Bien que les symptômes soient un déterminant majeur de la qualité de vie des patients atteints de fibrose pulmonaire, il existe une incertitude sur leur utilisation en tant que critères d'inclusion ou mesures des résultats. Dans l'essai INBUILD, portant sur une population de patients atteints de pneumopathies interstitielles diffuses (PID) fibrosantes progressives autres qu'une fibrose pulmonaire idiopathique (FPI), la dyspnée était évaluée par le questionnaire Living with Pulmonary Fibrosis (L-PF). Nous avons utilisé les données du groupe placebo pour évaluer les associations entre la dyspnée à l'inclusion et l'aggravation de la dyspnée et les résultats indiquant une progression de la PID. Les patients présentaient une PID fibrosante non-FPI d'étendue > 10 % à la tomodensitométrie haute résolution et répondaient aux critères de progression de la PID au cours des 24 mois précédents. Les patients ont été randomisés pour recevoir du nintédanib ou un placebo. Les patients ont complété le questionnaire L-PF lors de l'inclusion et à la semaine 24. Le domaine dyspnée de ce questionnaire fournit un score compris entre 0 et 100 ; plus le score est élevé, plus la dyspnée est sévère. Les seuils de variation pertinente du score de la dyspnée dans cette population de patients ont été estimés à 6 à 7 points. En utilisant les données du groupe placebo, nous avons évalué les associations entre le score de dyspnée du questionnaire L-PF à l'inclusion (< médiane vs ≥ médiane) et les résultats ultérieurs et entre les variations du score de dyspnée du questionnaire L-PF entre l'inclusion et la semaine 24 (< 6 vs ≥ 6 points ; < 7 vs ≥ 7 points) et les résultats ultérieurs. Les résultats évalués incluaient la progression de la PID (déclin de la CVF ≥ 10 % de la valeur théorique), la progression de la PID ou le décès ; l'exacerbation aiguë ou le décès ; le décès. La cohorte d'analyse comprenait 331 patients. Le score médian de dyspnée du questionnaire L-PF à l'inclusion était de 17,2. L'exposition médiane au placebo était de 17,4 mois. Par rapport à un score plus bas, un score de dyspnée au questionnaire L-PF ≥ 17,2 à l'inclusion était associé à une augmentation significative du risque de progression de la PID ou de décès (HR 1,42 [IC à 95 % : 1,05, 1,93] ; p = 0,02), d'exacerbation aiguë ou décès (HR 1,67 [IC à 95 % : 1,00, 2,82] ; p = 0,05) et de décès (HR 2,21 [IC à 95 % : 1,15, 4,25] ; p = 0,02) et à un risque numériquement supérieur de progression de la PID (HR 1,36 [IC à 95 % : 0,98, 1,87] ; p = 0,06). Des variations des scores de dyspnée sur le questionnaire L-PF ≥ 6 points (vs < 6 points) ou ≥ 7 points (vs < 7 points) à la semaine 24 étaient associées à des risques significativement supérieurs de progression de la PID ou de décès, d'exacerbation aiguë ou de décès, et de décès, entre la semaine 24 et la fin de l'essai (Fig. 1). Chez les patients présentant des PID fibrosantes progressives non-FPI, des scores moins bons de dyspnée sur le questionnaire L-PF à l'inclusion et une détérioration des scores de dyspnée sur le questionnaire L-PF sur 24 semaines étaient associés à un risque plus élevé de progression de la PID.

The pathologic diagnosis of pleural mesothelioma is generally based on international guidelines, but no compulsory points based on different drugs approvals in different European countries are required to be reported. According to the last (2021) edition of the World Health Organization classification of pleural tumors, the nuclear grade of epithelioid-type mesothelioma should be always inserted in the pathologic report, while the presence of BRCA-associated protein-1 (BAP1) (clone C4) loss and a statement on the presence of the sarcomatoid/nonepithelioid component are fundamental for both a screening of patients with suspected BAP1 tumor predisposition syndrome and the eligibility to perform first-line immunotherapy at least in some countries. Several Italian experts on pleural mesothelioma who are deeply involved in national scientific societies or dedicated working groups supported by patient associations agreed that the pathology report of mesothelioma of the pleura should always include the nuclear grade in the epithelioid histology, which is an overt statement on the presence of sarcomatoid components (at least 1%, in agreement with the last classification of pleural mesothelioma) and the presence of BAP1 loss (BAP1-deficient mesothelioma) or not (BAP1-retained mesothelioma) in order to screen patients possibly harboring BAP1 tumor predisposition syndrome. This review aims to summarize the most recent data on these three important elements to provide evidence regarding the possible precision needs for mesothelioma.

