Blood lipid profiles as a prognostic biomarker in idiopathic pulmonary fibrosis.

BACKGROUND: Dysregulation of lipid metabolism is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the association between the blood lipid profiles and the prognosis of IPF is not well defined. We aimed to identify the impacts of lipid profiles on prognosis in patients with IPF. METHODS: Clinical data of 371 patients with IPF (145 and 226 in the derivation and validation cohorts, respectively), including serum lipid profiles (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I [Apo A-I], and apolipoprotein B), were retrospectively collected. The association with mortality was analyzed using the Cox proportional hazard model. RESULTS: In the derivation cohort, the mean age was 67.5 years, 86.2% were men, and 30.3% died during the follow-up (median: 18.0 months). Non-survivors showed lower lung function and greater gender-age-physiology scores than survivors. Among the serum lipid profiles, the levels of triglyceride and Apo A-I were significantly lower in non-survivors than in survivors. In the multivariate Cox analysis, low Apo A-I levels (< 140 mg/dL) were independently associated with the risk of mortality (hazard ratio 3.910, 95% confidence interval 1.170-13.069; P = 0.027), when adjusted for smoking history, body mass index, GAP score, and antifibrotic agent use. In both derivation and validation cohorts, patients with low Apo A-I levels (< 140 mg/dL) had worse survival (median survival: [derivation] 34.0 months vs. not reached, P = 0.003; [validation] 40.0 vs. 53.0 months, P = 0.027) than those with high Apo A-I levels in the Kaplan-Meier survival analysis. CONCLUSIONS: Our results indicate that low serum Apo A-1 levels are an independent predictor of mortality in patients with IPF, suggesting the utility of serum Apo A-I as a prognostic biomarker in IPF.

Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 µM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.

Delineating excess comorbidities in idiopathic pulmonary fibrosis: an observational study.

BACKGROUND: Our study examined whether prevalent and incident comorbidities are increased in idiopathic pulmonary fibrosis (IPF) patients when compared to matched chronic obstructive pulmonary disease (COPD) patients and control subjects without IPF or COPD. METHODS: IPF and age, gender and smoking matched COPD patients, diagnosed between 01/01/1997 and 01/01/2019 were identified from the Clinical Practice Research Datalink GOLD database multiple registrations cohort at the first date an ICD-10 or read code mentioned IPF/COPD. A control cohort comprised age, gender and pack-year smoking matched subjects without IPF or COPD. Prevalent (prior to IPF/COPD diagnosis) and incident (after IPF/COPD diagnosis) comorbidities were examined. Group differences were estimated using a t-test. Mortality relationships were examined using multivariable Cox proportional hazards adjusted for patient age, gender and smoking status. RESULTS: Across 3055 IPF patients, 38% had 3 or more prevalent comorbidities versus 32% of COPD patients and 21% of matched control subjects. Survival time reduced as the number of comorbidities in an individual increased (p < 0.0001). In IPF, prevalent heart failure (Hazard ratio [HR] = 1.62, 95% Confidence Interval [CI]: 1.43-1.84, p < 0.001), chronic kidney disease (HR = 1.27, 95%CI: 1.10-1.47, p = 0.001), cerebrovascular disease (HR = 1.18, 95%CI: 1.02-1.35, p = 0.02), abdominal and peripheral vascular disease (HR = 1.29, 95%CI: 1.09-1.50, p = 0.003) independently associated with reduced survival. Key comorbidities showed increased incidence in IPF (versus COPD) 7-10 years prior to IPF diagnosis. INTERPRETATION: The mortality impact of excessive prevalent comorbidities in IPF versus COPD and smoking matched controls suggests that multiorgan mechanisms of injury need elucidation in patients that develop IPF.

