Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with poor prognosis and limited therapeutic options. The 2011 ATS/ERS/JRS/ALAT consensus statement provided a number of recommendations for the management of IPF patients. The primary objective of this study was to determine if “bundling” these recommendations in the management of patients with IPF impacts clinical outcomes.
Methods
We conducted a single center, retrospective cohort study of 284 patients diagnosed with IPF. The proposed bundle of care (BOC) components were: (1) visits to a specialized interstitial lung diseases clinic with evaluation of pulmonary function tests at least twice yearly; (2) referral to pulmonary rehabilitation yearly; (3) timed walk test yearly; (4) echocardiogram yearly; and (5) gastroesophageal reflux therapy. Each component of the BOC was given a score of “1” per year of follow up, and the average sum of the scores (ranging from 0-5) was determined for the entire period of follow-up (BOCS), as well as during the first year of follow-up (BOCY1). The primary outcome measure was transplant-free survival.
Results
Age, gender, smoking status, BMI, %FVC, %DLCO did not differ between levels of BOCS and BOCY1. Lowest BOCS (≤1) was associated with a lower transplant-free survival independent of age and %FVC compared to patients with the highest BOCS (>4) (HR 2.274, CI 1.12- 4.64, p=0.024). Lower BOCY1 was associated with a higher risk for transplant or death independent of age and %FVC in comparison to patients with highest BOCY1 (≤1 vs. >4, HR 2.23, p=0.014; > 1 to 2 vs. >4, HR 1.87, p=0.011; >2 to 3 vs. >4, HR 1.72, p=0.019).
Conclusion
IPF patients with higher BOC scores had improved transplant-free survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of patients with IPF.
Keywords: Idiopathic pulmonary fibrosis, transplant-free survival, bundled care
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown etiology characterized by radiological or histopathological pattern of usual interstitial pneumonia. The management of IPF patients is challenging. The prognosis is poor, with a median survival time of 2 to 3 years from the time of diagnosis (1). No pharmacological therapies improve survival and the recently approved drugs only reduce the rate of disease progression (2, 3). Lung transplantation is a costly option for only a selected few (4), and standards and best practices for the clinical management of IPF patients have not been firmly established.
The 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) consensus guidelines recommend clinical follow-up every 4 to 6 months, the consideration of long-term oxygen therapy if hypoxemia is present, and pulmonary rehabilitation (PR) as “non-pharmacological” strategies in addition to the treatment of comorbidities such as gastroesophageal reflux (GER) for the majority of patients, and treatment of pulmonary hypertension for a selected minority (1). However, these recommendations are not informed by large prospective randomized trials and the impact of adherence to them as a “bundle” is not known.
A “bundle of care” (BOC) is a set of structured practices that, when performed collectively and reliably, improves patient outcomes. The individual components are most effective when they are “bundled” together to produce synergistic effects on outcome measures. Care bundles for acute exacerbations of chronic conditions including heart failure and chronic obstructive pulmonary disease as well as central-line associated infections and ventilator-associated pneumonia (VAP) demonstrated improved hospital mortality (5). Evidence-based bundles of care for prevention of central line-associated bloodstream infections and VAP are now well established and can improve patient outcomes (6, 7). Additionally, implementation of care bundles for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has been shown to improve hospital outcomes and reduce hospital re-admission rates (8, 9).
In this retrospective cohort study, we aimed to test whether adherence to a BOC based on the recommendations listed in the 2011 guidelines for the diagnosis and management of IPF correlates with patient outcomes. We hypothesized that higher adherence to the proposed BOC correlates with improved transplant-free survival in IPF patients. To our knowledge, this is the first study to research the impact of bundled care on transplant-free survival in IPF.
Methods
Study design
We conducted a retrospective, single-center cohort study to assess the impact of adherence to a set of recommended practices (bundle of care) on outcomes of patients with IPF. All patients diagnosed with IPF (1) and enrolled in the University of Alabama at Birmingham (UAB) Pulmonary Translational Research and Clinical Database (P-TREC) from January 1, 2000 to December 31, 2013 were reviewed for inclusion in the study. This project was reviewed and approved by the UAB Institutional Review Board for Human Research (IRB number X140702007).
