non-IPF Interstitial Lung Disease Research Articles

A comparative study to evaluate factors affecting adverse outcomes in interstitial lung diseases with Idiopathic pulmonary fibrosis (IPF) and other non-IPF interstitial lung diseases at 6 months in a tertiary care centre

A comparative study to evaluate factors affecting adverse outcomes in interstitial lung diseases with Idiopathic pulmonary fibrosis (IPF) and other non-IPF interstitial lung diseases at 6 months in a tertiary care centre

Epidemiology and Prognostic Significance of Cough in Fibrotic Interstitial Lung Disease.

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objective: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100mm-Cough Severity Visual Analog Scale (VAS) from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF (n=1061) had higher median baseline cough severity than those with non-IPF fibrotic ILD (n=2825) [24 vs 20mm, p<0.001], with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in DLCO, development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2mm, 95% CI 1.6-2.9mm) had larger annualized increments in cough severity compared to the non-IPF fibrotic ILD cohort (1.1mm, 95% CI 0.8-1.4mm; p=0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusion: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

Clinical characteristics and outcome of lung cancer in patients with fibrosing interstitial lung disease

BackgroundLung cancer (LC) is an important comorbidity of interstitial lung disease (ILD) and has a poor prognosis. The clinical characteristics and outcome of each ILD subtype in LC patients have not been sufficiently investigated. Therefore, this study aimed to evaluate the difference between idiopathic pulmonary fibrosis (IPF) and non-IPF ILD as well as prognostic factors in patients with ILD-LC.MethodsThe medical records of 163 patients diagnosed with ILD-LC at Asan Medical Center from January 2018 to May 2023 were retrospectively reviewed. Baseline characteristics and clinical outcomes were compared between the IPF-LC and non-IPF ILD-LC groups, and prognostic factors were analyzed using the Cox proportional-hazard model.ResultsThe median follow-up period was 11 months after the cancer diagnosis. No statistically significant differences were observed in clinical characteristics and mortality rates (median survival: 26 vs. 20 months, p = 0.530) between the groups. The independent prognostic factors in patients with ILD-LC were higher level of Krebs von den Lungen-6 (≥ 1000 U/mL, hazard ratio [HR] 1.970, 95% confidence interval [CI] 1.026-3.783, p = 0.025) and advanced clinical stage of LC (compared with stage I, HR 3.876 for stage II, p = 0.025, HR 5.092 for stage III, p = 0.002, and HR 5.626 for stage IV, p = 0.002). In terms of treatment, surgery was the significant factor for survival (HR 0.235; 95% CI 0.106-0.520; p < 0.001).ConclusionsNo survival difference was observed between IPF-LC and non-IPF ILD-LC patients. A higher level of Krebs von den Lungen-6 may act as a prognostic marker in ILD-LC patients.

A multidimensional classifier to support lung transplant referral in patients with pulmonary fibrosis

BackgroundLung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die prior to transplant. Tools to optimize the timing of transplant referral are urgently needed. MethodsLeast absolute shrinkage and selection operator (LASSO) was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multi-dimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model fitted values were dichotomized at the point of maximal sensitivity and specificity and decision curve analysis used to select the best performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18-32 to increase likelihood of transplant eligibility. ResultsIPF derivation, IPF validation and non-IPF ILD validation cohorts consisted of 314, 105 and 295 patients, respectively. A multi-dimensional model comprising two clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multi-dimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort. ConclusionsA multi-dimensional classifier of near-term outcome accurately discriminated this endpoint with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant eligible individuals.

Clinical manifestations and prognostic factors analysis of patients hospitalised with acute exacerbation of idiopathic pulmonary fibrosis and other interstitial lung diseases

BackgroundAcute exacerbation (AE) is a life-threatening condition taking place not only in idiopathic pulmonary fibrosis (IPF) but also in interstitial lung diseases (ILD) other than IPF (non-IPF ILD). This study...