The impact of antifibrotic use on long-term clinical outcomes in the pulmonary fibrosis foundation registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib have been in use since 2014 for this disorder and are associated with improved rate of lung function decline. Less is known about their long-term outcomes outside of the clinical trial context. METHODS: The Pulmonary Fibrosis Foundation Patient Registry was used for this study. Patients with an IPF diagnosis made within a year of enrollment were included. The treated group was defined as patients receiving either pirfenidone or nintedanib for at least 180 days. The untreated group did not have any record of antifibrotic use. Demographic data, comorbidities, serial lung function, hospitalization, and vital status data were collected from the registry database. The primary outcomes were transplant-free survival, time to first respiratory hospitalization, and time to 10% absolute FVC decline. Time-to-event analyses were performed utilizing Cox proportional hazards models and the log-rank test. Model covariates included age, gender, smoking history, baseline lung function, comorbidities, and oxygen use. RESULTS: The registry contained 1212 patients with IPF; ultimately 288 patients met inclusion criteria for the treated group, and 101 patients were designated as untreated. Patients treated with antifibrotics were significantly younger (69.8 vs. 72.6 years, p = 0.008) and less likely to have smoked (61.1% ever smokers vs. 72.3% never smokers, p = 0.04). No significant differences were seen in race, gender, comorbidities, or baseline pulmonary function between groups. The primary outcome of transplant-free survival was not significantly different between the two groups (adjusted HR 0.799, 95% CI 0.534-1.197, p = 0.28). Time to respiratory hospitalization was significantly shorter in the treated group (adjusted HR 2.12, 95% CI 1.05-4.30, p = 0.04). No significant difference in time to pulmonary function decline was seen between groups. CONCLUSIONS: This multicenter study demonstrated 63% of newly diagnosed IPF patients had continuous antifibrotic usage. Antifibrotics were not associated with improved transplant-free survival or pulmonary function change but was associated with an increased hazard of respiratory hospitalization. Future studies should further investigate the role of antifibrotic therapy in clinically important outcomes in real-world patients with IPF and other progressive ILDs.

Computed tomography machine learning classifier correlates with mortality in interstitial lung disease.

BACKGROUND: A machine learning classifier system, Fibresolve, was designed and validated as an adjunct to non-invasive diagnosis in idiopathic pulmonary fibrosis (IPF). The system uses a deep learning algorithm to analyze chest computed tomography (CT) imaging. We hypothesized that Fibresolve is a useful predictor of mortality in interstitial lung diseases (ILD). METHODS: Fibresolve was previously validated in a multi-site >500-patient dataset. In this analysis, we assessed the usefulness of Fibresolve to predict mortality in a subset of 228 patients with IPF and other ILDs in whom follow up data was available. We applied Cox regression analysis adjusting for the Gender, Age, and Physiology (GAP) score and for other known predictors of mortality in IPF. We also analyzed the role of Fibresolve as tertiles adjusting for GAP stages. RESULTS: During a median follow-up of 2.8 years (range 5 to 3434 days), 89 patients died. After adjusting for GAP score and other mortality risk factors, the Fibresolve score significantly predicted the risk of death (HR: 7.14; 95% CI: 1.31-38.85; p = 0.02) during the follow-up period, as did forced vital capacity and history of lung cancer. After adjusting for GAP stages and other variables, Fibresolve score split into tertiles significantly predicted the risk of death (p = 0.027 for the model; HR 1.37 for 2nd tertile; 95% CI: 0.77-2.42. HR 2.19 for 3rd tertile; 95% CI: 1.22-3.93). CONCLUSIONS: The machine learning classifier Fibresolve demonstrated to be an independent predictor of mortality in ILDs, with prognostic performance equivalent to GAP based solely on CT images.

Machine learning classifier is associated with mortality in interstitial lung disease: a retrospective validation study leveraging registry data.