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.

Background: IPF remains a deadly and unpredictable disease. Loss of muscle mass (LOM) seems to be associated with poor prognosis in chronic illnesses but its significance in IPF remains unexplored. Thus, we aimed to investigate the role of muscle loss in patients with IPF under antifibrotic treatment. Methods: 88 patients with IPF (16 females, 72 males) were retrospectively enrolled between March 2014 and December 2021. Demographic, functional and radiological data were collected at diagnosis. We recorded the mean Hounsfield Unit (Hu) value of the right paravertebral muscle at the level of the 12th thoracic vertebra and defined loss of muscle mass (LOM) as MeanHu < 30. Survival and Cox regression analysis were applied to assess the prognostic significance. Results: the prevalence of LOM at the time of diagnosis was 47% (41 out of 88). Patients with LOM were older (74 vs 67 years; <0.0001) and presented less metabolic comorbidities (39% vs 62%; p=0.03) compared with not-LOM patients. Indeed, male patients with LOM had a lower survival rate at two-years compared to males without loss of muscle mass [HR 5.3 (95%CI 1.4 - 20); p=0.02]. By Cox regression analysis, low HighGreyLevelRunEmphasis at baseline and the need of oxygen therapy at rest were both independent risk factors of death at 2 years. The optimal cut-off of HighGreyLevelRunEmphasis, in male patients was 13.4 (sens67% and spec81%; AUC 0.79; p=0.005). Conclusion: loss of muscle mass is highly prevalent in IPF patients at the time of diagnosis. Moreover, male patients with muscle loss presented a reduction in survival rate at two years. Low HighGreyLevelRunEmphasis at baseline and oxygen need at rest are independent predictors of mortality.

Background: limited data exist on the prevalence of radiographic abnormalities after COVID-19 pneumonia, and the extent to which High Resolution CT (HRCT) features correlate with symptoms and function after 12-month from hospitalization remains unclear. Aims: To prospectively assess and characterize, among all discharged patients with COVID-19, those with persisting pulmonary sequalae after 12-month follow-up. Methods: 354 patients were evaluated in our post-COVID-clinic from June 2020 to January 2021. Symptoms and functional parameters were recorded. According to the absence or presence of HRCT abnormalities after 12-months, patients were categorized as recovered (REC) or not recovered (NOT-REC) and the extension of radiographic changes was scored. Results: 296/354 patients(84%) completed the 12-month follow up. 21/296(7%) presented pulmonary sequelae with a mean extension of interstitial changes of 11% of the whole lung. REC displayed a median full recovery time of 131(60-203) days. Compared to REC, NOT-REC were mainly current smokers [3(14%) vs.12(4%);p=0.05], with a longer in-hospital stay [13 (7.5–40.5) vs.10.0(6.0–16.0);p=0.02], need for a higher maximal FiO2 during hospitalization [60(29–100) vs. 33 (21–65);p<0.004] and higher intensity medical care [10(48%) vs.48(17%);p<0.001]. Conversely, lung function did not differ [FVC 97%(88-109) vs.93(82-105),p=0.32; FEV1 102%(86–116) vs. 96(85-106);p=0.11]. Conclusion: A low percentage of patients discharged for COVID-19 pneumonia showed fibrotic-like changes at 12-month follow-up, yet with preserved lung function. They are mainly current smokers, with a higher level of medical care during hospitalization and a prolonged in-hospital stay.