Use of 6-minute walk distance to predict lung transplant-free survival in fibrosing non-IPF interstitial lung diseases.

The identification of progression in patients with fibrosing non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs) represents an ongoing clinical challenge. Lung function decline alone may have significant limitations in the detection of clinically significant progression. We hypothesized that longitudinal changes of 6-min walk distance (6MWD) from baseline, simultaneously considered with measures of lung function, may independently predict survival and identifying clinically significant progression of disease. Forced vital capacity (FVC), diffusing lung capacity (DLCO) and 6MWD were considered both at baseline and at 1 year in a discovery cohort (n = 105) and in a validation cohort (n = 138) from different centres. The primary endpoint was lung transplant (LTx)-free survival. Average follow-up was 3 years in both cohorts. Combined incidence of deaths and LTx was 29% and 21%, respectively. No collinearity and no strong correlations were observed among FVC, DLCO and 6MWD longitudinal changes. While age, gender and BMI were not significant, 6MWD decline ≥24 m predicted LTx-free-survival significantly and independently from FVC and DLCO declines, with high sensitivity and specificity, in both the discovery and the validation cohorts. Although FVC and DLCO declines remained significant predictors of LTx-free survival, 6MWD decline was more accurate than the proposed ATS/ERS/JRS/ALAT functional criteria. Results were confirmed after stratifying patients by baseline FVC. Longitudinal declines of 6MWD are associated with poor survival in fibrosing ILDs across a wide range of baseline severity, with high accuracy. 6MWD longitudinal decline is largely independent from lung function decline and may be integrated into the routine assessment of progression.

Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease.

Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD). A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure. The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. fHP and uILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26-10.92; p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (discovery pinteraction=0.013; replication pinteraction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for CTD-ILD. Similar to IPF, fHP and uILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

Clinical Impact of Physical Activity and Cough on Disease Progression in Fibrotic Interstitial Lung Disease.

Physical activity limitations and cough are common in patients with interstitial lung disease (ILD), potentially leading to reduced health-related quality of life. We aimed to compare physical activity and cough between patients with subjective, progressive idiopathic pulmonary fibrosis (IPF) and fibrotic non-IPF ILD. In this prospective observational study, wrist accelerometers were worn for seven consecutive days to track steps per day (SPD). Cough was evaluated using a visual analog scale (VAScough) at baseline and weekly for six months. We included 35 patients (IPF: n = 13; non-IPF: n = 22; mean ± SD age 61.8 ± 10.8 years; FVC 65.3 ± 21.7% predicted). Baseline mean ± SD SPD was 5008 ± 4234, with no differences between IPF and non-IPF ILD. At baseline, cough was reported by 94.3% patients (mean ± SD VAScough 3.3 ± 2.6). Compared to non-IPF ILD, patients with IPF had significantly higher burden of cough (p = 0.020), and experienced a greater increase in cough over six months (p = 0.009). Patients who died or underwent lung transplantation (n = 5), had significantly lower SPD (p = 0.007) and higher VAScough (p = 0.047). Long-term follow up identified VAScough (HR: 1.387; 95%-CI 1.081-1.781; p = 0.010) and SPD (per 1000 SPD: HR 0.606; 95%-CI: 0.412-0.892; p = 0.011) as significant predictors for transplant-free survival. In conclusion, although activity didn't differ between IPF and non-IPF ILD, cough burden was significantly greater in IPF. SPD and VAScough differed significantly in patients who subsequently experienced disease progression and were associated with long-term transplant-free survival, calling for better acknowledgement of both parameters in disease management.

Serum Progranulin Level Might Differentiate Non-IPF ILD from IPF.

