Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)−1β and IL-8 in sputum, accompanied by decreasedPseudomonasburden and restoration of secretory leukoprotease inhibitor levels. Once treated with ETI, all airway inflammatory markers studied in PWCF had reduced to levels found in matched non-CF bronchiectasis controls. In PWCF with advanced disease, ETI resulted in decreased plasma concentrations of IL-6, C-reactive protein and soluble TNF receptor one as well as normalisation of levels of the acute phase protein, alpha-1 antitrypsin. These data clarify the immunomodulatory effects of ETI and underscore its role as a disease modifier.

Platinum-based chemotherapy is the standard of care for ovarian cancer and non-small cell lung cancer (NSCLC). However, resistance to platinum agents invariably develops. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have great potential here as they exert their anti-tumour effect via alternative mechanisms to platinum-based drugs and as such may remain unaffected by emergent resistance to platinum. A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFR-TKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated. Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150mg/day erlotinib and 250mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients. Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for EGFR-TKIs; EGFR mutations are rare in ovarian cancer. Newer TKIs may improve response rates in these cohorts and future clinical trials need to collect tumour biopsies from all patients to ensure the success of personalised chemotherapy.

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV1. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P < 0.001). We uncovered two distinct AATD phenotypes based on an initial respiratory diagnosis: lung index and non–lung index. Lung indexes demonstrated a more rapid FEV1 decline between the ages of 20 and 50 and subsequently entered a plateau phase of minimal decline from 50 onward. Consequentially, IV-AAT had no effect on FEV1 decline, except in patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 lung index. Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV1 decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV1 is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations.

Mastitis is the most economically important disease affecting dairy cattle worldwide. Staphylococcus aureus is a highly prevalent cause of mastitis, causing infections ranging from sub-clinical to gangrenous. However, the interaction between the genotype of the infecting strain of S. aureus and the host response remains largely uncharacterised. To better understand the variation in presentation and outcomes of S. aureus-mediated bovine mastitis, we studied the interaction of a panel of mastitis isolates from several prominent bovine-associated lineages with bovine mammary epithelial cells (bMEC) and neutrophils. Significant differences in immune gene expression by infected primary or immortalised bMEC, or their elaboration of neutrophil chemoattractants, were observed and were dependent on the lineage of the infecting strain. Differences were also apparent in the invasiveness of S. aureus strains and their ability to survive killing by neutrophils. Our results demonstrate that a range of immune responses occur, suggesting the importance of S. aureus strain in dictating mastitis disease course. S. aureus lineages may therefore have adopted differing strategies for exploitation of the intramammary niche. Consequently, improved diagnosis of infecting lineage may enable better prognosis for S. aureus mastitis and reduce morbidity and economic loss.

Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy.