Impact of Lung Biopsy Information on Treatment Strategy of Patients with Interstitial Lung Diseases.

Rationale: Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives: This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods: We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results: Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P < 0.001, and in 38% of SLB, 61/160, P < 0.001). After LBx, the MDT was less inclined to "wait and see" (from 15% to 4% of cases, P < 0.001) or to prescribe steroids only (from 54% to 37%, P < 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P < 0.001) or immunosuppressive drugs (from 7% to 14%, P < 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75-8.3); P = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18-0.94; P = 0.03). Conclusions: Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: where to go from here?

Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth.

Disease progression across the spectrum of idiopathic pulmonary fibrosis: A multicentre study.

BACKGROUND AND OBJECTIVE: In clinical practice, a working diagnosis of IPF may be performed to provide effective antifibrotic treatment to patients who cannot undergo SLB. In this study, we compared the disease course across IPF diagnostic categories in a real-life clinical setting to clarify the appropriateness of a working diagnosis of IPF and treatment initiation in these patients. METHODS: Longitudinal data from IPF patients receiving antifibrotic treatment (pirfenidone or nintedanib) were retrospectively collected at three tertiary centres in Italy. Univariate and multivariate analyses were performed to compare time to death and to a composite endpoint of disease progression between two diagnostic subgroups, that is, patients with UIP on HRCT and/or SLB, and patients with possible UIP and no histological confirmation. RESULTS: A total of 249 IPF patients were included in the analysis. Among patients with a possible UIP pattern on HRCT, 41 (55%) were prescribed antifibrotic treatment (either nintedanib or pirfenidone) despite absence of histological confirmation. This group demonstrated similar mortality and disease progression as compared to patients with a definite diagnosis of IPF as per diagnostic guidelines (log-rank test P = 0.771 and P = 0.139, respectively). Such findings were confirmed on multivariate analysis (HR: 1.19, 95% CI: 0.49-2.89, P = 0.7 for death; HR: 1.42, 95% CI: 0.83-2.44, P = 0.201 for disease progression). CONCLUSION: In patients receiving antifibrotics following a working diagnosis of IPF, disease progression rates were similar to patients with a confident diagnosis of IPF according to consensus guidelines, supporting the rationale for treatment initiation in these patients by expert multidisciplinary teams.

Assessment of Lung Cancer Development in Idiopathic Pulmonary Fibrosis Patients Using Quantitative High-Resolution Computed Tomography: A Retrospective Analysis.

PURPOSE: The purpose of this study was to investigate histogram-based quantitative high-resolution computed tomography (HRCT) indexes in the assessment of lung cancer (LC) development in idiopathic pulmonary fibrosis (IPF) patients. MATERIALS AND METHODS: From IPF databases of 2 national respiratory centers, we retrospectively studied patients with and without LC development-respectively, divided into Group A (n=16) and Group B (n=33). The extent of fibrotic disease was quantified on baseline and follow-up HRCT examinations using kurtosis, skewness, percentage of high attenuation area (HAA%), and percentage of fibrotic area (FA%). These indexes were compared between the 2 groups using the Mann-Whitney U test. In the prediction of LC development, receiver operating characteristic analysis was performed to assess threshold values of HRCT indexes. RESULTS: At baseline, no difference was reported among groups for kurtosis, skewness, HAA%, and FA%, with P-values of 0.0881, 0.0606, 0.0578, and 0.0606, respectively. On follow-up, significant differences were reported, with P-values of 0.0174 for kurtosis, 0.0313 for skewness, 0.0297 for HAA%, and 0.0407 for FA%.On baseline HRCT, in the prediction of LC development, receiver operating characteristic analysis reported sensibility and specificity of 87.5% and 45.45% for kurtosis, 68.75% and 63.64% for skewness, 81.25% and 54.55% for FA%, and 75% and 60.61% for HAA%. CONCLUSIONS: LC development is associated with progression of fibrosis; at baseline, FA% and HAA% reported more convenient sensitivity/specificity ratios in the prediction of LC development.