Diagnosing interstitial lung disease (ILD) can be a challenging process. New biomarkers may support diagnostic decisions. Elevated serum progranulin (PGRN) levels have been reported in liver fibrosis and dermatomyositis-associated acute interstitial pneumonia. Our aim was to assess the role of PGRN in the differential diagnosis of idiopathic pulmonary fibrosis (IPF) and other ILDs. Serum levels of PGRN were measured by enzyme-linked immunosorbent assay in stable IPF (n = 40), non-IPF ILD (n = 48) and healthy controls (n = 17). Patient characteristics, lung function, CO diffusion (DLCO), arterial blood gases, 6-min walk test, laboratory parameters and high-resolution (HR)CT pattern were assessed. In stable IPF, PGRN levels did not differ from healthy controls; however, serum PGRN levels were significantly higher in non-IPF ILD patients compared to healthy subjects and IPF (53.47 ± 15.38 vs. 40.99 ± 5.33 vs. 44.66 ± 7.77 ng/mL respectively; p < 0.01). The HRCT pattern of usual interstitial pneumonia (UIP) was associated with normal PGRN level, while for non-UIP patterns, significantly elevated PGRN level was measured. Elevated serum PGRN levels may be associated with non-IPF ILD, especially non-UIP patterns and might be helpful in cases of unclear radiological patterns in the differentiation between IPF and other ILDs.

Expanded T regulatory cells fail to control germinal center responses in the lung lymph nodes of pulmonary fibrosis patients

Abstract Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung diseases (ILD), which is characterized by progressive scarring of the lung. While immune suppression is a viable therapeutic option for many ILDs, it is detrimental in IPF. Nevertheless, enlargement of lung-draining lymph nodes (LLN) is prevalent and predicts survival outcomes in all ILD patients, including IPF, suggesting that there is also an immune component to IPF pathogenesis. To test this hypothesis, we investigated the cellular composition of the LLN in IPF and non-IPF ILD patients. All ILD patients’ LLN had increased germinal centers (GC), implicating that immune responses are not being resolved. As T regulatory cells (Tregs) are key in the control and resolution of immune responses, we investigated the phenotype of Tregs in the LLN of both IPF and non-IPF ILD patients to reveal their role in lung fibrosis. Tregs were expanded in LLN of all ILD patients compared to controls. Interestingly, there was a predominance of GATA3-expressing Tregs in ILD patients’ LLN. However, Tregs of ILD patients expressed significantly elevated levels of ICOS and CD137 compared to controls, indicating recent activation. Surprisingly, CD25 expression was significantly lower on Tregs from ILD patients’ LLN. Sc-RNAseq confirms similar Treg phenotypes in the lungs of IPF patients. In a mouse model of bleomycin-induced pulmonary fibrosis, Tregs expand and display a similar activated phenotype. Preliminary experiments suggest that GATA3 expression in Tregs is detrimental in this model. Together, these data indicate that there are unresolved GC responses in the LLN of all ILD patients, including IPF, and suggest that Tregs are ineffectual at controlling the GC response. American Heart Association Postdoctoral Fellowship, Award number (835938)

Exertional Desaturation Is More Severe in Idiopathic Pulmonary Fibrosis Than in Other Interstitial Lung Diseases.

Interstitial lung disease (ILD) is classified into several disease groups. Among them, idiopathic pulmonary fibrosis (IPF) has higher incidence and poor prognosis; therefore, it is important to characterize specific IPF symptoms. Exercise desaturation is a strong factor related to mortality in patients with ILD. Thus, the purpose of this study was to compare the degree of oxygen desaturation between IPF and other ILD (non-IPF ILD) patients during exercise, using the 6-minute walk test (6MWT). This retrospective study included 126 stable patients with ILD who underwent 6MWT in our outpatient department. The 6MWT was used to assess desaturation during exercise, 6-minute walk distance (6MWD), and dyspnea at the end of exercise. In addition, patient characteristics and pulmonary function test results were recorded. Study subjects were divided into 51 IPF patients and 75 non-IPF ILD patients. The IPF group had significantly lower nadir oxygen saturation determined by pulse oximetry (SpO2) during 6MWT than the non-IPF ILD group (IPF, 86.5 ± 4.6%; non-IPF ILD, 88.7 ± 5.3%; p = 0.02). The significant association between the nadir SpO2 and IPF or non-IPF ILD grouping remained even after adjusting for gender, age, body mass index, lung function, 6MWD, and dyspnea (β = -1.62; p <0.05). Even after adjusting for confounding factors, IPF patients had lower nadir SpO2 during 6MWT. Early assessment of exercise desaturation using the 6MWT may be more important in patients with IPF compared with patients with other ILDs.

