Implementation of guideline recommendations and outcomes in patients with idiopathic pulmonary fibrosis: Data from the IPF-PRO registry

Open AccessPublished:September 29, 2021DOI:https://doi.org/10.1016/j.rmed.2021.106637

      Highlights

      • We investigated the implementation of guidelines for the management of IPF.
      • Guidelines were more likely to be implemented in patients with more severe disease.
      • In adjusted models, there were no associations between guideline use and outcomes.

      Abstract

      Background

      Few data are available on the extent to which clinical practice is aligned with international guidelines for the management of idiopathic pulmonary fibrosis (IPF). We investigated the extent to which management guidelines for IPF have been implemented in the US IPF-PRO Registry and associations between implementation of guidelines and clinical outcomes.

      Methods

      We assessed the implementation of eight recommendations in clinical practice guidelines within the 6 months after enrollment: visit to a specialized clinic; pulmonary function testing; use of oxygen in patients with resting hypoxemia and exercise-induced hypoxemia; referral for pulmonary rehabilitation; treatment of gastro-esophageal reflux disease; initiation of anti-fibrotic therapy; referral for lung transplant evaluation. An implementation score was calculated as the number of recommendations achieved divided by the number for which the patient was eligible. Associations between implementation score and outcomes were analyzed using logistic regression and Cox proportional hazards models.

      Results

      Among 727 patients, median (Q1, Q3) implementation score was 0.6 (0.5, 0.8). Patients with an implementation score >0.6 had greater disease severity than those with a lower score. Implementation was lowest for referral for pulmonary rehabilitation (19.5%) and lung transplant evaluation (22.3%). In unadjusted models, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization, but no significant associations were observed in adjusted models.

      Conclusions

      Management guidelines were more likely to be implemented in patients with IPF with greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and clinical outcomes.

      Graphical abstract

      Keywords

      Abbreviations:

      ALAT (Latin American Thoracic Association), ATS (American Thoracic Society), BMI (Body mass index), CASA-Q (Cough and Sputum Assessment Questionnaire), DLco (Diffusing capacity of the lungs for carbon monoxide), EQ-5D (EuroQoL 5-D), ERS (European Respiratory Society), FEV1 (Forced expiratory volume in 1 s), FVC (Forced vital capacity), GERD (Gastroesophageal reflux disease), IPF (Idiopathic pulmonary fibrosis), JRS (Japanese Respiratory Society), MCS (Mental component summary), PCS (Physical component summary), SGRQ (St. George's Respiratory Questionnaire), SF-12 (Short Form-12), VAS (Visual analog scale)

      1. Introduction

      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by decline in lung function and high mortality [
      • Raghu G.
      • Remy-Jardin M.
      • Myers J.L.
      • et al.
      Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
      ]. Guidelines for the management of IPF published by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) in 2011 provided recommendations for the frequency of clinic visits and pulmonary function testing, the use of oxygen and non-pharmacological therapies, and referral for evaluation for lung transplantation [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ]. Updated clinical practice guidelines published in 2015 included conditional recommendations for the use of the FDA-approved antifibrotic drugs nintedanib and pirfenidone in patients with IPF and for the use of anti-acid therapy in patients with IPF and asymptomatic acid gastroesophageal reflux disease (GERD) [
      • Raghu G.
      • Rochwerg B.
      • Zhang Y.
      • et al.
      An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.
      ]. Clinical practice guidelines are increasingly being used to set standards and provide metrics on the delivery of patient care. A report from a working group of the ATS recommended that performance measures focused on patient care should ideally be linked to clinical practice guidelines based on evidence and patient-centered outcomes [
      • Kahn J.M.
      • Gould M.K.
      • Krishnan J.A.
      • et al.
      An official American Thoracic Society workshop report: developing performance measures from clinical practice guidelines.
      ]. However, few data are available on the extent to which the care provided to patients with IPF is in line with the recommendations provided in international guidelines, or whether alignment with these guidelines is associated with better outcomes.
      The Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry (NCT01915511) is a multi-center US registry of patients with IPF, which aims to provide a better understanding of the course of IPF, how it affects patients, and current practices in diagnosis and patient care [
      • O'Brien E.C.
      • Durheim M.T.
      • Gamerman V.
      • et al.
      Rationale for and design of the idiopathic pulmonary fibrosis-PRospective outcomes (IPF-PRO) registry.
      ]. We used data from the IPF-PRO Registry to investigate the extent to which international guidelines for the management of IPF [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ,
      • Raghu G.
      • Rochwerg B.
      • Zhang Y.
      • et al.
      An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.
      ] have been implemented and whether implementation of these recommendations was associated with differences in clinical outcomes.

      2. Materials and methods

      The design of the IPF-PRO Registry has been published [
      • O'Brien E.C.
      • Durheim M.T.
      • Gamerman V.
      • et al.
      Rationale for and design of the idiopathic pulmonary fibrosis-PRospective outcomes (IPF-PRO) registry.
      ]. Briefly, patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months were eligible. Patients who were on a lung transplant list or participating in a randomized clinical trial could not be enrolled, but patients could be listed for transplant or enter clinical trials after enrollment. Retrospective data from the 12 months prior to enrollment were obtained from patient records. Patients in the registry are followed prospectively, with follow-up data captured at approximately 6-month intervals, for a maximum of 60 months, or until death, lung transplant, or withdrawal.
      A total of 1002 patients at 46 sites were enrolled between June 2014 and October 2018. Data for this analysis were extracted from the database in March 2020. We assessed the implementation of eight recommendations in the ATS/ERS/JRS/ALAT 2011 [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ] or 2015 [
      • Raghu G.
      • Rochwerg B.
      • Zhang Y.
      • et al.
      An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.
      ] management guidelines for IPF within the 6 months after enrollment. This required “operationalizing” some of the recommendations in the guidelines, through which we aimed to make the recommendations measurable while reflecting the spirit of the guidelines. In summary, we investigated the implementation of: 1) visit to a specialized clinic (a center experienced in the management of patients with ILD) approximately every 6 months; 2) pulmonary function testing approximately every 6 months; 3) use of oxygen therapy in patients with resting hypoxemia; 4) use of oxygen therapy in patients with exercise-induced hypoxemia; 5) referral for pulmonary rehabilitation; 6) treatment of GERD; 7) initiation of anti-fibrotic therapy; 8) referral for lung transplant evaluation. The patients who were eligible for each recommendation, and how implementation of each recommendation was determined, are shown in Table 1. Assessment of whether a patient had visited a specialized center in the 6 months after enrollment was based on the recommendation in the guidelines that all patients should be monitored for disease progression and complications every 4–6 months at the latest [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ]. While the guidelines do not provide a specific recommendation regarding the use of oxygen therapy in patients with exercise-induced hypoxemia, they discuss the need to measure oxygen saturation with exertion to identify patients who need supplemental oxygen [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ].
      Table 1Recommendations, patients eligible for the recommendation and how achievement of the recommendation was determined.
      RecommendationPatients eligible*Achievement of recommendation
      Visit to specialized clinic approximately every 6 monthsAllPatient had at least 1 visit to enrolling center in the 6 months after enrollment
      Pulmonary function testing approximately every 6 monthsAllPulmonary function test data (at least one of FVC, FEV1, DLco, lung volume) present in the 6 months after enrollment
      Use of oxygen for resting hypoxemiaOn oxygen at rest or with resting SpO2 <89%

