Karan Chohan, MD Candidate ¹ and Dmitry Rozenberg, MD, PhD ^1,2
Department of Medicine, University of Toronto
Respirology and Lung Transplantation, Toronto General Hospital Research Institute,
Ajmera Transplant Center, University Health Network

Frailty is a syndrome that represents decreased physiologic reserve across a number of organ systems, which can result in an exaggerated decline in health status. ¹ Originally described in the field of gerontology, frailty in community dwelling adults has been associated with physical and cognitive impairments, both of which are associated with an increased risk of falls, hospitalizations, and decreased survival. ^2-4 In the pulmonary field, frailty has been associated with decreased physical function, higher risk of hospitalizations and lower transplant-free survival. ^5-7 Frailty in lung transplant candidates has also been shown to be associated with increased delisting/mortality ⁸ and increased risk for early post-transplant mortality. ⁹

Three frailty models have been applied in pulmonary disease including the Fried frailty index, ^{1 , 10 , 11} Short-Physical Performance Battery (SPPB) ⁸ and the cumulative deficits frailty index. ^{5 , 12} The Fried frailty index captures physical frailty defined by the presence of 3 or more criteria: unintentional weight loss, self-reported exhaustion, weakness measured with grip strength, slow gait speed, and low physical activity. ¹ SPPB evaluates three domains of physical function: balance, chair stands and gait speed with each domain scored out of 4.  A total SPPB score of 9 or less has been considered to represent decreased lower extremity function and an important marker of physical frailty. ^{8 , 13} The cumulative deficits frailty model captures comorbidities, laboratory investigations and accumulation of functional and health status limitations, felt to be more encompassing than physical frailty models and a better surrogate marker of biologic age. ¹⁴ The three frailty models are highlighted in Table 1 below.

Table-1: Frailty Measures Applied in Chronic Lung Disease and Lung Transplantation

Frailty has been recognized as an important prognostic marker in chronic obstructive pulmonary disease (COPD), ¹⁵ interstitial lung disease (ILD) ⁵ and lung transplant populations. ⁹ The Fried frailty index has also been applied in the setting of pulmonary rehabilitation in a large cohort of COPD patients. ¹⁸ In this study, frailty was observed in one-quarter of COPD patients attending pulmonary rehabilitation and associated with approximately a two-fold risk of program non-completion.  However, 61% of 115 COPD patients who completed the rehabilitation program were no longer categorized as frail.  Similarly, frail lung transplant candidates derived significant benefits from lung transplantation with greater improvements in post-transplant exercise capacity and health-related quality of life (HRQL) compared to those that were categorized as non-frail pre-transplant. ^{11 , 19}

The literature on frailty in COPD, ²⁰ ILD ⁷ and lung transplantation ²¹ has been evolving over the last five years with recent reviews in each of these respective respiratory conditions.  However, there appears to be several areas that require further investigation.  Specifically, the application of frailty in other respiratory disease states, pulmonary rehabilitation, and with hospitalizations has not been well described.  Thus, we undertook a review of all published abstracts at the American Thoracic Society (ATS) 2020 conference that had utilized one of the three frailty models in pulmonary disease or lung transplantation, with a specific interest on seeing frailty applied in other chronic respiratory states or clinical settings, including rehabilitation.  A total of 5 abstracts were identified that had applied one of the three frailty models in chronic lung disease, including lung transplant candidates.  The published abstracts are summarized below with a reference link. 

Published Abstracts

1. Understanding the Impact of Physical Activity, Age, and Frailty on 30-Day Readmissions on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD); Sweetnam, VI, et al.
   
   https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A7386
   
   The main purpose of this study was to assess the impact of age, frailty and early post-discharge physical activity levels on 30-day readmission rates for those experiencing an acute exacerbation of chronic obstruction pulmonary disease (AECOPD).  Frailty was evaluated in 15 patients with AECOPD using the Fried frailty index with 47% (7 out of 15) deemed frail. No significant risk factor differences were observed with respect to frailty, age, physical activity levels, or with participation in pulmonary rehabilitation in predicting readmissions.  The study is ongoing and a larger sample size may help discern the contribution of frailty on rates of hospital re-admission post AECOPD.