Quantitative assessment of interstitial lung disease in Sjögren's syndrome.

BACKGROUND: Interstitial lung disease (ILD) is a frequent manifestation of Sjögren's syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity. AIM: To determine whether QCT assessment can identify extensive or limited lung disease in patients with SS and ILD. METHODS: This multi-center, cross-sectional and retrospective study enrolled patients with SS and a chest CT scan. SQCT assessment was carried out in a blinded and centralized manner to calculate both Goh and Taouli scores. An operator-independent analysis of all CT scans with the open-source software platform Horos was used to evaluate the QCT indices. Patients were classified according to the extent of ILD and differences in QCT index distribution were investigated with non-parametric tests. RESULTS: From a total of 102 consecutive patients with SS, the prevalence of ILD was 35.3% (36/102). There was a statistically significant difference in QCT index distribution between the SS with ILD and SS without ILD groups (p<0.001). Moreover, SS-ILD patients with ILD >20% (by Goh score) had a QCT index statistically different from those with limited ILD extent (p<0.001). Finally, QCT indices showed a moderate-to-good correlation with the Goh and Taouli scores (from 0.44 to 0.65; p<0.001). CONCLUSIONS: QCT indices can identify patients with SS and ILD and discriminate those with lesser or greater lung disease.

Contribution of pulmonary function tests (PFTs) to the diagnosis and follow up of connective tissue diseases.

INTRODUCTION: Connective Tissue Diseases (CTDs) are systemic autoimmune conditions characterized by frequent lung involvement. This usually takes the form of Interstitial Lung Disease (ILD), but Obstructive Lung Disease (OLD) and Pulmonary Artery Hypertension (PAH) can also occur. Lung involvement is often severe, representing the first cause of death in CTD. The aim of this study is to highlight the role of Pulmonary Function Tests (PFTs) in the diagnosis and follow up of CTD patients. MAIN BODY: Rheumatoid Arthritis (RA) showed mainly an ILD with a Usual Interstitial Pneumonia (UIP) pattern in High-Resolution Chest Tomography (HRCT). PFTs are able to highlight a RA-ILD before its clinical onset and to drive follow up of patients with Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO). In the course of Scleroderma Spectrum Disorders (SSDs) and Idiopathic Inflammatory Myopathies (IIMs), DLCO appears to be more sensitive than FVC in highlighting an ILD, but it can be compromised by the presence of PAH. A restrictive respiratory pattern can be present in IIMs and Systemic Lupus Erythematosus due to the inflammatory involvement of respiratory muscles, the presence of fatigue or diaphragm distress. CONCLUSIONS: The lung should be carefully studied during CTDs. PFTs can represent an important prognostic tool for diagnosis and follow up of RA-ILD, but, on their own, lack sufficient specificity or sensitivity to describe lung involvement in SSDs and IIMs. Several composite indexes potentially able to describe the evolution of lung damage and response to treatment in SSDs are under investigation. Considering the potential severity of these conditions, an HRCT jointly with PFTs should be performed in all new diagnoses of SSDs and IIMs. Moreover, follow up PFTs should be interpreted in the light of the risk factor for respiratory disease related to each disease.

Clinical, serological and radiological features of a prospective cohort of Interstitial Pneumonia with Autoimmune Features (IPAF) patients.