      or on oxygen during resting SpO2 measurement

      or required oxygen at rest at 6MWT

      or on oxygen at time of arterial blood gas measurement

      or with PaO2 ≤55 mmHg

      or with PaO2 ≥56–59 mmHg and pulmonary hypertension

      or required oxygen at rest at time of discharge from medical encounter
      Patient given oxygen at rest at enrollment or in the 6 months after enrollment
      Use of oxygen for exercise-induced hypoxemiaOn oxygen with activity or required oxygen during 6MWT

      or had 6MWT with oxygen saturation <89%

      or required oxygen with activity at time of discharge from medical encounter
      Patient given oxygen with activity at enrollment or in the 6 months after enrollment
      Referral for pulmonary rehabilitationAllPatient underwent pulmonary rehabilitation at least once in the 6 months after enrollment
      Treatment of GERDWith history of GERD at enrollment or with GERD reported on follow-up

      or on PPI or H2 blocker
      Patient given PPI or H2 blocker at enrollment or in the 6 months after enrollment
      Initiation of anti-fibrotic therapyAllPatient on or has ever been on pirfenidone or nintedanib
      Referral for lung transplant evaluationAge <70 yearsPatient had been referred for lung transplant evaluation (ever) at enrollment, or at follow-up, patient had undergone lung transplant evaluation
      *Eligibility was determined at enrollment or at any data abstraction up to 6 months after enrollment. 6MWT, 6-min walk test; DLco, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.
      For each patient, an implementation score was calculated as the number of recommendations achieved divided by the number of recommendations for which the patient was eligible. Scores ranged from 0 (no recommendations implemented) to 1 (all recommendations implemented). Implementation score was assessed based on the first 6 months of a patient's participation in the registry. The correlation between implementation score and the number of recommendations a patient was eligible for was assessed by calculation of a Spearman correlation coefficient.
      For descriptive purposes, patients were grouped by implementation score less than or equal to versus above the median observed in the analysis cohort. In comparisons of the baseline characteristics of these groups, continuous variables, presented as median (25th percentile, 75th percentile), were compared using Wilcoxon rank sum tests, while categorical variables, presented as number and percentage of patients, were compared using Pearson's chi-squared tests.
      We assessed event rates of categorical changes in diffusing capacity of the lungs for carbon monoxide (DLco) (relative and absolute declines ≥15% in mmol/min/kPa and % predicted, respectively), forced vital capacity (FVC) (relative and absolute declines ≥10% in mL and % predicted, respectively), and patient-reported outcomes in the 6 months following enrollment (5–9 month window) in the subgroups by median implementation score. The patient-reported outcomes assessed were the St. George's Respiratory Questionnaire (SGRQ) [
      • Jones P.W.
      • Quirk F.H.
      • Baveystock C.M.
      The St george's respiratory questionnaire.
      ], the Cough and Sputum Assessment Questionnaire (CASA-Q) [
      • Crawford B.
      • Monz B.
      • Hohlfeld J.
      • Roche N.
      • et al.
      Development and validation of a cough and sputum assessment questionnaire.
      ], the Short Form-12 (SF-12) questionnaire [
      • Ware Jr., J.
      • Kosinski M.
      • Keller S.D.
      A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity.
      ] and the EuroQoL 5-D (EQ-5D) index score and visual analog scale (VAS) [
      • Rabin R.
      • de Charro F.
      EQ-5D: a measure of health status from the EuroQol Group.
      ]. The proportions of patients who had categorical changes in these patient-reported outcomes that reflected minimal clinically important differences for worsening proposed based on previous studies, i.e., an increase in SGRQ total score ≥7, increase in SGRQ activity score ≥5, increase in SGRQ impact score ≥7, increase in SGRQ symptoms score ≥8, decrease in CASA-Q cough domains ≥11, decrease in EQ-5D index score ≥0.06, decrease in EQ-5D VAS ≥8, decrease in SF-12 mental component summary (MCS) score ≥6, and decrease in SF-12 physical component summary (PCS) score ≥5, were assessed [
      • Pickard A.S.
      • Neary M.P.
      • Cella D.
      Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.
      ,
      • Swigris J.J.
      • Brown K.K.
      • Behr J.
      • et al.
      The SF-36 and SGRQ: validity and first look at minimum important differences in IPF.
      ,
      • Zanini A.
      • Aiello M.
      • Adamo D.
      • et al.
      Estimation of minimal clinically important difference in EQ-5D visual analog scale score after pulmonary rehabilitation in subjects with COPD.
      ,
      • Witt S.
      • Krauss E.
      • Barbero M.A.N.
      • et al.
      Psychometric properties and minimal important differences of SF-36 in idiopathic pulmonary fibrosis.
      ,
      • Rebelo P.
      • Oliveira A.
      • Paixão C.
      • Valente C.
      • Andrade L.
      • Marques A.
      Minimal clinically important differences for patient-reported outcome measures of cough and sputum in patients with COPD.
      ]. Associations between implementation score and categorical changes in FVC, DLco and patient-reported outcomes were analyzed using logistic regression models. The models used were unadjusted and adjusted for variables identified as being associated with the outcome. Age, body mass index (BMI), forced expiratory volume in 1 s (FEV1) % predicted, DLco % predicted, oxygen use with activity and the presence of emphysema at enrollment were included as adjustment variables in the model assessing changes in FVC. Sex, distance to the enrolling site, FEV1% predicted, DLco % predicted and hospitalization prior to enrollment were included as adjustment variables in the model assessing changes in DLco. Age, sex, diagnosis of IPF prior to referral to enrolling center, and the value of the respective patient-reported outcome at enrollment were included as adjustment variables in the models assessing change in each patient-reported outcome.
      We assessed time to death, time to a composite of death or lung transplant, and time to hospitalization following measurement of the implementation score. Cumulative event counts and event rates following measurement of the implementation score, stratified by median implementation score, were estimated using the Kaplan–Meier method. Associations between implementation score and time to the first event based on the whole follow-up period were analyzed using Cox proportional hazards models (for death and death or lung transplant) or Fine and Gray models with death considered as a competing risk (for hospitalization). In each model, “time zero” was 6 months after enrollment. The models used were unadjusted and adjusted for variables identified as being associated with the outcome. Age, BMI, FEV1% predicted, FVC % predicted, DLco % predicted, oxygen use with activity, oxygen use at rest, the presence of coronary artery disease or heart failure at enrollment and diagnosis of IPF prior to referral to the enrolling center were included as adjustment variables in the model assessing time to death or lung transplant. Age, BMI, FVC % predicted, DLco % predicted, oxygen use at rest and the presence of coronary artery disease or heart failure at enrollment were included as adjustment variables in the model assessing time to death. BMI, FEV1% predicted and oxygen use at rest at enrollment were included as adjustment variables in the model assessing time to hospitalization. Implementation score was considered in its continuous form. If the implementation score had a significant relationship with an outcome in an unadjusted or adjusted model, we assessed the association between individual recommendations and the outcome.
      Analyses were based on patients who were alive and in the registry 6 months after enrollment. Patients with insufficient data to determine an implementation score were excluded. In the analyses of event rates of categorical changes in DLco, FVC, and patient-reported outcomes, patients were required to have a measurement at enrollment and 5–9 months after enrollment. Missing data on adjustment covariates were handled using multiple imputation: the missing data were filled in five times to generate five complete data sets using the Full Conditional Specification method; each complete data set was analyzed using standard statistical analyses; the results from the five complete datasets were averaged to generate the final inferential results.