Multi-scale, domain knowledge-guided attention + random forest: a two-stage deep learning-based multi-scale guided attention models to diagnose idiopathic pulmonary fibrosis from computed tomography images.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and usually fatal lung disease of unknown reasons, generally affecting the elderly population. Early diagnosis of IPF is crucial for triaging patients' treatment planning into anti-fibrotic treatment or treatments for other causes of pulmonary fibrosis. However, current IPF diagnosis workflow is complicated and time-consuming, which involves collaborative efforts from radiologists, pathologists, and clinicians and it is largely subject to inter-observer variability. The purpose of this work is to develop a deep learning-based automated system that can diagnose subjects with IPF among subjects with interstitial lung disease (ILD) using an axial chest computed tomography (CT) scan. This work can potentially enable timely diagnosis decisions and reduce inter-observer variability. Our dataset contains CT scans from 349 IPF patients and 529 non-IPF ILD patients. We used 80% of the dataset for training and validation purposes and 20% as the holdout test set. We proposed a two-stage model: at stage one, we built a multi-scale, domain knowledge-guided attention model (MSGA) that encouraged the model to focus on specific areas of interest to enhance model explainability, including both high- and medium-resolution attentions; at stage two, we collected the output from MSGA and constructed a random forest (RF) classifier for patient-level diagnosis, to further boost model accuracy. RF classifier is utilized as a final decision stage since it is interpretable, computationally fast, and can handle correlated variables. Model utility was examined by (1) accuracy, represented by the area under the receiver operating characteristic curve (AUC) with standard deviation (SD), and (2) explainability, illustrated by the visual examination of the estimated attention maps which showed the important areas for model diagnostics. During the training and validation stage, we observe that when we provide no guidance from domain knowledge, the IPF diagnosis model reaches acceptable performance (AUC±SD=0.93±0.07), but lacks explainability; when including only guided high- or medium-resolution attention, the learned attention maps are not satisfactory; when including both high- and medium-resolution attention, under certain hyperparameter settings, the model reaches the highest AUC among all experiments (AUC±SD=0.99±0.01) and the estimated attention maps concentrate on the regions of interests for this task. Three best-performing hyperparameter selections according to MSGA were applied to the holdout test set and reached comparable model performance to that of the validation set. Our results suggest that, for a task with only scan-level labels available, MSGA+RF can utilize the population-level domain knowledge to guide the training of the network, which increases both model accuracy and explainability.

Trajectories and Prognostic Significance of 6-Minute Walk Test Parameters in Fibrotic Interstitial Lung Disease: A Multicenter Study

Functional capacity, as measured by the 6-min walk test (6MWT), is often reduced in fibrotic interstitial lung disease (ILD). This study evaluated longitudinal changes and the prognostic significance of 6MWT parameters, and explored change in oxygenation status as a physiological criterion to define disease progression in patients with fibrotic ILD. What are the trajectories and prognostic value of 6MWT parameters in patients with fibrotic ILD? Using prospective registries in Australia and Canada, patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD were stratified by the presence of criteria for progressive pulmonary fibrosis (PPF). The cumulative incidence of exertional and resting hypoxemia and changes in 6-min walk distance (6MWD) and composite indices (distance-saturation product and distance-saturation-oxygen product) were determined, with prognostic significance evaluated at the time of meeting criteria for PPF. New-onset exertional or resting hypoxemia was evaluated as another potential criterion for PPF. Patients with IPF/PPF (n= 126) and non-IPF/PPF (n= 227) had a similar cumulative incidence of exertional hypoxemia and annualized decline in 6MWD and composite indices, which varied across each PPF criterion. Patients with IPF/non-PPF (n= 231) and non-IPF/non-PPF (n= 531) had a significantly lower incidence of hypoxemia than those with IPF/PPF, with an annualized increase in 6MWD and composite indices in the non-IPF/non-PPF group. Exertional or resting hypoxemia at the time of meeting criteria for PPF was independently associated with reduced transplant-free survival in IPF and non-IPF, adjusting for patient demographics and lung function. Adding new-onset exertional or resting hypoxemia as a physiological criterion reduced the median time to development of PPF from 11.2 to 6.7months in IPF and from 11.7 to 5.6months in non-IPF in patients who eventually met both definitions (P< .001 for both). Patients with IPF/PPF and non-IPF/PPF have comparable deterioration in functional capacity. Oxygenation status provides prognostic information in PPF and may assist in defining disease progression in fibrotic ILD.