BACKGROUND: The term Interstitial Pneumonia with Autoimmune Features (IPAF) describes patients with Interstitial Lung Diseases (ILDs) and clinical or serological features of autoimmune diseases insufficient to reach a specific classification of a Connective Tissue Disease (CTD). Currently, retrospective studies on IPAF patients have proven to be heterogeneous in general characteristics, outcomes and High-Resolution Computed Tomography (HRCT) pattern. This study aims to describe for the first time the clinical, serological and radiological features of a prospective cohort of IPAF patients. This cohort is then compared to a group of patients with Idiopathic Pulmonary Fibrosis (IPF). MATERIAL AND METHODS: From 626 consecutive ILD patients evaluated, 45 IPAF and a comparison cohort of 143 IPF patients were enrolled. All patients underwent clinical assessment with rheumatologic and respiratory evaluation, HRCT, Pulmonary Function Tests and Nailfold Videocapillaroscopy. RESULTS: The IPAF patients had a predominance of female gender (62.12%) with a median age of 66 years. The most common findings were: Nonspecific Interstitial Pneumonia (NSIP, 68.89%), Antinuclear Antibody positivity (17.77%) and Raynaud Phenomenon (31.11%). In comparison with IPF, IPAF patients showed younger age, better performances in Pulmonary Function Tests, less necessity of O2 support and predominance of female sex and NSIP pattern. DISCUSSION: This is the first report of a prospective cohort of IPAF patients. IPAF patients seem to have a less severe lung disease than IPF. IPAF criteria probably need to be revisited and validated, but their capacity to recruit patients with incomplete forms or early onset of CTD could be useful for further research.

Interstitial Lung Disease in patients with Polymyalgia Rheumatica: A case series.

INTRODUCTION: Severe morning stiffness with painful involvement of the girdles are often referred by patients with Interstitial Lung Disease (ILD), but the association between ILD and Polymyalgia Rheumatica (PMR) is rarely reported. The purpose of the work is to describe a series of patients classified as having PMR with ILD. MATERIAL AND METHODS: We retrospectively enrolled patients with a diagnosis of PMR referred to our center during the previous year for respiratory symptoms. Data concerning clinical and serological manifestations suggesting Connective Tissue Disease (CTD), High-Resolution Chest Tomography (HRCT), and Pulmonary Function Tests (PFTs) were systematically collected in order to verify the diagnosis. RESULTS: Fifteen out of seventeen PMR patients had ILD. Ten patients had a confirmed diagnosis of PMR, while in five patients a CTD was discovered. Seven patients showed a severe restrictive pattern at PFTs requiring oxygen supplementation (five with PMR and two with CTD). In thirteen patients pulmonary symptoms started before or together with muscular symptoms. Regarding HRCT patterns, patients showed a Nonspecific Interstitial Pneumonia in nine cases, Usual Interstitial Pneumonia (UIP) and possible UIP in two and three cases, and a single case of Organizing Pneumonia and Combined Pulmonary Fibrosis and Emphysema Syndrome. CONCLUSIONS: Lung involvement should be evaluated in PMR patients, especially if asthenia is poorly responsive to low doses of steroids. In these cases, the diagnosis should be re-evaluated in depth, looking for a seronegative Rheumatoid Arthritis, a clinically amyopathic myositis or Interstitial Pneumonia with Autoimmune features.

Assessment of survival in patients with idiopathic pulmonary fibrosis using quantitative HRCT indexes.

BACKGROUND: The assessment of Idiopathic Pulmonary Fibrosis (IPF) using HRCT requires great experience and is limited by a significant inter-observer variability, even between trained radiologists. The evaluation of HRCT through automated quantitative analysis may hopefully solve this problem. The accuracy of CT-histogram derived indexes in the assessment of survival in IPF patients has been poorly studied. METHODS: Forty-two patients with a diagnosis of IPF and a follow up time of 3 years were retrospectively collected; HRCT and Pulmonary Function Tests (PFTs) performed at diagnosis time were analysed; the extent of fibrotic disease was quantified on HRCT using kurtosis, skewness, Mean Lung Density (MLD), High attenuation areas (HAA%) and Fibrotic Areas (FA%). Univariate Cox regression was performed to assess hazard ratios for the explored variables and a multivariate model considering skewness, FVC, DLCO and age was created to test their prognostic value in assessing survival. Through ROC analysis, threshold values demonstrating the best sensitivity and specificity in predicting mortality were identified. They were used as cut-off points to graph Kaplan-Meier curves specific for the CT-indexes. RESULTS: Kurtosis, skewness, MLD, HAA% and FA% were good predictors of mortality (HR 0.44, 0.74, 1.01, 1.12, 1.06; p = 0.03, p = 0.01, p = 0.02, p = 0.02 and p = 0.017 respectively). Skewness demonstrated the lowest Akaike's information criterion value (55.52), proving to be the best CT variable for prediction of mortality. Significant survival differences considering proposed cut-off points were also demonstrated according to kurtosis (p = 0.02), skewness (p = 0.005), MLD (p = 0.003), HAA% (p = 0.009) and FA% (p = 0.02) - obtained from quantitative HRCT analysis at diagnosis time. CONCLUSIONS: CT-histogram derived indexes may provide an accurate estimation of survival in IPF patients. They demonstrate a correlation with PFTs, highlighting their possible use in clinical practice.