      3. Results

      Of the 1002 patients enrolled in the registry, 79 were excluded as they were not alive and in the registry 6 months after enrollment and 196 patients had insufficient data for determining the implementation score. Thus, the analysis cohort comprised 727 patients. The numbers of patients eligible for each recommendation and achieving each recommendation are shown in Table 2. Each of the individual recommendations was implemented by over 70% of eligible patients except for referral for pulmonary rehabilitation (19.5%), referral for lung transplant evaluation (22.3%) and use of anti-fibrotic therapy (58.7%). However, only 6.3% of patients had all the recommendations that they were eligible for implemented (i.e., an implementation score of 1). For some of the recommendations, particularly referral for lung transplant evaluation, implementation of the guideline was more likely in patients with higher GAP stage (Table 2). The mean (standard deviation) implementation score was 0.6 (0.2) and the median (25th percentile, 75th percentile) was 0.6 (0.5, 0.8). Implementation score was higher among patients eligible for more recommendations (Spearman correlation coefficient r = 0.31). Baseline characteristics of the subgroups by implementation score less than or equal to and above the median (0.6) are shown in Table 3. Compared with patients with implementation score ≤0.6, those with an implementation score >0.6 had greater disease severity based on prior hospitalizations, GAP stage [
      • Ley B.
      • Ryerson C.J.
      • Vittinghoff E.
      • et al.
      A multidimensional index and staging system for idiopathic pulmonary fibrosis.
      ], composite physiologic index [
      • Wells A.U.
      • Desai S.R.
      • Rubens M.B.
      • et al.
      Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.
      ], FEV1% predicted, FVC % predicted, and DLco % predicted, and worse quality of life based on SGRQ total score, SF-12 PCS score and EQ-5D VAS.
      Table 2Implementation of each recommendation in the overall population and in subgroups by GAP stage.
      RecommendationAll patientsGAP stage IGAP stage IIGAP stage III
      Eligible for recommend-ation, nAchieved recommend-ation, n (%)Eligible for recommend-ation, nAchieved recommend-ation, n (%)Eligible for recommend-ation, nAchieved recommend-ation, n (%)Eligible for recommend-ation, nAchieved recommend-ation, n (%)
      Visit to specialized clinic approximately every 6 months727642 (88.3)189164 (86.8)318278 (87.4)9486 (91.5)
      Pulmonary function testing approximately every 6 months727522 (71.8)189137 (72.5)318222 (69.8)9473 (77.7)
      Use of oxygen for resting hypoxemia201152 (75.6)3323 (69.7)8260 (73.2)5745 (78.9)
      Use of oxygen for exercise-induced hypoxemia355281 (79.2)5537 (67.3)166129 (77.7)7768 (88.3)
      Referral for pulmonary rehabilitation727142 (19.5)18925 (13.2)31866 (20.8)9426 (27.7)
      Treatment of GERD548501 (91.4)144134 (93.1)243217 (89.3)6966 (95.7)
      Initiation of anti-fibrotic therapy727427 (58.7)189109 (57.7)318188 (59.1)9459 (62.8)
      Referral for lung transplant evaluation33675 (22.3)12516 (12.8)14132 (22.7)199 (47.4)
      GERD, gastroesophageal reflux disease.
      Table 3Patient characteristics at enrollment by implementation score less than or equal to versus above the median (0.6).
      Implementation score ≤0.6 (n = 360)Implementation score >0.6 (n = 367)p-value
      Age, years70 (64, 76)71 (66, 75)0.26
      Male259 (71.9)276 (75.2)0.32
      White332 (94.9)336 (94.1)0.67
      US region0.13
       Northeast54 (15.0)67 (18.3)
       Midwest71 (19.7)78 (21.3)
       South190 (52.8)194 (52.9)
       West45 (12.5)28 (7.6)
      Smoking history0.084
       Current6 (1.7)4 (1.1)
       Past216 (60.0)249 (67.8)
       Never138 (38.3)114 (31.1)
      FEV1% predicted79.8 (68.8, 90.6)76.1 (64.4, 89.0)0.031
      FVC % predicted71.9 (62.7, 82.1)68.2 (57.2, 79.9)0.003
      DLco % predicted47.2 (39.1, 55.4)39.6 (31.2, 48.1)<0.001
      GAP stage
      Higher GAP stage indicates greater risk of mortality [15].
      <0.001
       I112 (38.1)77 (25.1)
       II157 (53.4)161 (52.4)
       III25 (8.5)69 (22.5)
      CPI
      Higher CPI indicates greater extent of pulmonary fibrosis on radiography [16].
      48.8 (42.4, 55.5)54.6 (47.8, 61.3)<0.001
      Supplemental oxygen
       With activity45 (12.8)166 (46.5)<0.001
       At rest15 (4.3)93 (26.0)<0.001
      Diagnostic criteria for IPF
      According to 2011 ATS/ERS/JRS/ALAT diagnostic guidelines [2].
      0.14
       Definite IPF219 (60.8)239 (65.1)
       Probable IPF108 (30.0)87 (23.7)
       Possible IPF33 (9.2)41 (11.2)
      Prior diagnosis of IPF (before referral to enrolling center)146 (40.6)166 (45.5)0.18
      Referred to enrolling center by pulmonologist174 (48.6)222 (61.0)<0.001
      Hospitalization in prior 12 months81 (24.0)114 (31.9)0.019
      Respiratory hospitalization in prior 12 months39 (11.5)76 (21.3)<0.001
      Distance to enrolling center, miles26 (12, 77)31 (14, 85)0.072
      History of GERD184 (51.5)213 (58.0)0.079
      Proton pump inhibitor144 (44.9)215 (64.0)<0.001
      H2 blocker27 (8.4)38 (11.3)0.21
      Pirfenidone61 (16.9)159 (43.3)<0.001
      Nintedanib67 (18.6)120 (32.7)<0.001
      SGRQ total score33.2 (19.4, 47.8)40.6 (29.4, 53.3)<0.001
      SGRQ activity score47.7 (29.6, 66.2)59.5 (47.7, 72.8)<0.001
      SGRQ impact score20.5 (10.6, 36.0)27.7 (16.9, 40.3)<0.001
      SGRQ symptoms score40.6 (26.4, 56.7)42.9 (29.4, 59.2)0.089
      CASA-Q cough impact domain81.3 (59.4, 96.9)81.3 (59.4, 96.9)0.95
      CASA-Q cough symptoms domain58.3 (41.7, 83.3)62.5 (41.7, 75.0)0.90
      EQ-5D index score0.8 (0.7, 1.0)0.8 (0.7, 1.0)0.10
      EQ-5D VAS score80.0 (70.0, 90.0)75.0 (60.0, 85.0)0.001
      SF-12 MCS score54.3 (45.9, 59.7)54.1 (46.0, 59.9)0.91
      SF-12 PCS score41.8 (34.0, 50.0)37.9 (32.1, 44.4)<0.001
      Data are median (25th, 75th percentile) or n (% of patients without missing data). Information on all variables was not available for all patients.
      CASA-Q, cough and sputum assessment questionnaire; CPI, composite physiologic index; DLco, diffusing capacity of the lungs for carbon monoxide; FEV1 forced expiratory volume in 1 s; FVC, forced vital capacity; GAP, gender, age and lung physiology; GERD, gastroesophageal reflux disease; ILD interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MCS, mental component summary; PCS, physical component summary; SF-12, short form-12; SGRQ, St. George's Respiratory Questionnaire; VAS, visual analog scale.
      a Higher GAP stage indicates greater risk of mortality [
      • Ley B.
      • Ryerson C.J.
      • Vittinghoff E.
      • et al.
      A multidimensional index and staging system for idiopathic pulmonary fibrosis.
      ].
      b Higher CPI indicates greater extent of pulmonary fibrosis on radiography [
      • Wells A.U.
      • Desai S.R.
      • Rubens M.B.
      • et al.
      Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.
      ].
      c According to 2011 ATS/ERS/JRS/ALAT diagnostic guidelines [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ].