Study population
A total of 458 subjects enrolled in P-TREC with the primary diagnosis of IPF were screened for inclusion in the study by two study investigators. Of those, 360 subjects fulfilled IPF diagnosis criteria according to the 2011 guidelines (1). We excluded 74 subjects that did not follow up at our center and 2 subjects with emphysema that was more extensive than fibrosis in chest high resolution CAT scan (HRCT). 284 subjects were included in the final analysis (Figure I). 164 (58%) had surgical lung biopsy showing usual interstitial pneumonia pattern.
Figure I. Study population diagram.
Bundle of Care Components and Scoring
The choice of components in our proposed BOC was based on the 2011 guidelines for the diagnosis and management of IPF. The components included were: (1) visits to a specialized interstitial lung disease (ILD) Center with evaluation of pulmonary physiology at least every 6 months; (2) referral to pulmonary rehabilitation at least once a year; (3) timed walk test to screen for hypoxemia at least once a year; (4) echocardiogram (ECHO) at least once a year; and (5) continuous pharmacological anti GER therapy. If fulfilled, each component of the BOC was given a score of “1” per year of follow up. Conversely, a score of “0” was given for each component that was not fulfilled. The scores of each component were then added up and averaged for the number of years of follow up. Hence, the final score for each individual component for each patient ranged from 0 to 1. A subject's BOC score (BOCS) is the sum of the average scores of the 5 components of the BOC determined for the entire period of follow-up. As an example, if a given subject had all components of the BOC fulfilled every single year of follow up, the final score was “5”. If only one component of the BOC was fulfilled for every year of follow up, the final score was “1”. In order to explore the impact of early adherence to the BOC and to mitigate the effect of early death, we also determined the BOC score during the first year of follow up (BOCY1). BOC Y1 was the sum of the scores of each of the 5 components for the first year of follow-up only. To assess the relative impact of each individual component of BOC through the entire period of follow-up, the effect of adherence to each component on the risk of death or lung transplant was also analyzed.
Clinical variables
Clinical data obtained from P-TREC included gender, age, smoking history, body mass index (BMI), HRCT pattern, availability of a surgical lung biopsy for review, anti-GER therapies, forced vital capacity (%FVC) and diffusing capacity for carbon monoxide (%DLCO) expressed as a percentage of the predicted value, availability of a timed walk test, whether an echocardiogram was performed or not, and whether referral to a cardio-pulmonary rehabilitation program was made or not.
Outcome measures
The primary outcome measure was transplant-free survival time, which was defined as the time from the initial visit to our center to the first occurrence of either lung transplantation or death up to December 31, 2013. Dates of death were obtained from PTREC or the Social Security Death Index. The secondary outcome measure was absolute change in %FVC from the first visit to either the last %FVC prior to death or lung transplantation, or up to December 31, 2013.
Statistical Analysis
For statistical analysis, patients were grouped into 5 levels of score ≤1, >1 to 2, >2 to 3, >3 to 4 and >4, according to their BOCS and BOCY1, respectively. Descriptive statistics of patients' characteristics were presented as means ± SD and frequency with proportion by BOCs groups. Comparison statistics were evaluated by performing analysis of variance (ANOVA), Chi-square test or Fisher's exact test, as appropriate. Difference in probability distribution of time-to-event among groups with five different levels of BOCS and BOCY1 was evaluated by performing Kaplan-Meier survival analysis and log-rank test. Cox proportional- hazards regression analysis was used to assess the effects of adherence to BOCS and BOCY1 (BOCS > 4 and BOCY1 >4 were the reference groups, respectively) on transplant-free survival time after adjustment for age at diagnosis and baseline %FVC. We also evaluated association of each dichotomized component of BOC (≥0.5 vs. <0.5) with transplant-free survival probability by replicating aforementioned survival and regression analyses. Both parametric and non-parametric test of correlation between BOCS and change in %FVC were evaluated. A p-value of less than 0.05 was considered statistically significant and all statistical tests were two-sided. All statistical analyses were performed using the most current version of SAS software™ (SAS 9.4).