BACKGROUND: Mortality prediction in interstitial lung disease (ILD) poses a significant challenge to clinicians due to heterogeneity across disease subtypes. Currently, forced vital capacity (FVC) and Gender, Age, and Physiology (GAP) score are the two most utilized metrics in prognostication. Recently, a machine learning classifier system, Fibresolve, designed to identify a variety of computed tomography (CT) patterns associated with idiopathic pulmonary fibrosis (IPF), was demonstrated to have a significant association with mortality across multiple subtypes of ILD. The purpose of this follow-up study was to retrospectively validate these findings in a large, external cohort of patients with ILD. METHODS: In this multi-center validation study, Fibresolve was applied to chest CT scans of patients with confirmed ILD that had available follow-up data. Fibresolve scores categorized by tertile were analyzed using Cox regression analysis adjusted for tobacco use and modified GAP (mGAP) score. RESULTS: Of 643 patients included, 446 (69.3%) died over a median follow-up time of 144 [1-821] weeks. The median [range] mGAP score was 5 [3-7]. In multivariable analysis, Fibresolve score categorized by tertile was significantly associated with mortality (Tertile 2 HR 1.47, 95% CI 0.82-2.37, p = 0.11; Tertile 3 HR 3.12, 95% CI 1.98-4.90, p < 0.001). Subgroup analyses revealed significant associations amongst those with non-IPF ILDs (Tertile 2 HR 1.95, 95% CI 1.28-2.97, Tertile 3 HR 4.66, 95% CI 2.94-7.38) and severe disease, defined by a FVC ≤ 75% (Tertile 2 HR 2.29, 95% CI 1.43-3.67, Tertile 3 HR 4.80, 95% CI 2.93-7.86). CONCLUSIONS: Fibresolve is independently associated with mortality in ILD, particularly amongst patients with non-IPF ILDs and in those with severe disease.

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study.

BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

Body mass index is associated with clinical outcomes in idiopathic pulmonary fibrosis.

Association between body mass index (BMI) and prognosis in patients with idiopathic pulmonary fibrosis (IPF) remains uncertain. We investigated the association between BMI and clinical outcomes in patients with IPF using national health claims data. The study included 11,826 patients with IPF and rare incurable disease exemption codes (mean age: 68.9 years, male: 73.8%) and available BMI data who visited medical institutions between January 2002 and December 2018. Multivariable Cox proportional hazard models were used to evaluate the association of BMI with all-cause mortality and hospitalization. Based on BMI, 3.1%, 32.8%, 27.8%, and 36.4% were classified as underweight, normal, overweight, and obese, respectively. Multivariable analysis showed independent associations of overweight (hazard ratio [HR] 0.856, 95% confidence interval [CI] 0.801-0.916) and underweight (HR 1.538, 95% CI 1.347-1.757) with mortality in patients with IPF. Similarly, overweight (HR 0.887, 95% CI 0.834-0.943) and underweight (HR 1.265, 95% CI 1.104-1.449) were also associated with hospitalization in patients with IPF in the multivariable analysis. Spline HR curve analysis adjusted for all covariates revealed a non-linear relationship between BMI and mortality in patients with IPF. Our data suggest that BMI is associated with clinical outcomes in patients with IPF.

Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in England from 2008 to 2018: a cohort study.

BACKGROUND: Owing to discrepancies in methodologies and how idiopathic pulmonary fibrosis (IPF) is diagnosed it is challenging to establish a consistent understanding of the disease burden In the UK, over 10 years ago, the incidence and prevalence of IPF were reported as 2.8-8.7 per 100 000 person-years (from 2000 to 2012) and 39 per 100 000 persons (in 2012), respectively. Here, we estimated the incidence and prevalence of IPF in England from 2008 to 2018 and investigated IPF mortality. METHODS: Using Clinical Practice Research Datalink Aurum and Hospital Episode Statistics (HES) linked datasets, we estimated incidence and prevalence using four validated diagnostic-code-based algorithms. Using the registered number of deaths (from Office of National Statistics) with the underlying cause being recorded as IPF, we estimated IPF mortality for the same period. RESULTS: Using Aurum-based definitions, incidence increased over time by 100% for Aurum narrow (3-6.1 per 100 000 person-years) and by 25% for Aurum broad (22.4-28.6 per 100 000 person-years). However, using HES-based definitions showed a decrease in incidence over the same period and lay between the two extremes derived for Aurum-based definition. IPF mortality in 2018 was 7.9 per 100 000 person-years and increased by 53% between 2008 and 2018. INTERPRETATION: When using best-case definitions, incidence rose throughout the study period. Scaling this to England's population (2018), our best estimate would be in the range of 8000-9000 new cases per year which is higher than previously reported estimates (5000-6000). This increased burden in the new cases of IPF each year impacts future health service planning and resource allocation.