      4. Event rates of outcomes by implementation score

      Event rates of relative decline in DLco (mmol/min/kPa) ≥15%, relative decline in FVC (mL) ≥10%, and worsening of SGRQ total score by ≥7 points, SF-12 MCS score by ≥6 points, and SF-12 PCS score by ≥5 points in the 6 months after enrollment were higher in patients with an implementation score >0.6 versus ≤0.6 (Table 4). Event rates of death, death or lung transplant, and hospitalization 1 year after assessment of the implementation score were higher in patients with an implementation score >0.6 versus ≤0.6 (Table 5). Time to death or lung transplant and time to hospitalization after assessment of the implementation score by implementation score ≤0.6 and >0.6 are shown in Fig. 1.
      Table 4Categorical changes from baseline in FVC, DLco and patient-reported outcomes in the 6 months after enrollment in patients with implementation score ≤0.6 or >0.6.
      Event rate, % (95% CI)
      Implementation score ≤0.6Implementation score >0.6
      Relative decline in FVC (mL) ≥10%17.6 (13.1, 22.0)21.4 (15.5, 27.4)
      Absolute decline in FVC ≥10% predicted11.5 (7.6, 15.4)10.1 (5.5, 14.6)
      Relative decline in DLco (mmol/min/kPa) ≥15%24.9 (19.5, 30.3)33.8 (26.1, 41.5)
      Absolute decline in DLco ≥15% predicted6.4 (3.3, 9.5)7.4 (3.0, 11.8)
      Increase in SGRQ total score ≥729.0 (23.4, 34.7)34.0 (26.5, 41.4)
      Increase in SGRQ activity score ≥547.7 (41.5, 53.8)49.0 (41.2, 56.9)
      Increase in SGRQ impact score ≥726.4 (21.0, 31.8)31.0 (23.8, 38.2)
      Increase in SGRQ symptoms score ≥830.7 (25.0, 36.4)26.1 (19.2, 33.0)
      Decrease in CASA-Q cough impact domain ≥1121.6 (16.6, 26.5)23.2 (16.7, 29.6)
      Decrease in CASA-Q cough symptoms domain ≥1128.6 (23.2, 34.0)25.6 (18.9, 32.3)
      Decrease in EQ-5D index score ≥0.0632.1 (26.5, 37.7)28.6 (21.6, 35.5)
      Decrease in EQ-5D VAS score ≥828.6 (23.2, 34.1)37.9 (30.4, 45.4)
      Decrease in SF-12 MCS score ≥619.2 (14.3, 24.1)22.1 (15.5, 28.6)
      Decrease in SF-12 PCS score ≥530.2 (24.5, 36.0)36.4 (28.8, 44.0)
      CASA-Q, cough and sputum assessment questionnaire; DLco, diffusing capacity of the lungs for carbon monoxide; FVC, forced vital capacity; MCS, mental component summary; PCS, physical component summary; SF-12, short form-12; SGRQ, St. George's Respiratory Questionnaire; VAS, visual analog scale.
      Table 5Kaplan–Meier estimated event rates of death, death or lung transplant and hospitalization in the 1 year following measurement of implementation score by score ≤0.6 or >0.6.
      Event rate at 1 year, % (95% CI)
      Implementation score ≤0.6Implementation score >0.6
      Death5.0 (3.1, 7.8)13.5 (10.2, 17.7)
      Death or lung transplant7.2 (4.9, 10.5)21.2 (17.2, 25.9)
      Hospitalization17.4 (13.5, 21.6)27.3 (22.7, 32.2)
      Fig. 1
      Fig. 1Time to death or lung transplant and time to hospitalization after assessment of implementation score in subgroups by implementation score ≤0.6 and >0.6.