2. Frailty and Body Fat in Patients with Pulmonary Arterial Hypertension; Goodman R, et al.
   
   https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A2081
   
   This study aimed to investigate the prevalence and significance of frailty in pulmonary arterial hypertension (PAH) patients using the SPPB. In this ongoing study of 22 participants, 13 (60%) were frail (SPPB < 7 points) or pre-frail (score of 7 to 9). Statistical significance was not reached between SPPB frailty groups with respect to body mass index, body composition measures with dual-energy absorptiometry, or HRQL.  Work is ongoing assessing longitudinal changes in frailty and body composition in PAH patients.

3. Prevalence and Prognostic Impact of Physical Frailty in Interstitial Lung Disease
   
   https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A1095
   
   This study aimed to assess the association between physical frailty using the Fried index and mortality in patients with fibrotic ILD. Of 462 ILD participants, 126 (26%) were frail and 261 (56%) were deemed pre-frail.   Patients had 1.33 (95% CI 1.05 to 1.69) odds of death per unit increase in frailty score, which remained significant after adjustment for Gender-Age Physiology (GAP) score.  Furthermore, the addition of frailty to the GAP index had re-classified 39% as high risk for mortality. This abstract demonstrates that physical frailty is prevalent in fibrotic ILD patients and provides additional prognostic value in predicting mortality independent of the GAP index.   

4. Clinical Implications of Frailty in Acute Exacerbations of Interstitial Lung Disease
   
   Chohan  ⁵
   
   https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A7377
   
   In patients with acute exacerbation of interstitial lung disease (AE-ILD), frailty was assessed at the time of hospital admission using a 30-point cumulative deficit model to assess associations with physical function, hospital length of stay, and one-year outcomes post discharge. In this single-center retrospective study of 59 AE-ILD patients, frailty (score > 0.21) was observed in 58% of ILD patients.  Frail patients were more likely to be female (Frail 47% vs Not Frail 20%), have a non-IPF diagnosis (44% vs 16%) and lower pre-exacerbation six-minute walk distance (6MWD: 58 ± 25% vs 87 ± 17 % predicted) with p < 0.05 for all comparisons. No significant differences were observed between frail and non-frail patients in Charlson Comorbidity Index, median hospital stay (9 days for both groups, p=0.60) or hospital mortality (26% vs. 36%, p=0.43). Frail patients had higher risk of mortality relative to being transplanted or surviving to one-year post exacerbation [64% vs 40%, OR: 5.2 95% CI (1.3 to 20.4), p=0.02] adjusted for age, sex and ILD diagnosis. Thus, assessment of frailty using the cumulative deficit index in AE-ILD patients may assist with prognosis and lung transplant evaluation.

5. Novel Cumulative Deficits Frailty Index Associated with Early Outcomes in Lung Transplant Recipients; Turner D, et al.
   
   https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A1020
   
   This study applied a transplant-specific 40-item cumulative deficits frailty index (CFI) incorporating comorbidities, laboratory investigations and several health domains from pre-transplant candidacy assessments to assess associations with pre-transplant physical function and early post-transplant outcomes.  190 lung transplant recipients (median age of 61 years old, 61% male and 55% had restrictive lung disease) were evaluated from a single center.  Higher CFI (greater frailty) was associated with a lower six-minute walk distance (6MWD, r= -0.15, p=0.048) and lower SPPB (r= -0.17, p=0.027) pre-transplant.  With hierarchical regression, a greater CFI was associated with a longer hospital length of stay (1 week longer stay for each increase in 7 points on the CFI), independent of 6MWD or SPPB. The authors concluded that CFI may provide prognostic utility in addition to pre-transplant physical function measures in predicting early post-transplant outcomes.

Summary:

The ATS virtual conference had five abstracts on frailty in pulmonary disease capturing all three frailty models.  The Fried frailty and cumulative deficits index were applied for assessment of prognosis across several clinical settings, including during hospitalization and pre-transplantation.  In three studies, frailty instruments were associated with disease severity measures and provided additional prognostic value in ILD patients relative to the GAP index.  Similarly, the CFI in lung transplant candidates appears to provide additional prognostic information on early post-transplant outcomes.  It is promising to see the application of varying frailty instruments to other chronic lung disease states such as PAH and ILD.