Body weight loss is a simple and useful indicator of prognosis and predictive tolerability in the first year of nintedanib therapy in patients with interstitial lung disease.

BACKGROUND: Nintedanib is generally safe and well tolerated and can improve prognosis in patients with various interstitial lung diseases (ILDs). Appropriate management of adverse events of nintedanib is important to ensure its long-term persistent use. Weight loss is a routinely assessed adverse event in clinical practice. This study aimed to elucidate whether body weight change in the first year of nintedanib therapy can indicate prognosis and predict tolerability in patients with ILD. METHODS: We analysed 245 consecutive ILD patients treated with nintedanib. We calculated the slope of body weight change using baseline weight and that recorded closest after the first year and then categorized percent change in body weight at this time. Significant weight loss was defined as that ≥5%. RESULTS: Subjects included 67 patients with idiopathic pulmonary fibrosis (IPF) and 76 with non-IPF progressive fibrosing-ILD including fibrotic hypersensitivity pneumonitis (n = 16), unclassifiable (n = 35), connective tissue disease-ILD (n = 21), and nonspecific interstitial pneumonia (n = 4). Older age, low body weight at initial examination, significant weight loss, and lower %FVC were significant predictors of discontinuation of nintedanib. Patients with weight loss ≥5% over the first year showed worse survival than those with weight loss <5% regardless of whether IPF existed or BMI indicated obesity. CONCLUSIONS: Careful monitoring of body weight change might suggest useful information for predicting long-term use of nintedanib and mortality risk in ILD patients treated with nintedanib. Appropriate body weight management is needed to prevent adverse events of nintedanib itself.

Presence of focal usual interstitial pneumonia is a key prognostic factor in progressive pulmonary fibrosis.

AIMS: Progressive pulmonary fibrosis (PPF) is a newly recognised clinical phenotype of interstitial lung diseases in the 2022 interstitial pulmonary fibrosis (IPF) guidelines. This category is based entirely on clinical and radiological factors, and the background histopathology is unknown. Our objective was to investigate the histopathological characteristics of PPF and to examine the correlation between usual interstitial pneumonia (UIP) and prognosis in this new disease type. We hypothesised that the presence of UIP-like fibrosis predicts patients' survival in PPF cases. METHODS AND RESULTS: We selected 201 cases fulfilling the clinical criteria of PPF from case archives. Cases diagnosed as IPF by a multidisciplinary team were excluded. Whole slide images were evaluated by three pathologists who were blinded to clinical and radiological data. We measured areas of UIP-like fibrosis and calculated what percentage of the total lesion area they occupied. The presence of focal UIP-like fibrosis amounting to 10% or more of the lesion area was seen in 148 (73.6%), 168 (83.6%) and 165 (82.1%) cases for each pathologist, respectively. Agreement of the recognition of UIP-like fibrosis in PPF cases was above κ = 0.6 between all pairs. Survival analysis showed that the presence of focal UIP-like fibrosis correlated with worsened survival under all parameters tested (P < 0.001). CONCLUSIONS: The presence of UIP-like fibrosis is a core pathological feature of clinical PPF, and its presence within diseased areas is associated with poorer prognosis. This study highlights the importance of considering the presence of focal UIP-like fibrosis in the evaluation and management of PPF.

Smoking status and clinical outcome in idiopathic pulmonary fibrosis: a nationwide study.