      5. Associations between implementation score and outcomes

      In adjusted models, patients with lower implementation scores were significantly less likely to have a relative decline in DLco (mmol/min/kPa) ≥15% (OR 0.76 [95% CI: 0.60, 0.97] for each 0.2 decrease in implementation score), absolute decline in DLco >15% predicted (OR 0.47 [95% CI: 0.27, 0.83] for each 0.2 decrease in implementation score), and worsening in SF-12 PCS score by ≥5 points (OR 0.72 [95% CI: 0.57, 0.91] for each 0.2 decrease in implementation score) (Fig. 2). There was a trend toward an association between higher implementation scores and worsening of SGRQ impact domain score by ≥7 points in the adjusted model (OR 0.82 [95% CI: 0.68, 1.01] for each 0.2 decrease in implementation score). There were no associations between the implementation score and other patient-reported outcomes, or FVC. In unadjusted models, patients with higher implementation scores had a significantly greater risk of death (HR 0.81 [95% CI: 0.69, 0.94] for each 0.2 decrease in implementation score), death or lung transplant (HR 0.75 [95% CI: 0.66, 0.85] for each 0.2 decrease in implementation score), and hospitalization (HR 0.83 [95% CI: 0.73, 0.94] for each 0.2 decrease in implementation score). In adjusted models, no associations were observed (Fig. 3).
      Fig. 2
      Fig. 2Association between implementation score and categorical changes in FVC, DLco and patient-reported outcomes in unadjusted (A) and adjusted (B) models. Changes and implementation score were measured at the same time point (6 months after enrollment into the registry).
      Fig. 2
      Fig. 2Association between implementation score and categorical changes in FVC, DLco and patient-reported outcomes in unadjusted (A) and adjusted (B) models. Changes and implementation score were measured at the same time point (6 months after enrollment into the registry).
      Fig. 3
      Fig. 3Association between implementation score and death, death or lung transplant and hospitalization after measurement of implementation score in unadjusted and adjusted models. Implementation score was measured 6 months after enrollment into the registry.
      Based on these findings, we assessed the association between implementation of individual recommendations and death, death or lung transplant, and hospitalization, and changes in DLco (mmol/min/kPa and % predicted), SF-12 PCS score and SGRQ impact domain score. In adjusted models, use of oxygen therapy for resting hypoxemia was significantly associated with risk of death (HR 3.02 [95% CI: 1.40, 6.50]), or death or lung transplant (HR 2.13 [95% CI: 1.19, 3.82]), referral for pulmonary rehabilitation was significantly associated with risk of hospitalization (HR 1.37 [95% CI: 1.01, 1.86]), and referral for lung transplant evaluation was significantly associated with risk of death or lung transplant (HR 1.85 [95% CI: 1.17, 2.92]), hospitalization (HR 1.62 [95% CI: 1.07, 2.45]) and worsening SGRQ impact domain score (OR 2.34 [95% CI: 1.11, 4.93]) and SF-12 PCS score (OR 2.30 [95% CI: 1.06, 5.00]) (Supplementary Table E1). There was a trend toward a lower risk of death in patients who visited a specialized clinic at least once in the 6 months following enrollment (HR 0.65 [95% CI: 0.41, 1.03]).