Background: Patients with ILD may display a progressive fibrosing behavior despite treatment. The phenotype and clinical characteristics of progressive IIM-ILDs still remain to be deeply investigated. Aim: To explore clinical and serological characteristics of progressive IIM-ILD patients in a multicentric population. Methods: We collected clinical, serological and radiological data of 125 IIM-ILD patients at diagnosis and during follow-up. Progression was defined when forced vital capacity (FVC) %pred. decline was ≥ 5% or when a high-resolution CT scan worsens over one-year follow-up. Results: In 79/125(63%) IIM-ILDs patients (age 64±11.5;24M,55F) functional and radiological date were available after one-year follow-up. 65(82%) were classified as stables (S) and 14(18%) as progressors (P). Sex, age and functional data at ILD diagnosis and the mortality rate (7vs.3%) did not differ among P and S. Compared to S, P displayed a significantly higher prevalence of anti-MDA5 antibodies (29vs.6%;p=0.03), heliotropic rash (29vs.5%;p=0.02), xerostomia (29vs.5%;p=0.02) and xerophthalmia (36vs.6%;p=0.007). Anti-MDA5 antibodies [HR6.10 95%CI(1.30–28.4);p=0.002], heliotropic rash [8.00(1.55–41.23);p=0.01], xerostomia [8.19 (1.84 – 36.36);p=0.006] and xerophthalmia [8.00 (1.55 – 41.2);p=0.01] were confirmed as progression-associated factors at univariate but not at multivariate analysis. Conclusions: Serological and clinical features at diagnosis may predict progression in IIM-ILD patients. Anti-MDA5 antibodies, heliotropic rash, xerostomia and xerophthalmia are prevalent in progressive IIM-ILD population, but their role as independent predictors need to be further investigated.

Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive interstitial lung disease (ILD) of unknown origin with limited therapeutic options (1). Although the mechanisms underpinning IPF pathogenesis have yet to be fully elucidated, susceptibility is likely driven by complex interactions between genetic, environmental, and demographic risk factors. Among susceptible individuals, repetitive alveolar injury appears to cause aberrant activation of alveolar epithelial cells, which secrete profibrotic mediators that induce the expansion of hyperactive and apoptosis-resistant mesenchymal cells (e.g., fibroblasts andmyofibroblasts). These cells produce an excess of extracellular matrix, which leads to irreversible distortion of the lung parenchyma and progressive organ failure (2). Despite these mechanistic insights, limited understanding of disease etiology continues to hinder prevention and development of novel pharmacotherapies. Just as IPF etiology remains elusive, so does the ability to predict disease trajectory. Although most patients display progressive decline, others may remain relatively stable, decline rapidly, or suffer an acute exacerbation (3). Predicting disease behavior in IPF is critically important for both clinical and research purposes, as understanding an individual’s risk of death could guide listing for lung transplantation andmaximize the likelihood of detecting treatment effects through clinical trial enrichment (4). Several clinical prediction models have been reported and discriminate IPF survival with variable success. Most models incorporate baseline clinical, radiologic, and physiologic parameters (5–7), whereas some incorporate longitudinally acquired variables, capitalizing on the predictive nature of changing physiology (8). Despite these advances, risk explanation remains variable for most clinical prediction models, likely influenced by the cohort in which they are applied (9). A number of biomarkers have also been shown to predict IPF survival (10), although rigorous validation is often lacking and their value beyond clinical prediction models remains unclear for most. In this issue of the Journal, Molyneaux and coworkers (pp. 1440–1448) address two critical gaps in knowledge through evaluation of cytokeratin 19 fragment (CYFRA 21-1), a cleavage fragment of the structural intracytoplasmic protein cytokeratin 19 (11). Among a subset of prospectively recruited patients with incident IPF from the Prospective Study of Fibrosis In the Lung Endpoints (PROFILE) study, Molyneaux and colleagues demonstrated that serum CYFRA 21-1 concentration is increased in this population compared with control subjects and is highly expressed inmultiple epithelial cell types in IPF lung tissue. These findings suggest cytokeratin 19 plays a crucial role in IPF pathogenesis and progression and support prior studies showing CYFRA 21-1 to be elevated in the BAL fluid of patients with IPF (12) and serum of patients with systemic sclerosis–associated ILD (13). These findings also corroborate a recent proteomic investigation showing cytokeratin 19 to predict disease progression across diverse ILD subtypes (14). Beyond mechanistic implications, Molyneaux and colleagues also showed that CYFRA 21-1 concentration predicted near-term progression and long-term survival when assessed in cross-section and at serial time points, notably beyond 3 months. These findings were then validated in an independent cohort of PROFILE patients recruited after those comprising the discovery cohort. These findings add to prior work identifying novel biomarkers in this cohort (15, 16) and add CYFRA 21-1 to the list of potentially attractive biomarkers in IPF. Whether CYFRA 21-1 will actually emerge as a viable biomarker in IPF remains to be seen. For a biomarker to be implemented clinically, it needs to augment or outperform clinical prediction models, which can be applied at minimal cost and effort. CYFRA 21-1 was shown to provide prognostic information independent of clinical variables comprising clinical prediction models but only modestly augmented an area-under-the-curve estimate when added to the gender, age, physiology index (6). This observation was restricted to analysis of near-term progression and was unfortunately not assessed using long-term survival data, which is the endpoint used to develop the gender, age, physiology index (6). Ultimately, area under the curve measures provide little information when assessing the clinical utility of a biomarker. Decision curve analysis has emerged as the preferred method to compare prediction models and would better assess the potential utility of this and other biomarkers (17). These limitations aside, Molyneaux and colleagues should be applauded for this study, as few biomarkers of near-term progression have been identified in IPF and more are urgently needed. Such biomarkers are more likely to help with future trial enrichment, as the change in FVC between treatment groups gets smaller with background antifibrotic therapy. Ultimately, multiple biomarkers may be needed to effectively predict near-term progression (14). Beyond risk prediction, analysis of CYFRA 21-1 concentration before and after the initiation of antifibrotic therapy would be of interest and could potentially support using CYFRA 21-1 as a marker of treatment response. Future research is also needed to expand these findings and elucidate whether pathways involving cytokeratin 19 may serve as potential therapeutic targets.