BACKGROUND: Smoking status has been linked to the development of idiopathic pulmonary fibrosis (IPF). However, the effect of smoking on the prognosis of patients with IPF is unclear. We aimed to investigate the association between smoking status and all-cause mortality or hospitalisation by using national health claims data. METHODS: IPF cases were defined as people who visited medical institutions between January 2002 and December 2018 with IPF and rare incurable disease exempted calculation codes from the National Health Insurance Database. Total 10,182 patients with available data on smoking status were included in this study. Ever-smoking status was assigned to individuals with a history of smoking ≥ 6 pack-years. The multivariable Cox proportional hazard model was used to evaluate the association between smoking status and prognosis. RESULTS: In the entire cohort, the mean age was 69.4 years, 73.9% were males, and 45.2% were ever smokers (current smokers: 14.2%; former smokers: 31.0%). Current smokers (hazard ratio [HR]: 0.709; 95% confidence interval [CI]: 0.643-0.782) and former smokers (HR: 0.926; 95% CI: 0.862-0.996) were independently associated with all-cause mortality compared with non-smokers. Current smokers (HR: 0.884; 95% CI: 0.827-0.945) and former smokers (HR: 0.909; 95% CI: 0.862-0.959) were also associated with a reduced risk of all-cause hospitalisation compared with non-smokers. A non-linear association between smoking amount and prognosis was found in a spline HR curve and showed increasing risk below 6 pack-years. CONCLUSION: Ever-smoking status may be associated with favourable clinical outcomes in patients with IPF.

Assessment of the impact of social deprivation, distance to hospital and time to diagnosis on survival in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive condition associated with a variable prognosis. The relationship between socioeconomic status or distance travelled to respiratory clinics and prognosis is unclear. RESEARCH QUESTION: To determine whether socioeconomic status, distance to hospital and time to referral affects survival in patients with IPF. STUDY DESIGN AND METHODS: In this retrospective cohort study, we used data collected from the British Thoracic Society Interstitial Lung Diseases Registry, between 2013 and 2021 (n = 2359) and calculated the quintile of Index of Multiple Deprivation 2019 score, time from initial symptoms to hospital attendance and distance as the linear distance between hospital and home post codes. Survival was assessed using Cox proportional hazards models. RESULTS: There was a significant association between increasing quintile of deprivation and duration of symptoms prior to hospital presentation, Gender Age Physiology (GAP) index and receipt of supplemental oxygen and antifibrotic therapies at presentation. The most deprived patients had worse overall survival compared to least deprived after adjusting for smoking status, GAP index, distance to hospital and time to referral (HR = 1.39 [1.11, 1.73]; p = 0.003). Patients living furthest from a respiratory clinic also had worse survival compared to those living closest (HR = 1.29 [1.01, 1.64]; p = 0.041). INTERPRETATION: The most deprived patients with IPF have more severe disease at presentation and worse outcomes. Living far from hospital was also associated with poor outcomes. This suggests inequalities in access to healthcare and requires consideration in delivering effective and equitable care to patients with IPF.

Antifibrotic treatment adherence, efficacy and outcomes for patients with idiopathic pulmonary fibrosis in Spain: a real-world evidence study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare disorder associated with increased mortality and morbidity. There are currently two drugs approved for IPF but their safety and efficacy profile in real-world settings in Spain is not well understood. METHODS: An observational, multicentre, prospective study was carried out among patients with IPF who started treatment with pirfenidone or nintedanib from 2015 to 2021. Data regarding clinical characteristics, drug adherence, safety profiles and clinical outcomes between these two drugs were collected. RESULTS: 232 patients were included in the analysis. There were no meaningful differences between both groups at baseline. Patients who started pirfenidone showed a decreased risk for treatment withdrawal compared with those starting nintedanib (HR 0.65 (95% CI 0.46 to 0.94; p=0.002)). Time to first adverse event and all-cause mortality was similar between study groups. Risk factors for withdrawal were female sex, diarrhoea and photosensitivity. CONCLUSIONS: in this real-world study, both pirfenidone and nintedanib showed similar efficacy profiles. Pirfenidone was associated with less treatment discontinuations due to side effects.

Impact of surgical lung biopsy on lung function and survival in patients with idiopathic pulmonary fibrosis in a multi-centre registry cohort.

BACKGROUND AND OBJECTIVE: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis. METHODS: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB. RESULTS: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both). CONCLUSION: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF.

