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The dysregulated release of cytokines has been identified as one of the key factors behind poorer outcomes in COVID-19. This cytokine storm produces an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress (ARDS), pulmonary edema and multi-organ failure. Alleviating this inflammatory state is crucial to improve prognosis. Pro-inflammatory factors play a central role in COVID-19 severity, especially in patients with comorbidities. In these situations, an overactive, untreated immune response can be deadly, suggesting that mortality in COVID-19 cases is likely due to this virally driven hyperinflammation. Administering immunomodulators has not yielded conclusive improvements in other pathologies characterized by dysregulated inflammation such as sepsis, SARS-CoV-1, and MERS. The success of these drugs at reducing COVID-19-driven inflammation is still anecdotal and comes with serious risks. It is also imperative to screen the elderly for risk factors that predispose them to severe COVID-19. Immunosenescence and comorbidities should be taken into consideration. In this review, we summarize the latest data available about the role of the cytokine storm in COVID-19 disease severity as well as potential therapeutic approaches to ameliorate it. We also examine the role of inflammation in other diseases and conditions often comorbid with COVID-19, such as aging, sepsis, and pulmonary disorders. Finally, we identify gaps in our knowledge and suggest priorities for future research aimed at stratifying patients according to risk as well as personalizing therapies in the context of COVID19-driven hyperinflammation., RR acknowledges funding from IdISBa/Impost turisme sostenible/Govern de les Illes Balears (Agencia d'Estrategia Turistica de les Illes Balears-Govern de les Illes Balears) through a Radix fellowship. MG-F acknowledges funding by the Miguel Servet Program (MS19/00201), Instituto de Salud Carlos III (ISCIII), Madrid. Figures were created with images from Canva (www.canva.com) under Free Media License Agreement.

Purpose: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. Trial registration: NCT01420744., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

[EN] Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients with asthma is airway inflammation. In recent decades, efforts have been made to characterise the heterogeneous clinical nature of asthma. The interest in improving the definitions of asthma phenotypes and endotypes is growing, although these classifications do not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts have been made to identify the most relevant molecular and cellular biomarkers underlying the immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E (IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature. Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum of asthma could contribute to the development of novel therapeutic strategies for the disease.

Background: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN beta-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naive to IFN beta. Methods: Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. Results: Biomarkers steadily increased during all study period by 45.3% for beta 2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. Conclusions: BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either., This study was sponsored by Merck S.L Spain, an affiliate of Merck KGaA, Darmstadt, Germany. Delicias Munoz, Received honoraria for scientific advice and speaking from de Biogen Idec, Merck Serono, Novartis, Bayer, Teva and Gemzime Sanofi Aventis. Antonio Escartin, Research fee from Bayer-Schering, Merck-Serono, Novartis, Teva and Biogen. Dolores Dapena, Fee for patient recruitment. Francisco Coret, Speaking honoraria, travel expenses for scientific meetings, or has participated in advisory boards of clinical trials in the past years, with the following companies: Biogen Idec, EMD Merck Serono, Novartis, and Teva Pharmaceuticals. Dionisio Fernandez-Uria, Speaking honoraria, fee for patient recruitement and assistance for congress attendance from Merck-Serono. Domingo Perez, Participated in studies carried out by Schering and Biogen. Bonaventura Casanova, Honoraria from Merck, Sanofi, Teva, Roche and Novartis. Cristina Guijarro, Received research funding by Merck-Serono. Actually, Merck-Serono employee. Elvira Munteis, Payment of travel expenses, accommodation and congress attendance. Merk-Serono and Teva-Sanofi: Speaking honoraria., Biogen: Fee for patient recruitment., Novartis, Merk-Serono: Funds for research. Biogen, Bayer, Merk-Serono, Teva-Sanofi, Novartis: Sponsoring contribution for educational programs. Biogen, Bayer, Merk-Serono, Teva-Sanofi, Novartis: Maria del Campo Amigo. Robustiano Pego, No conflict of interest. Carmen Calles, Fee for patient recruitment, Received speaking honoraria from Novartis, Sanofi and Biogen. Cesar Garcia-Rey, Contracted out by Merck to arrange this manuscript. Nuria Monsalve, Merck-Serono employee. David Sanchez-Matienzo, Merck-Serono employee.

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an enhanced inflammatory response to smoking that persists despite quitting. The resolution of inflammation (catabasis) is a complex and highly regulated process where tissue resident macrophages play a key role since they phagocytose apoptotic cells (efferocytosis), preventing their secondary necrosis and the spill-over of their pro-inflammatory cytoplasmic content, and release pro-resolution and tissue repair molecules, such as TGF beta, VEGF and HGF. Because inflammation does not resolve in COPD, we hypothesized that catabasis may be abnormal in these patients. Methods: To explore this hypothesis, we studied lung tissue samples obtained at surgery from 21 COPD patients, 22 smokers with normal spirometry and 13 non-smokers controls. In these samples we used: (1) immunohistochemistry to assess the expression of CD44, CD36, VEGF and TGF beta in lung macrophages; (2) real time PCR to determine HGF, PPAR gamma, TGF beta, VEGF and MMP-9 gene expression; and, (3) ELISA to quantify lipoxin A4, a lipid mediator of catabasis. Results: We found that current and former smokers with COPD showed: (1) more inflammation (higher MMP-9 expression); (2) reduced macrophage surface expression of CD44, a key efferocytosis receptor; and, (3) similar levels of TGF beta, VEGF, HGF, PPAR gamma, and lipoxin A4 than smokers with normal spirometry, despite the presence of inflammation and disease. Conclusions: These results identify several potential abnormalities of catabasis in patients with COPD., Supported, in part, by FIS 09/00629, FIS 10/00523 and an unrestricted grant from GSK.