article: Massive lung calcifications in a four times renal transplanted patient: the fight against dialysis, hyper and hypoparathyroidism - Minerva Endocrinology 2021 Nov 08 - Minerva Medica - Journals

Introduction: Abnormal liver function tests at hospital admission are frequently reported in patients with coronavirus disease 2019 (COVID-19), but their prognostic significance deserves further investigation. Aim: To assess whether aspartate aminotransferase (AST) and alanine aminotransferase (ALT) abnormalities at admission predict disease course in patients hospitalized for COVID-19. Methods: In this single-center retrospective study, data of 188 patients admitted to the Infectious Disease Unit of the Padova University Hospital between February and May 2020 were collected. Patients were considered to have transaminases abnormalities when AST, ALT or both were above the upper limit of normal (ULN). The disease was considered as severe in case of intensive care unit (ICU) patient admission or death. Results: At admission, 98 patients (52.1%) had abnormal transaminases, but only 12 patients (6.4%) showed levels above 3 x ULN. Patients with severe disease showed higher AST (50 [IQR, 37-77] vs. 30 [IQR, 24-43] U/L, p<0.0001) and a trend to higher ALT (32 [IQR, 20-56] vs. 25 [IQR, 18-39] U/L, p=0.07) levels. Altered transaminases at baseline were associated with a higher probability of ICU transfer (40.8% vs. 15.6%, p=0.0002), mechanical ventilation (19.4% vs. 3.3%, p=0.0005), non-invasive ventilation (12.2% vs. 4.4%, p=0.07), and longer hospital stay (9 vs. 7 days, p=0.002). The risk of severe disease (transfer to ICU or death) was remarkably higher in patients with altered transaminases at admission (46.9% vs. 15.6%; p<0.0001) (Figure), and this was confirmed on multivariable logistic regression analysis after adjusting for sex, age, comorbidities, circulating inflammatory markers (neutrophil-to-lymphocyte ratio and C-reactive protein) and albumin levels with a five-fold higher risk (OR=5.17, 95% CI 1.81-14.70; p=0.002). Conclusion: Hospitalized COVID-19 patients have frequently transaminases abnormalities at admission, and these alterations are able to independently predict a severe disease course.