Results
Baseline characteristics
The mean (± SD) age of all patients at the time of diagnosis was 65±9.5 years, 69% were men, and 94% were self-identified as non-Hispanic white. The mean %FVC was 63±17 and mean %DLCO was 45±15. The median transplant-free survival time was 20.5 months.
Overall BOC score (BOCS)
For statistical analysis, patients were grouped according to their BOCS. 15 subjects had BOCS ≤1, 59 subjects had BOCS >1 to 2, 104 subjects had BOCS > 2 to 3, 83 subjects had BOCS >3 to 4 and 23 subjects had BOCS >4. At baseline, groups were well matched for age, gender, race, smoking status, BMI, %FVC, %DLCO, HRCT pattern, and surgical lung biopsy (Table 1). Use of oral corticosteroids was similar across groups (p=0.94), but azathioprine use was significantly higher in the group with BOCS >4 (p=0.011). Figure II shows the probability of transplant-free survival across the 5 levels of BOCS (log-rank p=0.007). BOCS ≤1 was associated with a higher risk for transplant or death independent of age and %FVC compared to patients with BOCS >4 (HR 2.274, CI 1.12- 4.64, p=0.024). Subjects with intermediate BOCS (>1 to 4) had a non-statistically significant lower transplant-free survival time compared to subjects with BOCS >4 (Table 2). Other possible adjustors including BMI, smoking and immunosuppressant therapy did not change the effect estimate of BOCS. BOCS did not correlate with absolute change in %FVC from the initial visit to either the last %FVC prior to death or lung transplantation, or up to December 31, 2013 (r= -0.09, p=0.18).
Table 1. Baseline Characteristics based on the BOC score (BOCS).
| BOCS ≤1 (n=15) | BOCS >1 to 2 (n=59) | BOCS >2 to 3 (n=104) | BOCS >3 to 4 (n=83) | BOCS >4 to 5 (n=23) | p-value | |
|---|---|---|---|---|---|---|
| Age at diagnosis (years) | 68±10 | 67±10 | 65±8 | 64±10 | 62±10 | 0.14 |
| Gender (male) | 67 | 66 | 65 | 72 | 87 | 0.30 |
| Race (white) | 100 | 91.5 | 93.3 | 100 | 94 | 0.59 |
| Current/Former smoker | 86 | 71 | 66 | 71 | 83 | 0.64 |
| Body Mass Index | 28±5 | 29±4 | 29±4 | 30±6 | 30±7 | 0.81 |
| Definite UIP on HRCT | 80 | 81.1 | 71.8 | 68.7 | 69.6 | 0.69 |
| Surgical Lung Biopsy# | 33 | 46 | 62 | 68 | 52 | 0.06 |
| %predicted FVC | 57±19 | 62±18 | 64±17 | 63±14 | 61±17 | 0.46 |
| FEV1:FVC ratio % | 71±27 | 82±7 | 83±7 | 83±6 | 85±6 | 0.14 |
| %predicted DLCO | 35±12 | 43±18 | 46±15 | 46±14 | 42±12 | 0.13 |
| Corticosteroid use | 40 | 34 | 34 | 31 | 39 | 0.94 |
| Azathioprine use* | 7 | 19 | 27 | 41 | 35 | 0.01 |
Data represent means ±SD or percentages. There were no significant differences between the groups in any of the baseline characteristics shown.
Surgical lung biopsies were reviewed and consistent with Usual Interstitial Pneumonia.
Azathioprine use was significantly higher in the group with BOCS >4 (p=0.011). UIP: Usual Interstitial Pneumonia; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; DLCO: Diffusing capacity for carbon monoxide.
Figure II. Transplant-free survival by BOC score.
Kaplan–Meier distribution for the probability of transplant-free survival across the 5 bundle of care (BOCS) groups. The p-value was obtained by log-rank test.
