) and a lower 6-minute walking distance (median, 241.6 [IQR, 177.2–321.6] meters vs 296.4 [IQR, 218.8–378.7] meters, p = 0.01). Of note, frail patients did not differ from non-frail patients in prednisone use (p = 0.78) or age (p = 0.95). Of the 14 activities of daily living assessed, the most frequent functional deficits in frail patients were difficulty climbing stairs (45 [98%]), dependency on oxygen or non-invasive ventilation for normal breathing (44 [96%]), and difficulty with housekeeping (37 [80%]).

      Survival

      In this cohort, there were 32 deaths in the first 3 years. The causes of death were respiratory failure in 7, infection in 6, post-transplant lymphoproliferative disorder in 4, neurologic injury in 4, other in 4, and unknown in 7.
      Frailty was associated with a decreased survival compared with non-frail patients. Kaplan-Meier curves showed the 1-year and 3-year estimated survival rate for frail patients was 71.7% and 41.3% compared with 92.9% and 66.1% for non-frail patients, respectively (p = 0.005 by log-rank test; Figure 1). The unadjusted HR for death for frail patients compared with non-frail patients was 2.28 (95% CI, 1.27–4.16; p = 0.006). The HR for death adjusted for age, gender, and double- vs single-lung transplantation was 2.24 (95% CI, 1.22–4.19; p = 0.0089).
      Figure thumbnail gr1
      Figure 1Kaplan-Meier curve shows time-to-event data for mortality in lung transplant patients according to frail (frailty deficit index score >0.25, solid line) or non-frail (frailty deficit score ≤0.25, dotted line) status. A p-value of < 0.05 is considered statistically significant.

      Secondary outcomes

      Frail patients and non-frail patients had similar for peri-operative outcomes. Frail patients had a trend toward increased use of cardiopulmonary bypass (p = 0.05); however, minutes spent on bypass were not different between frail and non-frail patients (228 [IQR, 200.5–265.5] minutes vs 210 [IQR, 183–280] minutes, respectively; p = 0.47). Frail patients showed trends toward increased hospital length of stay after transplantation (median, 14 [IQR, 8–18.3] days vs 10.5 [IQR, 7.3–16] days, p = 0.26) as well as increased ICU length of stay after transplantation (median, 7.5 [IQR, 3–15.3] days vs 6 [IQR, 4–9] days, p = 0.36), although these tests did not reach statistical significance. There were no differences in the length of mechanical ventilation after transplantation (median, 2 [IQR, 1–3] days vs 2 [IQR, 1–3] days, p = 0.26) and no differences in occurrence of primary graft dysfunction between the groups. The percentage of patients with Grade 3 primary graft dysfunction at 24, 48, or 72 hours did not differ for the frail and non-frail groups at 39.1% vs 45.4% (p = 0.52).

      Potential confounding variables

      The 6-minute walking distance, BMI, and LAS are colinear variables to the frailty deficit index and therefore cannot be adjusted for in our Cox proportional hazard model. Reassuringly, BMI was not different between the frail and non-frail groups (Table 1). The unadjusted HR for death for patients with a BMI < 18.5 kg/m2 was non-significant (HR, 3.42; 95% CI, 0.56–11.18; p = 0.15); however, the number of included underweight patients was low (n = 2). Likewise, although LAS and the 6-minute walk distance were expectedly different between frail and non-frail groups (Table 1), neither variable was independently associated with death. The unadjusted HR per 1-unit increase in LAS was 1.02 (95% CI, 0.99–1.04; p = 0.27). The unadjusted HR per 1-meter increase in the 6-minute walk distance was 0.998 (95% CI, 0.993–1.002; p = 0.33). Length of time on the transplant waiting list was not associated with increased mortality (HR, 1.00; 95% CI, 0.999–1.00).