Epidemiology and real-life experience in progressive pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), characterized by relentless disease progression from the time of diagnosis, is part of a larger group of chronic fibrosing interstitial lung diseases (ILDs). A proportion of patients with non-IPF ILDs may develop, despite conventional treatment, a progressive pulmonary fibrosis (PPF), also referred to as ILD with a progressive fibrosing phenotype (PF-ILD). These patients experience worsening of respiratory symptoms, decline in lung function, and early mortality. The goal of this review is to describe the epidemiology and recent real-life cohorts of PF-ILD, with implications for management. The relatively new concept of PF-ILD has aroused active clinical research over the past years. To understand risk factors for progression and the real burden of the disease is crucial to improve management. In the last 2 years, different cohort studies have addressed these questions. They showed that almost one-third of the non-IPF fibrotic ILD patients develop PF-ILD or PPF. Emerging data show similarities in prognosis between patients with IPF or with non-IPF PF-ILD patients. Early detection and appropriate treatment of this group of patients is a priority. Further research is needed to identify risk factors of progression, to clarify the assessment of progression in clinical practice, for a better management of patients with PF-ILD in a real-world setting.

Burden of illness in progressive fibrosing interstitial lung disease.

BACKGROUND: Progressive fibrosing interstitial lung disease (ILD) is a relatively new clinical concept describing a variety of ILDs characterized by progressive pulmonary fibrosis with associated lung function decline and worsening chest imaging. Little is known about health care resource utilization (HCRU) and costs associated with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF). This study analyzed the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that had not yet progressed. METHODS: This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures. RESULTS: The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1) (P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease (mean [SD] 1.6 [2.4] days vs 1.0 [1.3] days, P < 0.001). Mean weighted PPPM (SD) all-cause health care costs were also significantly higher for progressive vs not-yet-progressed patients, including total costs ($4,382 [$9,597] vs $2,243 [$4,162], P < 0.001), medical costs ($3,662 [$9,150] vs $1,627 [$3,524], P < 0.001), and pharmacy costs ($720 [$2,097] vs $616 [$2,070], P = 0.002). The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients ($1,729 [$7,557] vs $523 [$2,118], P < 0.001). CONCLUSIONS: Progressive fibrosing ILD carries a substantial economic and health care burden. Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for the progressive cohort. Disclosures: This work was funded by Boehringer Ingelheim Pharmaceuticals, Inc. Drs Conoscenti and Shetty are employees of Boehringer Ingelheim (BI). Dr Singer was an employee of BI at the time the study was conducted. Dr Brown was a paid consultant for BI for this study. Dr Bengtson, Ms Anderson, and Dr Brekke are employees of Optum, which was contracted by BI to conduct the study. Medical writing assistance was provided by Yvette Edmonds, PhD (Optum), and was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.

Diagnosis of Idiopathic Pulmonary Fibrosis in High-Resolution Computed Tomography Scans Using a Combination of Handcrafted Radiomics and Deep Learning.