La FPI est une pneumopathie interstitielle fibrosante progressive d’évolution clinique variable mais d’issue fatale. Le score GAP permet de prédire le pronostic chez les patients atteints de FPI avec quatre variables : sexe, âge, CVF en % de la valeur prédite (CVF %p) et DLco en % de la valeur prédite (DLco %p). Les patients sont classés en stade GAP I, II ou III, le risque de mortalité augmentant avec le stade GAP. Le nintédanib ralentit la progression de la maladie en réduisant le taux de déclin de la CVF. Nous avons comparé la mortalité observée chez les patients traités pendant 52 semaines par nintédanib 150 mg 2 fois/jour ou placebo dans les essais TOMORROW et lNPULSlS avec la mortalité prédite sur la base du stade GAP à l’inclusion. Patients des essais TOMORROW et lNPULSlS atteints de FPI au cours des 5 années précédentes avec CVF %p ≥ 50 % ; DLco %p entre 30 et 79 %, traités par nintédanib ou placebo pendant 52 semaines. Le nombre de décès observés entre la randomisation et le jour 372 chez les patients traités par nintédanib ou placebo et le nombre de décès prédits sur la base du stade GAP à l’inclusion ont été analysés de manière descriptive sur la base des données groupées des trois essais. Sur 1231 patients traités dans les essais TOMORROW et lNPULSlS, 1228 avaient des données permettant de calculer le stade GAP à l’inclusion (722 dans le groupe nintédanib ; 506 dans le groupe placebo). Dans la population totale des essais, le nombre de décès observés (n = 83) était plus faible que le nombre de décès prédits sur la base du stade GAP à l’inclusion (n = 154). Dans le groupe nintédanib, le nombre de décès observés représentait 46,7 % du nombre de décès prédits (42 versus 89) (Tableau 1). Dans le groupe placebo, le nombre de décès observés représentait 63,9 % du nombre de décès prédits (41 versus 64) (Tableau 1). En fonction du nombre de décès observés et du nombre de décès prédits, le nintédanib était associé à une réduction relative du risque de mortalité de 26,8 % versus placebo. Dans les essais TOMORROW et lNPULSlS, moins de décès se sont produits que le nombre de décès prédits, démontrant que les patients inclus dans ces essais cliniques avaient une mortalité à 1 an plus faible que la population générale des patients atteints de FPI. D’après la différence entre les décès observés et les décès prédits, le traitement par le nintédanib a été associé à une réduction du risque de mortalité sur 1 an versus placebo.

Interstitial lung disease (ILD) is an increasingly recognized complication of rheumatoid arthritis (RA) and is associated with significant morbidity and mortality. In addition, approximately one‐third of patients have subclinical disease with varying degrees of functional impairment. Although risk factors for RA‐related ILD are well established (e.g., older age, male sex, ever smoking, and seropositivity for rheumatoid factor and anti–cyclic citrullinated peptide), little is known about optimal disease assessment, treatment, and monitoring, particularly in patients with progressive disease. Patients with RA‐related ILD are also at high risk of infection and drug toxicity, which, along with comorbidities, complicates further treatment decision‐making. There are distinct histopathologic patterns of RA‐related ILD with different clinical phenotypes, natural histories, and prognoses. Of these, the usual interstitial pneumonia (UIP) subtype of RA‐related ILD shares a number of clinical and histopathologic features with idiopathic pulmonary fibrosis, the most common and severe of the idiopathic interstitial pneumonias, suggesting the existence of common mechanistic pathways and possibly therapeutic targets. There remain substantial gaps in our knowledge of RA‐related ILD. Concerted multinational efforts by expert centers has the potential to elucidate the basic mechanisms underlying RA‐related UIP and other subtypes of RA‐related ILD and facilitate the development of more efficacious and safer drugs.