Impact of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplant Outcomes.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are acute, significant respiratory deteriorations in patients with IPF and can lead to increased morbidity and mortality. It remains unclear how AE-IPF impacts lung transplant (LTX) outcomes. METHODS: All adult patients who were listed for LTX between July 2005 and October 2020 at the Loyola University Medical Center with a diagnosis of IPF were included. Pretransplant characteristics and posttransplant outcomes were gathered via retrospective chart review. The primary outcome was short- and long-term survival for patients transplanted during stable IPF versus those with AE-IPF. RESULTS: One hundred fifty-nine patients were included in this study, 17.6% of whom were transplanted during AE-IPF. AE-IPF patients were more likely to have higher oxygen needs pretransplant, have higher lung allocation score, and were more likely to be intubated or be on extracorporeal membrane oxygenation as compared with stable IPF patients. Survival by AE status at transplant did not differ at 90 d or 1 y posttransplantation. There were also no significant differences in rates of severe primary graft dysfunction or acute rejection within 1 y. CONCLUSIONS: Patients with AE-IPF were more likely to have higher oxygenation requirements and higher lung allocation score at the time of LTX than those with stable IPF. Despite this, there were no differences in survival at 90 d, 1 y, or 3 y, or differences in incidence of severe primary graft dysfunction or acute cellular rejection. Transplantation of patients with AE-IPF has clinical outcomes comparable with transplantation of patients with stable IPF. This contrasts with previous studies examining LTX in patients with AE-IPF.

Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes.

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset (n = 2,143) and tested it in three independent populations: data from a prior publication (n = 127), a single-institution clinical cohort (n = 239), and a national registry of patients with pulmonary fibrosis (n = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [n = 127] and 0.79 [n = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality (n = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P < 0.001; and n = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n = 979; P < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Deep learning-based prognostication in idiopathic pulmonary fibrosis using chest radiographs.

OBJECTIVES: To develop and validate a deep learning-based prognostic model in patients with idiopathic pulmonary fibrosis (IPF) using chest radiographs. METHODS: To develop a deep learning-based prognostic model using chest radiographs (DLPM), the patients diagnosed with IPF during 2011-2021 were retrospectively collected and were divided into training (n = 1007), validation (n = 117), and internal test (n = 187) datasets. Up to 10 consecutive radiographs were included for each patient. For external testing, three cohorts from independent institutions were collected (n = 152, 141, and 207). The discrimination performance of DLPM was evaluated using areas under the time-dependent receiver operating characteristic curves (TD-AUCs) for 3-year survival and compared with that of forced vital capacity (FVC). Multivariable Cox regression was performed to investigate whether the DLPM was an independent prognostic factor from FVC. We devised a modified gender-age-physiology (GAP) index (GAP-CR), by replacing DLCO with DLPM. RESULTS: DLPM showed similar-to-higher performance at predicting 3-year survival than FVC in three external test cohorts (TD-AUC: 0.83 [95% CI: 0.76-0.90] vs. 0.68 [0.59-0.77], p < 0.001; 0.76 [0.68-0.85] vs. 0.70 [0.60-0.80], p = 0.21; 0.79 [0.72-0.86] vs. 0.76 [0.69-0.83], p = 0.41). DLPM worked as an independent prognostic factor from FVC in all three cohorts (ps < 0.001). The GAP-CR index showed a higher 3-year TD-AUC than the original GAP index in two of the three external test cohorts (TD-AUC: 0.85 [0.80-0.91] vs. 0.79 [0.72-0.86], p = 0.02; 0.72 [0.64-0.80] vs. 0.69 [0.61-0.78], p = 0.56; 0.76 [0.69-0.83] vs. 0.68 [0.60-0.76], p = 0.01). CONCLUSIONS: A deep learning model successfully predicted survival in patients with IPF from chest radiographs, comparable to and independent of FVC. CLINICAL RELEVANCE STATEMENT: Deep learning-based prognostication from chest radiographs offers comparable-to-higher prognostic performance than forced vital capacity. KEY POINTS: • A deep learning-based prognostic model for idiopathic pulmonary fibrosis was developed using 6063 radiographs. • The prognostic performance of the model was comparable-to-higher than forced vital capacity, and was independent from FVC in all three external test cohorts. • A modified gender-age-physiology index replacing diffusing capacity for carbon monoxide with the deep learning model showed higher performance than the original index in two external test cohorts.