      Discussion

      Our study demonstrates an association between frailty and survival after lung transplantation. Patients who were frail before lung transplantation had an increased risk of death that persisted after adjustment for age, sex, and bilateral lung transplantation. In addition, our study describes the prevalence of frailty in a lung transplant population. We found that the prevalence of frailty was high at 45.1% (46 of 102), which is notable, given that lung transplant patients are a carefully scrutinized and selected population (the selected “healthier” and younger individuals of the end-stage lung disease population). Although the prevalence of frailty in lung transplant or chronic lung diseases is not well described, the prevalence in a COPD population was also found to be high, at 57.8%.
      • Park S.K.
      • Richardson C.R.
      • Holleman R.G.
      • Larson J.L.
      Frailty in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006).
      Our findings that frailty is associated with an increased risk of adverse outcome after lung transplantation corresponds to a growing body of existing literature that shows similar increased risk for frail patients with other disease conditions. Frailty data from other solid organ transplants—such as liver and kidney—have shown increased mortality and delayed kidney graft function.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.
      • Garonzik-Wang J.M.
      • Govindan P.
      • Grinnan J.W.
      • et al.
      Frailty and delayed graft function in kidney transplant recipients.
      Aside from 3 studies in COPD, characterization of the effect of frailty on the outcomes of patients with other chronic lung conditions is absent.
      • Park S.K.
      • Richardson C.R.
      • Holleman R.G.
      • Larson J.L.
      Frailty in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006).
      • Galizia G.
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      • et al.
      Role of clinical frailty on long-term mortality of elderly subjects with and without chronic obstructive pulmonary disease.
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      • Benzo R.P.
      Frailty is associated with increased mortality and hospitalization in COPD [abstract].
      Other potential markers of frailty or physical function in pulmonary transplant candidate evaluation include low BMI (< 18.5 kg/m2) and the 6-minute walk distance.
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      However, a low BMI was recently found to be a poor surrogate for muscle wasting: a large study describing body composition in lung transplantation found that low BMI commonly overestimates or underestimates muscle wasting.
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      In addition, neither the 6-minute walk distance nor the BMI were predictive of death in our study, although our study was likely underpowered to detect such a difference for low BMI.
      While the potential physiologic underpinnings of frailty are under investigation, one consistent piece of evidence in favor of the presence of frailty is the cumulative burden of physical disability, symptoms, and medical conditions.
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      • Rockwood K.
      • Andrew M.
      • Mitnitski A.
      A comparison of two approaches to measuring frailty in elderly people.
      Studying the collective burden of these “deficits,” rather than examining each deficit individually, has proven useful in identifying a cohort of patients that has increased risk for adverse outcomes such as death. Although the exact reason why frailty is associated with increased mortality is unknown, patients who are frail have been shown to develop a number of comorbidities and intermediary adverse outcomes, such as increased falls, osteoporosis, infection, and vaccine failures, which in turn could lead to increased mortality.
      A primary reason for performing lung transplantation is to prolong survival in patients with end-stage lung disease.
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      Thus, identification of factors that affect survival after lung transplantation is important for patients, families, and clinicians. Because frailty is associated with sub-optimal survival outcomes, frailty should be assessed during patient selection for lung transplant. In addition, future research should address whether frailty is a modifiable risk factor before lung transplant and study intervention strategies that may improve frailty.
      Clinical success of frailty interventions in other populations has been mixed. Studies have shown that rehabilitation or structured aerobic and strength-training regimens for frail elders improve physical function and performance.
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      Other interventions, such as a multifaceted program that provided individualized management of each specific aspect of the frailty phenotype identified (e.g., weakness, weight loss, exhaustion, etc) showed modest improvements in physical function in the outpatient setting over 12 months.
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      • Fairhall N.
      • Aggar C.
      • Kurrle S.E.
      • et al.
      Frailty Intervention Trial (FIT).
      COPD was present in 69% of patients in our cohort, and COPD was the primary indication for transplant in 40% of these. By the frailty deficit index, 51% of COPD patients were frail. The association between frailty and COPD has previously been described. Frail COPD patients have worse outcomes such as increased mortality and increased hospitalizations.
      • Park S.K.
      • Richardson C.R.
      • Holleman R.G.
      • Larson J.L.
      Frailty in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006).
      • Galizia G.
      • Cacciatore F.
      • Testa G.
      • et al.
      Role of clinical frailty on long-term mortality of elderly subjects with and without chronic obstructive pulmonary disease.