Table 2. Adherence to bundle of care and risk of death or lung transplant.
| BOC score | Overall BOC (BOCS) | Year-1 BOC (BOCY1) | ||
|---|---|---|---|---|
| HR* (95% CI) | p-value | HR* (95% CI) | p-value | |
| ≤1 | 2.274 (1.12-4.64) | 0.024 | 2.234 (1.18-4.24) | 0.014 |
| >1 to 2 | 1.232 (0.72-2.11) | 0.445 | 1.874 (1.15-3.04) | 0.011 |
| >2 to 3 | 0.993 (0.59-1.66) | 0.978 | 1.721 (1.09-2.72) | 0.019 |
| >3 to 4 | 1.129 (0.66-1.91) | 0.649 | 1.287 (0.82-2.00) | 0.267 |
The risk of death or lung transplant across the values of BOCS and BOCY1 with BOCS > 4 and BOCY1 >4 as reference groups.
All presented hazard ratios (HR) and p-values are estimated by performing Cox regression models and were adjusted for age and %FVC.
Fewer clinic visits (score <0.5) was associated with increased risk of death or lung transplant (HR 1.563, CI 1.14- 2.15, p=0.006) (Table 3). Annual timed walk testing to screen for hypoxemia (HR 0.770, CI 0.59- 1.00, p=0.051), annual referral to pulmonary rehabilitation (HR 1.107, CI 0.85- 1.44, p=0.447) and anti GER therapy (HR 1.021, CI 0.79- 1.32, p=0.877) did not impact transplant free survival. Fewer echocardiograms was associated with decreased risk of death or lung transplant (HR 0.561, CI 0.43- 0.73, p=0.0001).
Table 3. Low adherence to each component of BOC and risk of death or lung transplant.
| BOC component* | HR* (95% CI) | p-value |
|---|---|---|
| Fewer clinic visits | 1.563 (1.14-2.15) | 0.006 |
| Fewer referrals to Pulmonary Rehabilitation | 1.107 (0.85-1.44) | 0.447 |
| Less anti-reflux therapy | 1.021 (0.79-1.32) | 0.877 |
| Fewer timed walk tests | 0.770 (0.59-1.00) | 0.051 |
| Fewer echocardiograms | 0.561 (0.43-0.73) | 0.0001 |
The impact of adherence to each component of BOC and the risk of death or lung transplant.
Fewer or less is defined by score<0.5 for each respective component.
All presented hazard ratios (HR) and p-values are estimated by performing Cox regression models and were adjusted for age and %FVC.
Year 1 BOC score (BOCY1)
For statistical analysis, patients were grouped according to their mean BOCY1. 18 subjects had BOCY1 ≤1, 50 subjects had BOCY1 > 1 to 2, 83 subjects had BOCY1 >2 to 3, 98 subjects had BOCY1 >3 to 4 and 35 subjects had BOCY1 >4. At baseline, subjects were well matched for age, gender, race, smoking status, BMI, %FVC, %DLCO and HRCT pattern (Table 4). Use of oral corticosteroids was similar across groups (p=0.75) but azathioprine use was significantly higher in the group with BOCY1 >4 (p=0.004). Figure III shows the probability of transplant-free survival across the 5 levels of BOCY1 (log-rank p=0.0007). A lower BOCY1 score was associated with a higher risk for transplant or death independent of age at diagnosis and initial %FVC (≤1 vs. >4, HR 2.23 (1.18-4.24), p=0.014; >1 to 2 vs. >4, HR 1.87 (1.15-3.04), p=0.011; >2 to 3 vs. >4, HR 1.72 (1.09-2.72), p=0.019) (Table 2). Other possible adjustors including BMI, smoking and immunosuppressant therapy did not change the effect estimate of BOCY1. The BOCY1 did not correlate with absolute change in %FVC from the initial visit to either the last %FVC prior to death or lung transplantation, or up to December 31, 2013 (r= -0.11, p=0.11).