      6. Discussion

      We used data from the IPF-PRO Registry to assess the alignment of clinical practice with international guidelines for the management of IPF at referral centers in the US. We found that patients who had higher implementation scores, i.e., for whom more of the guidelines for which they were eligible had been implemented, had more severe disease and worse quality of life at enrollment, and were more likely to have clinically relevant declines in lung function in the 6 months following enrollment. Although in unadjusted analyses, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization over the follow-up period, when these analyses were adjusted for clinical variables associated with these outcomes, no association was observed between these outcomes and a higher implementation score. This suggests that the greater risk of death or lung transplant and hospitalization seen in patients with higher implementation scores reflects the greater severity of disease in these patients.
      Only 6.3% of patients had all the recommendations that they were eligible for implemented. Implementation was lowest for referral for pulmonary rehabilitation (19.5% of eligible patients). Studies of European registries of patients with IPF have also reported low proportions of patients undergoing pulmonary rehabilitation [
      • Behr J.
      • Kreuter M.
      • Hoeper M.M.
      • et al.
      Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.
      ,
      • Guenther A.
      • Krauss E.
      • Tello S.
      • et al.
      The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.
      ,
      • Fernández-Fabrellas E.
      • Molina-Molina M.
      • Soriano J.B.
      • et al.
      Demographic and clinical profile of idiopathic pulmonary fibrosis patients in Spain: the SEPAR national registry.
      ]. Among 525 patients in the European IPF registry, 15.4% and 5.0% had ever participated in in-patient and out-patient rehabilitation programs, respectively [
      • Guenther A.
      • Krauss E.
      • Tello S.
      • et al.
      The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.
      ]. The low rate of referral for pulmonary rehabilitation in the IPF-PRO Registry may partly reflect the limitations of insurance coverage: some insurance providers only reimburse one course of pulmonary rehabilitation, so patients who had undergone pulmonary rehabilitation prior to entering the registry would not have been able to claim for a second course after enrollment. Other possible reasons include patient preference, frailty, or lack of access to a local pulmonary rehabilitation center.
      Our data suggest that 18% of patients did not have documentation of pulmonary function testing within the 6 months after enrollment. This seems high but may partly reflect that some pulmonary function tests performed outside the enrolling center could not be obtained by the registry. In our analyses, 59% of patients had initiated anti-fibrotic therapy before or in the 6 months after enrollment. This is largely consistent with observations made at baseline in other registries [
      • Kreuter M.
      • Swigris J.
      • Pittrow D.
      • et al.
      Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: INSIGHTS-IPF registry.
      ,
      • Holtze C.H.
      • Freiheit E.A.
      • Limb S.L.
      • et al.
      Patient and site characteristics associated with pirfenidone and nintedanib use in the United States; an analysis of idiopathic pulmonary fibrosis patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry.
      ]. Previous analyses of anti-fibrotic drug use in the IPF-PRO Registry suggested that patients with more severe disease were more likely to be treated [
      • Salisbury M.L.
      • Conoscenti C.S.
      • Culver D.A.
      • et al.
      Antifibrotic drug use in patients with IPF: data from the IPF-PRO Registry.
      ].
      GERD is a common comorbidity in patients with IPF and it has been hypothesized that acid reflux may contribute to chronic inflammation and fibrosis of the lungs through microaspiration [
      • Savarino E.
      • Carbone R.
      • Marabotto E.
      • et al.
      Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients.
      ]. As well as patients with IPF who have concomitant GERD, some patients with IPF who do not have GERD take anti-acid therapy [
      • Kreuter M.
      • Wuyts W.
      • Renzoni E.
      • et al.
      Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis.
      ]. In our study, 91% of eligible patients were being treated for GERD. However, the recommendation for treatment of asymptomatic abnormal acid GERD in the ATS/ERS/JRS/ALAT guidelines remains controversial, with no high-quality evidence to support a benefit of anti-acid therapy in slowing the progression of IPF, and an increased risk of infections observed in patients with IPF taking anti-acid therapy [
      • Kreuter M.
      • Wuyts W.
      • Renzoni E.
      • et al.
      Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis.
      ,
      • Johannson K.A.
      • Strâmbu I.
      • Ravaglia C.
      • et al.
      Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?.
      ,
      • Costabel U.
      • Behr J.
      • Crestani B.
      • et al.
      Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS trials.
      ].
      The recommendation for use of oxygen therapy in patients with resting hypoxemia was implemented in three-quarters of the patients in our study. A similar proportion of patients with exercise-induced hypoxemia were using oxygen therapy. Oxygen therapy is recommended in select patients to improve dyspnea, exercise capacity and quality of life [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ,
      • Lim R.K.
      • Humphreys C.
      • Morisset J.
      • Holland A.E.
      • Johannson K.A.
      O2 Delphi Collaborators
      Oxygen in patients with fibrotic interstitial lung disease: an international Delphi survey.
      ] but the evidence to guide its use is limited [
      • Johannson K.
      • Pendharkar S.R.
      • Mathison K.
      • et al.
      Supplemental oxygen in interstitial lung disease: an art in need of science.
      ]. Guidelines recently published by the American Thoracic Society recommended the use of long-term oxygen therapy in patients with ILD and severe chronic resting hypoxemia, and ambulatory oxygen use in patients with ILD and severe exertional hypoxemia [
      • Jacobs S.S.
      • Krishnan J.A.
      • Lederer D.J.
      • et al.
      Home oxygen therapy for adults with chronic lung disease. An official American Thoracic Society Clinical Practice Guideline.
      ]. Ambulatory liquid-oxygen was also recommended for patients who are mobile outside the home and require continuous-flow oxygen during exertion. Some studies have demonstrated an improvement in dyspnea, cough and quality of life in patients with IPF given supplemental oxygen [
      • Duck A.
      • Spencer L.G.
      • Bailey S.
      • et al.
      Perceptions, experiences and needs of patients with idiopathic pulmonary fibrosis.
      ,
      • Visca D.
      • Mori L.
      • Tsipouri V.
      • et al.
      Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial.
      ]. However, the implementation of oxygen therapy can pose practical and psychosocial challenges for patients [
      • Belkin A.
      • Albright K.
      • Swigris J.J.
      A qualitative study of informal caregivers' perspectives on the effects of idiopathic pulmonary fibrosis.
      ,
      • Khor Y.H.
      • Goh N.S.L.
      • McDonald C.F.
      • Holland A.E.
      Oxygen therapy for interstitial lung disease: physicians' perceptions and experiences.
      ,
      • Khor Y.H.
      • Goh N.S.L.
      • McDonald C.F.
      • Holland A.E.
      Oxygen therapy for interstitial lung disease. a mismatch between patient expectations and experiences.
      ].
      In our analyses, 22.3% of patients who were eligible for lung transplant based on a criterion of age <70 years had been referred for evaluation. We selected a single conservative measure for defining eligibility for lung transplant evaluation, but in clinical practice, several factors, including BMI, disease severity, and comorbidities, are likely to be considered prior to referral. Previous studies have demonstrated that many patients with IPF who meet eligibility criteria have not been referred for lung transplant evaluation [
      • Liu Y.
      • Vela M.
      • Rudakevych T.
      • Wigfield C.
      • Garrity E.
      • Saunders M.R.
      Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.
      ] or listed for lung transplant [
      • Behr J.
      • Kreuter M.
      • Hoeper M.M.
      • et al.
      Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.
      ]. In a study of patients with pulmonary fibrosis hospitalized at the University of Chicago Medical Center between 2006 and 2014, 63% of 43 patients who were eligible for transplant had been referred for lung transplant evaluation [
      • Liu Y.
      • Vela M.
      • Rudakevych T.
      • Wigfield C.
      • Garrity E.
      • Saunders M.R.
      Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.
      ]. The reasons for some eligible patients not being referred for lung transplant evaluation are unclear, but the decision on whether to refer a patient may take into consideration many factors, including the patient's preferences and values, current treatment, comorbidities and frailty. It should also be noted that patients already on a lung transplant list were not eligible to be enrolled into the IPF-PRO Registry.
      Few data are available on the association between the implementation of guidelines for the management of IPF and clinical outcomes. A prospective study of 129 adults with IPF found that delayed referral to a tertiary care center was associated with worse outcomes, irrespective of disease severity [
      • Lamas D.J.
      • Kawut S.M.
      • Bagiella E.
      • Philip N.
      • Arcasoy S.M.
      • Lederer D.J.
      Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study.
      ]. More recently, a retrospective study conducted at the University of Alabama (n = 284) found that greater adherence to a bundle of care based on the 2011 ATS/ERS/JRS/ALAT guidelines was associated with improved transplant-free survival when adjusted for age and FVC % predicted at baseline [
      • Kulkarni T.
      • Willoughby J.
      • Acosta Lara Mdel P.
      • et al.
      A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival.
      ]. In this study, the bundle of care comprised visits to a specialized ILD clinic with pulmonary function tests at least twice yearly; referral to pulmonary rehabilitation yearly; timed walk test to screen for hypoxemia yearly; echocardiogram yearly; and GERD therapy. When assessed individually, only fewer clinic visits and more echocardiograms were associated with an increased risk of death or lung transplant [
      • Kulkarni T.
      • Willoughby J.
      • Acosta Lara Mdel P.
      • et al.
      A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival.
      ]. The differences observed between this study and the current study are not clear, but may reflect a higher frequency of clinic visits in the patients in the IPF-PRO Registry.
      Our analyses have a number of limitations. The sites in the IPF-PRO Registry are centers with experience in the management of patients with IPF and may not represent general pulmonary practices in the US. Our analyses were based on referrals and prescriptions based on data extracted from medical records rather than on actual use of therapies. Patients with more severe disease were eligible for more interventions, which may have biased our assessment of implementation. Based on the data that we collected, we are unable to determine the reasons why certain recommendations were or were not implemented for a given patient. Guidelines for the management of IPF need to be complemented with clinical expertise and an understanding of patients' values and preferences in order to provide the best care for an individual patient [
      • Behr J.
      Guidelines or guidance for better idiopathic pulmonary fibrosis management?.
      ]. Use of simple checklists for implementation of management guidelines does not account for the nuanced and individualized care decisions made for patients with IPF in clinical practice and does not equate to quality of care. It is not necessarily the case that non-implementation of a guideline in our study represents a “failure” of the site to adhere to best practice. There may have been legitimate reasons why the guideline was not implemented that are not apparent from the data we collected; for example, referral for lung transplant evaluation or pulmonary rehabilitation may have been discussed with a patient, but the patient chose not to be referred; such a discussion may not be recorded in the patient's medical record. That said, while challenging from a methodological perspective, we regard the evaluation of the degree of implementation of management guidelines for IPF as an important topic, and the finding of generally low implementation of management guidelines in our analyses as of interest.

