Personalized Respiratory Medicine: Exploring the Horizon, Addressing the Issues. Summary of a BRN-AJRCCM Workshop Held in Barcelona on June 12, 2014.

This Pulmonary Perspective summarizes the content and main conclusions of an international workshop on personalized respiratory medicine coorganized by the Barcelona Respiratory Network (www.brn.cat)and the AJRCCM in June 2014. It discusses (1) its definition and historical, social, legal, and ethical aspects; (2) the view from different disciplines, including basic science, epidemiology, bioinformatics,and network/systems medicine; (3) the bottlenecks and opportunities identified by some currently ongoing projects; and (4) the implications for the individual, the healthcare system and the pharmaceutical industry. The authors hope that, although it is not a systematic review on the subject,this document can be a useful reference for researchers, clinicians, healthcare managers, policy-makers,and industry parties interested in personalized respiratory medicine

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis (DEFINE):A Phase Ib/IIa Randomised Controlled Trial

RATIONALE: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. OBJECTIVES: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. METHODS: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. MEASUREMENTS AND MAIN RESULTS: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2–7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. CONCLUSIONS: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020–002230–32)

Review: Differences in the pharmacodynamics of budesonide/formoterol and salmeterol/fluticasone reflect differences in their therapeutic usefulness in asthma

Although the available inhaled corticosteroid (ICS)/long-acting β 2 -agonist (LABA) combinations principally work in a similar fashion, they differ in several important ways, leading to different efficacy. The ICS/LABA combination product budesonide/formoterol can be used as both maintenance and reliever therapy, providing a fixed maintenance dose, which does not change, and replacing short-acting β 2 -agonists as relievers thereby allowing intervention to address the underlying inflammation at the earliest sign of symptomatic worsening. This approach is not suitable for other combination products such as salmeterol/fluticasone. Here we review the pharmacological differences of budesonide/ formoterol and salmeterol/fluticasone that permit the use of budesonide/formoterol as both maintenance and reliever therapy

Heterozygous, a1-antitrypsin deficiency may be associated with cold urticaria.

Proteins of the serpin family (serine protease inhibitor) control key steps in the inflammatory, coagulation and complement systems. C1‐inhibitor deficiency predisposes to hereditary angioneurotic oedema, and other serpins control proteolytic enzymes that may cause complement activation or the forming of oedema. We investigated whether deficiency of proteins of the serpin family may predispose to cold urticaria and therefore screened 7 male patients with severe cold urticaria for the presence of deficieney alleles of some of the members of the serpin antiprotease family. There were no findings of C1‐inhibitor, α1‐antitrypsin, α2‐antiplasmin, antithrombin III, tissue plasminogen activator inhibitor or thyroxine binding protein deficiency. The prevalence of heterozygous α1‐antichymotrypsin deficieney was significantly higher than expected (prevalence ratio 25.8 (95% confidence interval 6.0‐112), p< 0.0001). This finding is in concert with previous studies that have shown lower mean levels of α1‐antichymotrypsin among patients with cold urticaria and suggests that heterozygous deficiency of this antiprotease, which controls neutrophil eathepsin G and mast cell chymase may predispose to cold urticaria. The present series is, however, small and the results need confirmation in larger materials

Familial α1‐Antichymotrypsin Deficiency

ABSTRACT We studied patients and their relatives with partial deficiency, approximately 50% of normal plasma levels, of α1‐antichymotrypsin (ACT), an acute phase reactant with anti‐cathepsin G activity. Six of eight ACT deficient individuals, over 25 years of age, had liver and three of eight lung manifestations, varying from severe disease to subtle laboratory abnormalities. The ACT of deficient individuals (who are heterozygotes for a rare gene, q=0.003) had normal crossed immunoelectrophoretic properties. The abnormal gene is inherited in an autosomal, dominant way. The results suggest that deficiency of this antiprotease, which also has immune response modulating properties, may predispose to liver and lung disease. 1986 Association for the Publication of the Journal of Internal Medicin

The microheterogeneity of desialylated α1-antichymotrypsin : the occurrence of two amino-terminal isoforms, one lacking a His-Pro dipeptide

ACT (α1-antichymotrypsin), a serine antiproteinase with specificity against neutrophil cathepsin G, is homologous with α1-antitrypsin, plasminogen activator inhibitor and angiotensinogen, all with known amino-terminal microheterogeneity. Here we report that the two predominant isoforms of desialylated ACT obtained on isoelectric focusing correspond to a microheterogeneity at the amino terminus of ACT: one isoform (His-Pro-Asn-Ser-Pro-) and a two residues shorter isoform (Asn-Ser-Pro-). The relative occurrence of the two isoforms was comparable both in normal plasma, acute-phase plasma and plasma from subjects with heterozygous familial ACT deficiency. When desialyllated ACT, isolated by affinity chromatography from ACT-deficient, normal or acute-phase plasma, was compared with regard to mass and charge microheterogeneity, we found no significant differences in either respect. Nor was the isoform pattern of desialylated plasma from patients with rheumatoid arthritis different. Although the occurrence of heterozygous familial ACT deficiency implies genotypic variation, isolated ACT from patients with the trait was not found to exhibit any phenotypic variation detectable by standard electrophoretic methods

Predictive role of galectin-3 for immune checkpoint blockades (ICBs) in advanced or metastatic non-small cell lung cancer: a potential new marker for ICB resistance

Purpose: We aimed to assess the predictive value of galectin-3 (Gal-3) in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint blockades (ICBs) therapy using both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Methods: This retrospective study was conducted at Seoul National University Hospital. Patients with EGFR/ALK-wild-type advanced or metastatic NSCLC who received ICBs between December 2013 and December 2019 were enrolled. Patients with archived blood samples collected prior to ICB treatment were assigned to the ELISA cohort. In addition, those with tissue samples from sites of recurrence or metastasis were assigned to an IHC cohort. Then, we analyzed Gal-3 expression in both cohorts. Results: Fifty-six patients in the ELISA cohort were grouped into low (N = 36) and high (N = 20) groups, using the mean Gal-3 ELISA level (13.24 pg/ml) as a cutoff. The high group demonstrated trends toward reduced progression-free survival (PFS) (0.9 vs. 3.7 months, p = 0.196) and significantly shorter overall survival (OS) (1.6 vs. 12.3 months, p = 0.018) than the low group. We categorized 94 patients in the IHC cohort into negative (N = 31) and positive (N = 63) groups based on Gal-3 IHC positivity. However, the median PFS (4.6 vs. 4.6 months for the negative vs. positive IHC group, respectively, p = 0.345) and OS (16.4 vs. 9.0 months, p = 0.137) were not significantly different. Conclusion: High blood Gal-3 levels may predict inferior survival in patients with advanced or metastatic NSCLC treated with ICBs.N

Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide

Background: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. Objective: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. Methods: In a randomized, double-blind, placebo-controlled trial, 7,241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 μg for adults. The study included 2,473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except fo