      • Kennedy C.C.
      • Novotny P.J.
      • LeBrasseur N.K.
      • Wise R.A.
      • Sciurba F.C.
      • Benzo R.P.
      Frailty is associated with increased mortality and hospitalization in COPD [abstract].
      To our knowledge, similar associations between frailty and adverse outcomes have not been described in other lung conditions such as idiopathic pulmonary fibrosis, pulmonary hypertension, or cystic fibrosis. Although the reasons for increased frailty in patients with COPD has not fully been elucidated, possible contributing reasons include increased association with other comorbid conditions, such as heart disease, increased association with other risk factors, such as smoking, and long-term chronicity of disease.
      • Park S.K.
      • Richardson C.R.
      • Holleman R.G.
      • Larson J.L.
      Frailty in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006).
      In our cohort, frailty was more common in women than men (Table 1). Although some prior studies have shown an increased prevalence of frailty in women,
      • Cigolle C.T.
      • Ofstedal M.B.
      • Tian Z.
      • Blaum C.S.
      Comparing models of frailty: the Health and Retirement Study.
      other studies have shown no difference.
      • Dunlay S.M.
      • Park S.J.
      • Joyce L.D.
      • et al.
      Frailty and outcomes after implantation of left ventricular assist device as destination therapy.
      The prevalence of frailty in women may be greater, depending on which model is used to define frailty.
      • Cigolle C.T.
      • Ofstedal M.B.
      • Tian Z.
      • Blaum C.S.
      Comparing models of frailty: the Health and Retirement Study.
      In determining why a greater proportion of women in our cohort were frail, we measured the prevalence of the frailty deficits and compared them between men and women. The major differences identified included: (1) “Do you have difficult housekeeping by yourself? (80% of women answered “yes” compared with 30% of men) and (2) “Do you depend on a device or oxygen to help you with normal breathing?” (94% of women answered “yes” compared with 78% of men). Removing these 2 indices from the frailty index, however, did not significantly change the proportion of women who were frail, providing evidence for the robustness of this finding.
      Our study has several limitations. First, our study was conducted in a single transplant center, which may limit the generalizability of our findings to other settings. Further research is needed to confirm our findings in additional lung transplant populations. Second, our outcomes were limited to mortality and immediate peri-operative outcomes such as cardiopulmonary bypass time, primary graft dysfunction, and length of mechanical ventilation, ICU, and hospital stay. Further studies should be done to assess the association with chronic lung allograft dysfunction, acute rejection, and patient-centered outcomes such as health-related quality of life. Third, we were unable to assess the effect of frailty on pre-transplant outcomes such as hospitalizations or disease exacerbations. Fourth, because the median waiting list time of the study patients was less than 6 months, our study was underpowered to detect changes in frailty while on the waiting list. Fifth, some variables, such as dementia or history of malignancy, captured in the deficit index represent absolute or relative contraindications to lung transplantation. These variables therefore occur infrequently or not at all in our cohort and will likely remain infrequent when tested in larger, multicenter frailty studies. The optimal way of incorporating such variables into frailty assessments in lung transplantation requires further investigation.
      Notable strengths of our investigation include use of a rigorous definition of frailty and a high completion rate of prospective functional deficit questionnaires. In addition, this method of assessing frailty is simple and could easily be instituted into clinical practice, although further multicenter studies are needed to verify the optimal way of doing this.
      In conclusion, the prevalence of frailty in the lung transplant population is as high as 45%, despite a regimented testing and selection criteria. Frailty was associated with worse survival compared with non-frail patients. The major potential contributions of this frailty research to pulmonary transplantation are 3-fold:
      First this information may be helpful in prognostication and engaging patients in shared decision making. If frail patients have worse transplant outcomes, such as survival, then this may affect the potential expected benefit of lung transplantation for the individual frail patient. This may in turn affect the patient or the practitioner’s willingness to undertake the risk of a lung transplant procedure for that patient.
      Second, as further studies are conducted to more clearly define the role of frailty and any potential reversibility, international candidate selection consensus guidelines and individual transplant center policies may consider frailty as a relative contraindication to lung transplantation—especially in the setting of organ scarcity.
      Third, at-risk patients accepted for transplant listing should be targeted for potential interventions to prevent or ameliorate frailty and monitored closely in hopes of improving survival after lung transplant.
      Frailty in lung transplant warrants further research and is likely to significantly affect prognostication, informed consent, shared decision making, and lung allocation.

      Disclosure statement

      None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
      This work was supported by the Mayo Clinic Department of Medicine Research Career Development Award (C.C.K). S.M.D. is supported by National Institutes of Health grant K23-HL1-16643.

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