      7. Conclusions

      Data from the IPF-PRO Registry suggest that there is variation in the implementation of guidelines for the management of IPF. Recommendations made in management guidelines were more likely to be implemented in patients who have greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and the risk of death, lung transplant, or hospitalization.

      Author contributions

      JAdA, MLN, ASH, CSC and LDS contributed to the design of this study. MLN and ASH were involved in the analysis of the data. All authors contributed to the interpretation of the data and the development of the manuscript. All authors approved the final version.

      Funding information

      The IPF-PRO/ILD-PRO™ Registry is funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and co-ordinated by the Duke Clinical Research Institute (DCRI) .

      Availability of data and material

      The datasets analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

      Ethics approval and consent to participate

      The study was approved by the Duke University Institutional Review Board (Pro00046131).
      The protocol was also approved by the relevant Institutional Review Boards and/or local Independent Ethics Committees prior to patient enrolment at each site listed in the Acknowledgments. All patients provided informed consent.

      Declaration of competing interest

      JAdA reports personal fees from BI. TK reports speaker fees from BI. MLN, ASH and LDS are faculty members at DCRI, which receives funding from BIPI to coordinate the IPF-PRO/ILD-PRO Registry. AHC reports personal fees and non-financial support from BI, personal fees from Genentech, and non-financial support from DCRI. KG has nothing to disclose. SB and CSC are employees of BIPI.

      Acknowledgements

      We thank the principal investigators and enrolling centers in the IPF-PRO Registry: Albert Baker, Lynchburg Pulmonary Associates, Lynchburg, VA; Scott Beegle, Albany Medical Center, Albany, NY; John A Belperio, University of California Los Angeles, Los Angeles, CA; Rany Condos, NYU Medical Center, New York, NY; Francis Cordova, Temple University, Philadelphia, PA; Daniel A Culver, Cleveland Clinic, Cleveland, OH; Daniel Dilling, Loyola University Health System, Maywood, IL; John Fitzgerald (formerly Leann Silhan), UT Southwestern Medical Center, Dallas, TX; Kevin R Flaherty, University of Michigan, Ann Arbor, MI; Kevin Gibson, University of Pittsburgh, Pittsburgh, PA; Mridu Gulati, Yale School of Medicine, New Haven, CT; Kalpalatha Guntupalli, Baylor College of Medicine, Houston, TX; Nishant Gupta, University of Cincinnati Medical Center, Cincinnati, OH; Amy Hajari Case, Piedmont Healthcare, Atlanta, GA; David Hotchkin, The Oregon Clinic, Portland, OR; Tristan J Huie, National Jewish Health, Denver, CO; Robert J Kaner, Weill Cornell Medical College, New York, NY; Hyun J Kim, University of Minnesota, Minneapolis, MN; Lisa H Lancaster (formerly Mark Steele), Vanderbilt University Medical Center, Nashville, TN; Joseph A Lasky, Tulane University, New Orleans, LA; Doug Lee, Wilmington Health and PMG Research, Wilmington, NC; Timothy Liesching, Lahey Clinic, Burlington, MA; Randolph Lipchik, Froedtert & The Medical College of Wisconsin Community Physicians, Milwaukee, WI; Jason Lobo, UNC Chapel Hill, Chapel Hill, NC; Tracy R Luckhardt (formerly Joao A de Andrade), University of Alabama at Birmingham, Birmingham, AL; Yolanda Mageto (formerly Howard Huang), Baylor University Medical Center at Dallas, Dallas, TX; Prema Menon (formerly Yolanda Mageto), Vermont Lung Center, Colchester, VT; Lake Morrison, Duke University Medical Center, Durham, NC; Andrew Namen, Wake Forest University, Winston Salem, NC; Justin M Oldham, University of California, Davis, Sacramento, CA; Tessy Paul, University of Virginia, Charlottesville, VA; David Zhang (formerly Anna Podolanczuk, David Lederer, Nina M Patel), Columbia University Medical Center/New York Presbyterian Hospital, New York, NY; Mary Porteous (formerly Maryl Kreider), University of Pennsylvania, Philadelphia, PA; Rishi Raj (formerly Paul Mohabir), Stanford University, Stanford, CA; Murali Ramaswamy, PulmonIx LLC, Greensboro, NC; Tonya Russell, Washington University, St. Louis, MO; Paul Sachs, Pulmonary Associates of Stamford, Stamford, CT; Zeenat Safdar, Houston Methodist Lung Center, Houston, TX; Shirin Shafazand (formerly Marilyn Glassberg), University of Miami, Miami, FL; Ather Siddiqi (formerly Wael Asi), Renovatio Clinical, The Woodlands, TX; Barry Sigal, Salem Chest and Southeastern Clinical Research Center, Winston Salem, NC; Mary E Strek (formerly Imre Noth), University of Chicago, Chicago, IL; Sally Suliman, (formerly Jesse Roman), University of Louisville, Louisville, KY; Jeremy Tabak, South Miami Hospital, South Miami, FL; Rajat Walia, St. Joseph's Hospital, Phoenix, AZ; Timothy PM Whelan, Medical University of South Carolina, Charleston, SC.
      The IPF-PRO/ILD-PRO™ Registry is funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and co-ordinated by the Duke Clinical Research Institute (DCRI) . The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for development of this article. Writing support was provided by Julie Fleming and Wendy Morris of Fleishman-Hillard, London, UK, which was contracted and funded by BIPI. Boehringer Ingelheim was given the opportunity to review the article for medical and scientific accuracy as well as intellectual property considerations.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