Future work will need to focus on application of these frailty instruments to other chronic lung disease states such as cystic fibrosis (CF), non-CF bronchiectasis, and PAH.  There is also a need to further develop these frailty instruments in other clinical settings such as with pulmonary rehabilitation or after discharge from hospital.  A comparison of the performance characteristics between the frailty indices will be helpful for clinicians and researchers on deciding which instruments to apply across clinical settings.  For instance, it is possible that the cumulative deficits frailty index may be less amenable to interventions such as exercise training, nutritional support, or recovery post-exacerbation when compared to physical frailty measures, but may have important prognostic implications such as seen with transplant free-survival in ILD or with post-transplant outcomes. ^{10 , 12} Future investigations are needed to understand the mechanisms associated with frailty such as body composition measures, sarcopenia, and inflammation, which may help refine treatment through rehabilitation and pharmacological strategies (i.e. molecular targets of inflammation or sarcopenia). ^{22 , 23}  Thus, the construct of frailty is evolving as an important measure in chronic lung disease patients that may enhance the clinical management of respiratory patients.    

Conflicts of Interest: None

Funding:  Dmitry Rozenberg is supported by the Sandra Faire and Ivan Fecan Professorship in Rehabilitation Medicine. 

Correspondence Email: Dmitry.Rozenberg@uhn.ca

References :

1. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:M146-156

2. Masel MC, Ostir GV, Ottenbacher KJ. Frailty, mortality, and health-related quality of life in older Mexican Americans. J Am Geriatr Soc 2010; 58:2149-2153

3. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173:489-495

4. Shamliyan T, Talley KM, Ramakrishnan R, et al. Association of frailty with survival: a systematic literature review. Ageing Res Rev 2013; 12:719-736

5. Guler SA, Kwan JM, Leung JM, et al. Functional ageing in fibrotic interstitial lung disease: the impact of frailty on adverse health outcomes. Eur Respir J 2020; 55

6. Singer JP, Lederer DJ, Baldwin MR. Frailty in Pulmonary and Critical Care Medicine. Ann Am Thorac Soc 2016; 13:1394-1404

7. Guler SA, Ryerson CJ. Frailty in patients with interstitial lung disease. Curr Opin Pulm Med 2020; 26:449-456

8. Singer JP, Diamond JM, Gries CJ, et al. Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation. Am J Respir Crit Care Med 2015; 192:1325-1334

9. Singer JP, Diamond JM, Anderson MR, et al. Frailty phenotypes and mortality after lung transplantation: A prospective cohort study. Am J Transplant 2018; 18:1995-2004

10. Montgomery E, Macdonald PS, Newton PJ, et al. Frailty as a Predictor of Mortality in Patients With Interstitial Lung Disease Referred for Lung Transplantation. Transplantation 2020; 104:864-872

11. Rozenberg D, Mathur S, Wickerson L, et al. Frailty and clinical benefits with lung transplantation. J Heart Lung Transplant 2018; 37:1245-1253

12. Wilson ME, Vakil AP, Kandel P, et al. Pretransplant frailty is associated with decreased survival after lung transplantation. J Heart Lung Transplant 2016; 35:173-178

13. Wickerson L, Rozenberg D, Gottesman C, et al. Pre-transplant short physical performance battery: Response to pre-habilitation and relationship to pre- and early post-lung-transplant outcomes. Clin Transplant 2020:e14095

14. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci 2007; 62:722-727

15. Kennedy CC, Novotny PJ, LeBrasseur NK, et al. Frailty and Clinical Outcomes in Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 2019; 16:217-224

16. Fermont JM, Mohan D, Fisk M, et al. Short physical performance battery as a practical tool to assess mortality risk in chronic obstructive pulmonary disease. Age Ageing 2020

17. Gale NS, Albarrati AM, Munnery MM, et al. Frailty: A global measure of the multisystem impact of COPD. Chron Respir Dis 2018; 15:347-355

18. Maddocks M, Kon SS, Canavan JL, et al. Physical frailty and pulmonary rehabilitation in COPD: a prospective cohort study. Thorax 2016; 71:988-995

19. Venado A, McCulloch C, Greenland JR, et al. Frailty trajectories in adult lung transplantation: A cohort study. J Heart Lung Transplant 2019; 38:699-707

20. Marengoni A, Vetrano DL, Manes-Gravina E, et al. The Relationship Between COPD and Frailty: A Systematic Review and Meta-Analysis of Observational Studies. Chest 2018; 154:21-40

21. Varughese R, Rozenberg D, Singer LG. An update on frailty in lung transplantation. Curr Opin Organ Transplant 2020; 25:274-279

22. Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clin Geriatr Med 2011; 27:79-87

23. Koons B, Greenland JR, Diamond JM, et al. Pathobiology of frailty in lung disease. Transl Res 2020; 221:1-22