Comorbidities of IPF: How do they impact on prognosis.

Idiopathic Pulmonary Fibrosis (IPF) is a severe parenchymal lung disease characterized by an intense deposition of collagen in the interstitial spaces. The introduction of anti-fibrotic drugs increased patients' life expectancy highlighting the role of comorbidities in patients' management and prognosis. IPF is frequently associated with other diseases mainly because of its onset during middle age and sometimes because of the presence of common pathogenic pathways such as in the case of lung cancer. Comorbidities may differently influence prognosis of IPF patients. However, except for major impacting ones as LC, PH and cardiovascular diseases, data exploring their impact on prognosis are still few and sometimes conflicting highlighting the need of new large and targeted studies. In this review we discuss the current knowledge on the most common comorbidities associated with IPF (cardiovascular diseases, pulmonary hypertension, lung cancer, emphysema, gastro-oesophageal reflux and depression), focusing on their prognostic role.

State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances.

The term interstitial pneumonia with autoimmune features (IPAF) has been proposed to define patients with interstitial lung disease (ILD) associated with autoimmune signs not classifiable for connective tissue diseases (CTDs). This new definition overcomes previous nomenclatures and provides a uniform structure for prospective studies through specific classification criteria.This work evaluates the characteristics of IPAF patients reported in the literature, to highlight potential limits through a comparative analysis and to suggest better performing classification criteria.Four retrospective studies on the IPAF population have been considered. The study subjects differed in age, sex, smoking habit, ILD pattern and outcomes. Another important difference lies in the diverse items considered in the classification criteria. The retrospective design of the studies and the absence from some of them of a rheumatologist clearly involved in the diagnosis may have influenced the data, but current IPAF criteria seem to include a rather heterogeneous population. To overcome these discrepancies, this review suggests a limitation in the use of single items and the exclusion of extremely specific CTD criteria. This should avoid the definition of IPAF for those diseases at different stages or at early onset. The investigation of a functional or morphological cut-off of pulmonary involvement would be useful.

When to start and when to stop antifibrotic therapies.

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive changes of the lung architecture causing cough and dyspnoea and ultimately leading to lung failure and death. Today, for the first time, two drugs that may reduce the inexorable progression of the disease are available, suggesting that treatment with specific drugs for IPF should be started as soon as diagnosis is made. This applies to any disease and particularly to IPF, which is marked by a 5-year survival comparable or even worse than many cancers. However, despite common sense and even worse, in spite of scientific data coming from clinical trials, post hoc analysis, long-term safety studies and real-life experiences, the question of when to start and when to stop treatment with antifibrotics is still debated. In IPF, particularly when the disease is diagnosed at an early stage, "wait and watch" behaviour is not rare to observe. This is largely due to the lack of awareness of both patients and clinicians regarding the progression of the disease and its prognosis. Another important issue is when treatment should be stopped. In general, there are two main reasons to stop a therapy: unbearable side-effects and/or lack of efficacy. According to current (although preliminary) evidence, antifibrotic drugs should not be discontinued except for safety issues.