      References

        • Raghu G.
        • Remy-Jardin M.
        • Myers J.L.
        • et al.
        Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
        Am. J. Respir. Crit. Care Med. 2018; 198: e44-e68
        • Raghu G.
        • Collard H.R.
        • Egan J.J.
        • et al.
        An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
        Am. J. Respir. Crit. Care Med. 2011; 183: 788-824
        • Raghu G.
        • Rochwerg B.
        • Zhang Y.
        • et al.
        An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.
        Am. J. Respir. Crit. Care Med. 2015; 192: e3-19
        • Kahn J.M.
        • Gould M.K.
        • Krishnan J.A.
        • et al.
        An official American Thoracic Society workshop report: developing performance measures from clinical practice guidelines.
        Ann Am Thorac Soc. 2014; 11: S186-S195
        • O'Brien E.C.
        • Durheim M.T.
        • Gamerman V.
        • et al.
        Rationale for and design of the idiopathic pulmonary fibrosis-PRospective outcomes (IPF-PRO) registry.
        BMJ Open Respir Res. 2016; 3e000108
        • Jones P.W.
        • Quirk F.H.
        • Baveystock C.M.
        The St george's respiratory questionnaire.
        Respir. Med. 1991; 85 (discussion 33–37): 25-31
        • Crawford B.
        • Monz B.
        • Hohlfeld J.
        • Roche N.
        • et al.
        Development and validation of a cough and sputum assessment questionnaire.
        Respir. Med. 2008; 102: 1545-1555
        • Ware Jr., J.
        • Kosinski M.
        • Keller S.D.
        A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity.
        Med. Care. 1996; 34: 220-233
        • Rabin R.
        • de Charro F.
        EQ-5D: a measure of health status from the EuroQol Group.
        Ann. Med. 2001; 33: 337-343
        • Pickard A.S.
        • Neary M.P.
        • Cella D.
        Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.
        Health Qual. Life Outcome. 2007; 5: 70
        • Swigris J.J.
        • Brown K.K.
        • Behr J.
        • et al.
        The SF-36 and SGRQ: validity and first look at minimum important differences in IPF.
        Respir. Med. 2010; 104: 296-304
        • Zanini A.
        • Aiello M.
        • Adamo D.
        • et al.
        Estimation of minimal clinically important difference in EQ-5D visual analog scale score after pulmonary rehabilitation in subjects with COPD.
        Respir. Care. 2015; 60: 88-95
        • Witt S.
        • Krauss E.
        • Barbero M.A.N.
        • et al.
        Psychometric properties and minimal important differences of SF-36 in idiopathic pulmonary fibrosis.
        Respir. Res. 2019; 20: 47
        • Rebelo P.
        • Oliveira A.
        • Paixão C.
        • Valente C.
        • Andrade L.
        • Marques A.
        Minimal clinically important differences for patient-reported outcome measures of cough and sputum in patients with COPD.
        Int. J. Chronic Obstr. Pulm. Dis. 2020; 15: 201-212
        • Ley B.
        • Ryerson C.J.
        • Vittinghoff E.
        • et al.
        A multidimensional index and staging system for idiopathic pulmonary fibrosis.
        Ann. Intern. Med. 2012; 156: 684-691
        • Wells A.U.
        • Desai S.R.
        • Rubens M.B.
        • et al.
        Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.
        Am. J. Respir. Crit. Care Med. 2003; 167: 962-969
        • Behr J.
        • Kreuter M.
        • Hoeper M.M.
        • et al.
        Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.
        Eur. Respir. J. 2015; 46: 186-196
        • Guenther A.
        • Krauss E.
        • Tello S.
        • et al.
        The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.
        Respir. Res. 2018; 19: 141
        • Fernández-Fabrellas E.
        • Molina-Molina M.
        • Soriano J.B.
        • et al.
        Demographic and clinical profile of idiopathic pulmonary fibrosis patients in Spain: the SEPAR national registry.
        Respir. Res. 2019; 20: 127
        • Kreuter M.
        • Swigris J.
        • Pittrow D.
        • et al.
        Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: INSIGHTS-IPF registry.
        Respir. Res. 2017; 18: 139
        • Holtze C.H.
        • Freiheit E.A.
        • Limb S.L.
        • et al.
        Patient and site characteristics associated with pirfenidone and nintedanib use in the United States; an analysis of idiopathic pulmonary fibrosis patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry.
        Respir. Res. 2020; 21: 48
        • Salisbury M.L.
        • Conoscenti C.S.
        • Culver D.A.
        • et al.
        Antifibrotic drug use in patients with IPF: data from the IPF-PRO Registry.
        Ann Am Thorac Soc. 2020; 17: 1413-1423
        • Savarino E.
        • Carbone R.
        • Marabotto E.
        • et al.
        Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients.
        Eur. Respir. J. 2013; 42: 1322-1331
        • Kreuter M.
        • Wuyts W.
        • Renzoni E.
        • et al.
        Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis.
        Lancet Respir Med. 2016; 4: 381-389
        • Johannson K.A.
        • Strâmbu I.
        • Ravaglia C.
        • et al.
        Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?.
        Lancet Respir Med. 2017; 5: 591-598
        • Costabel U.
        • Behr J.
        • Crestani B.
        • et al.
        Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS trials.
        Respir. Res. 2018; 19: 167
        • Lim R.K.
        • Humphreys C.
        • Morisset J.
        • Holland A.E.
        • Johannson K.A.
        • O2 Delphi Collaborators
        Oxygen in patients with fibrotic interstitial lung disease: an international Delphi survey.
        Eur. Respir. J. 2019; 541900421
        • Johannson K.
        • Pendharkar S.R.
        • Mathison K.
        • et al.
        Supplemental oxygen in interstitial lung disease: an art in need of science.
        Ann Am Thorac Soc. 2017; 14: 1373-1377
        • Jacobs S.S.
        • Krishnan J.A.
        • Lederer D.J.
        • et al.
        Home oxygen therapy for adults with chronic lung disease. An official American Thoracic Society Clinical Practice Guideline.
        Am. J. Respir. Crit. Care Med. 2020; 202: e121-e141
        • Duck A.
        • Spencer L.G.
        • Bailey S.
        • et al.
        Perceptions, experiences and needs of patients with idiopathic pulmonary fibrosis.
        J. Adv. Nurs. 2015; 71: 1055-1065
        • Visca D.
        • Mori L.
        • Tsipouri V.
        • et al.
        Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial.
        Lancet Respir Med. 2018; 6: 759-770
        • Belkin A.
        • Albright K.
        • Swigris J.J.
        A qualitative study of informal caregivers' perspectives on the effects of idiopathic pulmonary fibrosis.
        BMJ Open Respir Res. 2014; 1e000007
        • Khor Y.H.
        • Goh N.S.L.
        • McDonald C.F.
        • Holland A.E.
        Oxygen therapy for interstitial lung disease: physicians' perceptions and experiences.
        Ann Am Thorac Soc. 2017; 14: 1772-1778
        • Khor Y.H.
        • Goh N.S.L.
        • McDonald C.F.
        • Holland A.E.
        Oxygen therapy for interstitial lung disease. a mismatch between patient expectations and experiences.
        Ann Am Thorac Soc. 2017; 14: 888-895
        • Liu Y.
        • Vela M.
        • Rudakevych T.
        • Wigfield C.
        • Garrity E.
        • Saunders M.R.
        Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.
        J. Heart Lung Transplant. 2017; 36: 264-271
        • Lamas D.J.
        • Kawut S.M.
        • Bagiella E.
        • Philip N.
        • Arcasoy S.M.
        • Lederer D.J.
        Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study.
        Am. J. Respir. Crit. Care Med. 2011; 184: 842-847
        • Kulkarni T.
        • Willoughby J.
        • Acosta Lara Mdel P.
        • et al.
        A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival.
        Respir. Med. 2016; 115: 33-38
        • Behr J.
        Guidelines or guidance for better idiopathic pulmonary fibrosis management?.
        BMC Med. 2016; 14: 24