The proteolytic airway environment associated with pneumonia acts as a barrier for treatment with anti-infective antibodies.

Like pneumonia, coronavirus disease 2019 (COVID-19) is characterized by a massive infiltration of innate immune cells (such as polymorphonuclear leukocytes) into the airways and alveolar spaces. These cells release proteases that may degrade therapeutic antibodies and thus limit their effectiveness. Here, we investigated the in vitro and ex vivo impact on anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) IgG1s and other IgG subclasses (IgG2 and IgG4) of the neutrophil elastase, proteinase 3 and cathepsin G (the three main neutrophil serine proteases) found in endotracheal aspirates from patients with severe COVID-19. Although the IgGs were sensitive to neutrophil serine proteases, IgG2 was most resistant to proteolytic degradation. The two anti-SARS CoV2 antibodies (casirivimab and imdevimab) were sensitive to the lung's proteolytic environment, although neutrophil serine protease inhibitors only partly limited the degradation. Overall, our results show that the pneumonia-associated imbalance between proteases and their inhibitors in the airways contributes to degradation of antiviral antibodies.

[Real-life survival of idiopathic pulmonary fibrosis with anti-fibrotic medication]. / Survie en vie réelle des patients ayant une fibrose pulmonaire idiopathique sous traitement anti-fibrosant.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an irreversible fibrosing disease with median survival at diagnosis of 2-5 years. That said, pirfenidone and nintedanib slow down the gradual decline in respiratory function. Clinical trials have shown that while they are not curative, these drugs reduce mortality and increase survival time compared to placebo. This objective of this work was to compare the real-life survival of patients with IPF diagnosed at the Tours University Hospital depending on whether or not they took anti-fibrotic medication. METHODS: This is a monocentric retrospective study involving 176 patients diagnosed with IPF starting from 1997. Out of these 176 patients, 100 were treated with anti-fibrotic agents and 76 did not receive any anti-fibrotic treatment. RESULTS: Survival significantly increased in the group with anti-fibrotic medication, with median survival of 59 months [46-87] versus 39 months [29-65] (P=0.022). Predictive factors for death were neoplasia, IPF exacerbation and decreased DLCO. CONCLUSION: Our study corroborates the beneficial result observed in clinical trials by showing longer survival in patients using anti-fibrotic agents.

Therapeutic antibodies - natural and pathological barriers and strategies to overcome them.

Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a remarkable expansion with an expected acceleration in 2021-2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients' adherence to the treatment.

Impulse oscillometry and spirometry measurements relative to personal best values at the time of acute exacerbations of cystic fibrosis in adults.

BACKGROUND: Diagnosis of acute exacerbation (AE) of cystic fibrosis (CF) must be precise because both under- and over-prescription of antibiotics may be detrimental. How lung function tests contribute to diagnose AE is unclear. We aimed to describe variation of spirometry and oscillometry measurements, at Stable state and at AE in adults with CF. METHODS: Patients were included in a retrospective single-centre study when both spirometry (FEV1, FVC) and oscillometry (X5, R5, R5-R20 and AX) data were available for at least one Stable and one AE visit between December 2016 and July 2019. For each visit, we calculated variation (Δ) in spirometry and oscillometry indices in comparison with personal best values. Measurements were expressed as % of predicted values and Z-scores when applicable. Areas under ROC curves (AUC) were computed. RESULTS: Forty-two patients (28 ± 9 years, FEV1 64 ± 21%) were included; 80 AE and 104 Stable visits were analysed. FEV1 (L, %pred and Z-score) and FVC (%pred and Z-score) varied significantly between AE and Stable visits (p < .05), although differences were small (80 ml/2.7%pred for FEV1). Among oscillometry indices, X5 (kPa.s.L-1 ), R5-R20 (kPa.s.L-1 ) and AX (kPa/L) varied significantly. The AUCs for the variation in spirometry indices ranged from 0.601 (ΔFVC L) to 0.635 (ΔFEV1%pred). They were not significantly different from the AUCs for ΔX5 (0.589), ΔR5-R20 (0.649) and ΔAX (0.598). CONCLUSIONS: Performance of both spirometry and oscillometry to discriminate AE from Stable state was poor. Variation of oscillometry indices (X5, R5-R20, AX) may be helpful when spirometry is unreliable or uncomfortable.

Desquamative interstitial pneumonia induced by metal exposure. A case report and literature review.

BACKGROUND: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described. OBJECTIVES/METHODS: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking. RESULTS: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year. CONCLUSION: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 79-84).