PurposeTo develop handcrafted radiomics (HCR) and deep learning (DL) based automated diagnostic tools that can differentiate between idiopathic pulmonary fibrosis (IPF) and non-IPF interstitial lung diseases (ILDs) in patients using high-resolution computed tomography (HRCT) scans.Material and MethodsIn this retrospective study, 474 HRCT scans were included (mean age, 64.10 years ± 9.57 [SD]). Five-fold cross-validation was performed on 365 HRCT scans. Furthermore, an external dataset comprising 109 patients was used as a test set. An HCR model, a DL model, and an ensemble of HCR and DL model were developed. A virtual in-silico trial was conducted with two radiologists and one pulmonologist on the same external test set for performance comparison. The performance was compared using DeLong method and McNemar test. Shapley Additive exPlanations (SHAP) plots and Grad-CAM heatmaps were used for the post-hoc interpretability of HCR and DL models, respectively.ResultsIn five-fold cross-validation, the HCR model, DL model, and the ensemble of HCR and DL models achieved accuracies of 76.2 ± 6.8, 77.9 ± 4.6, and 85.2 ± 2.7%, respectively. For the diagnosis of IPF and non-IPF ILDs on the external test set, the HCR, DL, and the ensemble of HCR and DL models achieved accuracies of 76.1, 77.9, and 85.3%, respectively. The ensemble model outperformed the diagnostic performance of clinicians who achieved a mean accuracy of 66.3 ± 6.7% (p < 0.05) during the in-silico trial. The area under the receiver operating characteristic curve (AUC) for the ensemble model on the test set was 0.917 which was significantly higher than the HCR model (0.817, p = 0.02) and the DL model (0.823, p = 0.005). The agreement between HCR and DL models was 61.4%, and the accuracy and specificity for the predictions when both the models agree were 93 and 97%, respectively. SHAP analysis showed the texture features as the most important features for IPF diagnosis and Grad-CAM showed that the model focused on the clinically relevant part of the image.ConclusionDeep learning and HCR models can complement each other and serve as useful clinical aids for the diagnosis of IPF and non-IPF ILDs.

Translated article] Diagnostic and Therapeutic Developments in Progressive Pulmonary Fibrosis

In addition to idiopathic pulmonary fibrosis (IPF), other diffuse interstitial lung diseases (ILD) are also associated with pulmonary fibrosis and occur in a variable proportion of patients, depending on the entity. The name given to this fibrotic component, that may progress despite treatment, is progressive pulmonary fibrosis (PPF). In this context, PPF is not an entity per se but a common clinical condition or behavior that may occur in association with different types of fibrosing diffuse ILDs, compromising patient prognosis. PPF is identified from worsening clinical, physiological, and/or radiological criteria during patient follow-up. Randomized clinical trials in patients with IPF or progressive non-IPF ILD have shown that treatment with antifibrotic drugs, either nintedanib or pirfenidone, slows progression. We are seeing the start of a new era in the clinical management of this subgroup of patients, offering the perfect opportunity for exploring still uncharted territories.

Prospective Study of Proton Therapy for Lung Cancer Patients with Poor Lung Function or Pulmonary Fibrosis.