Table 4. Baseline Characteristics based on Year-1 BOC score (BOCY1).
| BOCY1 ≤1 (n=18) | BOC Y1 >1 to 2 (n=50) | BOC Y1 >2 to 3 (n=83) | BOC Y1 >3 to 4 (n=98) | BOC Y1 >4 to 5 (n=35) | p-value | |
|---|---|---|---|---|---|---|
| Age at diagnosis (years) | 69 ±10 | 67±10 | 66±8 | 65±10 | 64±9 | 0.06 |
| Gender (male) | 67 | 64 | 68 | 66 | 91 | 0.05 |
| Race (white) | 100 | 90 | 94 | 94 | 94 | 0.56 |
| Current/Former smoker | 78 | 76 | 66 | 70 | 74 | 0.81 |
| Body Mass Index | 27±5 | 30±5 | 30±6 | 29±5 | 32±8 | 0.9 |
| Definite UIP on HRCT | 83 | 76 | 75 | 68 | 74 | 0.68 |
| Surgical Lung Biopsy# | 22 | 46 | 63 | 64 | 66 | 0.01 |
| %predicted FVC | 61±21 | 63±17 | 62±17 | 64±16 | 60±14 | 0.69 |
| FEV1:FVC ratio∧ | 71±27 | 82±5 | 82±7 | 85±6 | 80±6 | 0.03 |
| %predicted DLCO | 43±19 | 41±15 | 44±17 | 46±14 | 48±13 | 0.34 |
| Corticosteroid use | 33 | 34 | 40 | 32 | 29 | 0.75 |
| Azathioprine use* | 6 | 22 | 23 | 35 | 49 | 0.004 |
Data represent means ±SD or percentages. There were no significant differences between the groups in any of the demographics and baseline characteristics shown.
Surgical lung biopsies were reviewed and consistent with Usual Interstitial Pneumonia, the percentage of patients diagnosed with lung biopsy was lower in the group with BOCY1 ≤1.
FEV1:FVC ratio was lower in the group with BOCY1 ≤1.
Azathioprine use was significantly higher in the group with BOC Y1 >4 (p=0.004). UIP: Usual Interstitial Pneumonia; FEV1: forced expiratory volume in one second, FVC: forced vital capacity; DLCO: Diffusing capacity for carbon monoxide.
Figure III. Transplant-free survival by Year-1 BOC score.
Kaplan–Meier distribution for the probability of transplant-free survival across the 5 year-1 bundle of care (BOCY1) groups. The p-value was obtained by log-rank test.
Discussion
The 2011 ATS/ERS/JRS/ALAT guidelines recommend a number of pharmacological and non-pharmacological interventions for the management of IPF patients (1). This is the first study to examine the impact of adherence to such measures as a bundle of care on the outcomes of IPF patients. The results of this single-center retrospective study suggest that IPF patients with greater adherence to the proposed BOC may have longer transplant-free survival compared to those with lower adherence. Higher adherence to BOC in the first year of follow up had a higher impact on transplant-free survival, independent of age at diagnosis and initial %FVC.
Our findings are similar to what has been reported for other complex chronic diseases. Studies have shown that integrated multidisciplinary care programs and resource-intensive approaches may improve outcomes in chronic diseases such as chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF) (10-13). Improvement in process reliability and coordination among levels of care may also be important in improving clinical outcomes with a multidisciplinary care bundle. Implementation of COPD discharge care bundles including pulmonary rehabilitation, smoking cessation, patient education, coordination among levels of care and improved accessibility was shown to be associated with a reduction in hospital readmission rates (8, 9, 12). A randomized control trial reported improved clinical outcomes including acute exacerbations with a multidisciplinary approach to outpatient CHF management (11). Furthermore, higher compliance to all the elements of care bundles has been shown to have higher efficacy in prevention of central line-associated bloodstream infections and ventilator-associated pneumonia with improvement in patient outcomes (6, 7). Notably, these studies focused on the importance of delivering “all or none” of the elements of the proposed bundle to evaluate patient outcomes.
The role of “care bundling” in the management of IPF has not been reported previously. Although the recommendations for patient management contained in the 2011 guidelines have not been informed by randomized controlled trials, many of the proposed components have evidence suggesting benefit (1, 14-19). We posit that compliance with all components of a bundle is critical to optimize outcome effects in patients. Hence, our objective was not to evaluate the effect of each component but rather to evaluate their effects when applied together as a bundle. In fact, when taken individually, annual referral to pulmonary rehabilitation, annual timed walk testing to screen for hypoxemia, and anti GER therapy did not impact transplant free survival. Fewer clinic visits was associated with increased risk of death or lung transplant in our cohort and this finding is aligned with previous report which suggested that delayed access to an experienced ILD center was associated with higher mortality rates in IPF patients (16). It is possible that the improvement in outcomes in our study population could be related to a synergistic effect of intense monitoring for disease progression, and availability of specialized resources at a quaternary care center leading to more prompt and effective management of co-morbidities. Importantly, our results suggest that early aggressive and resource intensive measures may actually have a stronger impact on patient outcomes than the eventual adherence to those practices over time.
There are several important limitations to this study. It reflects the experience and practices of a single center and could have been influenced by selection bias and other potential unmeasured confounders, as patients were not randomly assigned a level of adherence to the BOC. Although disease severity at baseline was similar among groups, it is possible that factors such as insurance status or cultural considerations might have impacted their ability to comply with some of the components of the BOC. This study was primarily designed to determine if adherence of physicians to the 2011 guidelines for the management of IPF patients influences clinical outcomes and not to assess the factors leading to the adherence. We recognize that elements such as patients' access to healthcare, socioeconomic status and health beliefs could impact adherence and prospective studies may direct more insight into improving these factors. Secondly, three of the proposed BOC components we measured are, in actuality, “surrogates” of the recommendations contained in the 2011 guidelines. We do not know whether patients referred to PR actually attended the program or whether a patient diagnosed with hypoxemia during a timed walk test complied with oxygen therapy. We also did not determine whether an echocardiogram led to a right heart catheterization or vasodilator therapy. Third, we recognize that %FVC, %DLCO, 6-minute walk test and presence of pulmonary arterial hypertension have all been associated with outcomes in IPF. However, because of missing data, the number of cases with concomitant values for all those variables was small to allow for adequate statistical modeling. Hence, we decided to include only %FVC in the model to adjust the effect of BOCS and BOCY1 on probability of transplant free survival as %FVC is recognized to be very reproducible and it has a very robust association with outcomes in IPF. Finally, other important and noteworthy general management strategies such as screening for sleep disordered breathing, depression or coronary artery disease, as well as referral to a palliative medicine program and ensuring timely immunizations were not included in proposed BOC as they are not listed as firm recommendations in the 2011 guidelines (20, 21). Notwithstanding these limitations, our results support a “bundled” approach to the recommendations contained in the 2011 guidelines.
Conclusion
In summary, our data suggests that adherence to a bundle of care that includes the management recommendations of the 2011 ATS/ERS/JRS/ALAT consensus statement may improve IPF survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of IPF patients beyond anti-fibrotic pharmacological therapies.
Highlights.
A “Bundle of Care” (BOC) for management of IPF patients is proposed.
The BOC is based on the 2011 ATS/ERS/JRS/ALAT consensus guidelines.
Higher adherence to the BOC improves transplant-free survival in IPF.
Early aggressive and resource intensive measures seem to have a stronger impact on survival in IPF.
Acknowledgments
Funding source: This study was funded by the UAB Interstitial Lung Disease Program and the NIH grant PO1HL114470.
Footnotes
Part of this work was presented in the form of an abstract at American Thoracic Society International Conference, May 19th 2015, Denver
Conflict of Interest: JAD has received research grants from the NIH, Genentech, Boehringer Ingelheim, and Fibrogen; and consulting fees from Genentech, Boehringer Ingelheim, and Immuneworks. TL has received research grants from the NIH, the Pulmonary Fibrosis Foundation, Gilead, Celgene, and Boehringer Ingelheim. VJT has received research grants from the NIH. TK, JW, PAL, YK, RR, and CBA have no conflicts of interest to disclose.
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