Simple SummaryUnderlying lung disease can affect the pulmonary toxicity after radiotherapy for lung cancer, but treatment outcomes after proton beam therapy (PBT) for lung cancer patients with underlying lung disease have been limited to small retrospective studies. In this prospective study, we aimed to assess pulmonary toxicity following PBT for lung cancer with poor lung function or pulmonary fibrosis. We found that idiopathic pulmonary fibrosis (IPF) was associated with severe pulmonary toxicity and poor survival even after PBT, while PBT seems to be a safe treatment modality for lung cancer patients with chronic obstructive pulmonary disease.PBT has a unique depth–dose curve with a Bragg peak that enables one to reduce the dose to normal lung tissue. We prospectively enrolled 54 patients with non-small cell lung cancer treated with definitive PBT. The inclusion criteria were forced expiratory volume in 1 s (FEV1) ≤ 1.0 L or FEV1 ≤ 50% of predicted or diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 50%, or pulmonary fibrosis. The primary endpoint was grade ≥ 3 pulmonary toxicity, and secondary endpoints were changes in pulmonary function and quality of life. The median age was 71.5 years (range, 57–87). Fifteen (27.8%) and fourteen (25.9%) patients had IPF and combined pulmonary fibrosis and emphysema, respectively. The median predicted forced vital capacity (FVC), FEV1, and DLco were 77% (range, 42–104%), 66% (range, 31–117%), and 46% (range, 23–94%), respectively. During the follow-up (median, 14.7 months), seven (13.0%) patients experienced grade ≥ 3 pulmonary toxicity. Seven months after the completion of PBT, patients with IPF or non-IPF interstitial lung disease (ILD) experienced a decrease in the FVC but the decrease in DLco was not significant. Under careful monitoring by pulmonologists, PBT could be a useful treatment modality for lung cancer patients with poor lung function or pulmonary fibrosis.

Claims-based Prevalence of Disease Progression among Patients with Fibrosing Interstitial Lung Disease Other than Idiopathic Pulmonary Fibrosis in the United States.

RationaleChronic fibrosing interstitial lung disease (ILD) with a progressive phenotype is a clinical concept describing the broad group of ILDs characterized by progressive pulmonary fibrosis. The prevalence of progressive fibrotic ILDs other than idiopathic pulmonary fibrosis (IPF) is not well understood.ObjectivesWe used a novel algorithm to estimate the prevalence range of disease progression among patients with non-IPF fibrotic ILD in a U.S. claims database.MethodsThis was a retrospective study including adults with commercial or Medicare Advantage with Part D (MAPD) insurance using administrative claims data from October 2015 to September 2019. Patients likely to have non-IPF fibrosing ILD with a progressive phenotype were identified via an algorithm that incorporated ILD-related diagnosis codes (excluding IPF) and claims-based proxies for fibrotic ILD progression, including pulmonary function tests, chest imaging, oral corticosteroid (OCS) medications, immunosuppressive medications, lung transplant, oxygen therapy, palliative care, and respiratory hospitalization. The prevalence range of non-IPF fibrotic ILD with progressive disease behavior was calculated using strict and lenient case definitions to account for potential imprecision in the progression proxies.ResultsOf nearly 9 million study-eligible patients, 17,136 were identified with non-IPF fibrosing ILD. The prevalence of disease progression per 10,000 (95% confidence interval) ranged from 12.14 (11.74–12.54) to 29.05 (28.43–29.67) over a mean observation time of 1.44 years for MAPD enrollees (n = 14,686), and from 0.89 (0.81–0.97) to 2.36 (2.24–2.48) over a mean observation time of 1.29 years for commercial enrollees (n = 2,450). Prevalence estimates increased with age for both insurance types. Among patients with progression, 4,097 met at least two progression proxies not considering OCS (strict case definition) and 9,946 met at least one progression proxy (lenient case definition). The mean (standard deviation) number of proxies met was 2.1 (1.3), and the most common individual proxies met (alone or in combination with other proxies) were OCS use (48.9%), respiratory hospitalization (44.2%), and oxygen therapy (44.1%).ConclusionsThis is among the first claims-based estimates of the prevalence of non-IPF chronic fibrosing ILD with a progressive phenotype. Our analysis indicates that this phenotype is rare in the overall population but increases substantially with increasing age.

Impact of Concomitant Medication Burden on Tolerability of Disease-targeted Therapy and Survival in Interstitial Lung Disease.

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (⩾5 medications), and the medication regimen complexity index (MRCI). Medication intolerance and discontinuation were evaluated at 6 months and 1 year after initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within 6 months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: P = 0.005; polypharmacy: P = 0.006; MRCI: P = 0.004). This association was not observed for immunosuppressive medications in 1,255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at 1 year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (P < 0.01 for both), which improved prognostication beyond common clinical factors and the ILD-GAP index (P < 0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD.