Cytokine release syndrome in COVID-19 patients, a new scenario for an old concern. The fragile balance between infections and autoimmunity

On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient’s clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk

Inflammation and Autonomic Function

Inflammation is generally a temporary and limited condition but may lead to a chronic one if immune and physiological homeostasis are disrupted. The autonomic nervous system has an important role in the short- and, also, long-term regulation of homeostasis and, thus, on inflammation. Autonomic modulation in acute and chronic inflammation has been implicated with a sympathetic interference in the earlier stages of the inflammatory process and the activation of the vagal inflammatory reflex to regulate innate immune responses and cytokine functional effects in longer processes. The present review focuses on the autonomic mechanisms controlling proinflammatory responses, and we will discuss novel therapeutic options linked to autonomic modulation for diseases associated with a chronic inflammatory condition such as sepsis

Longitudinal evaluation of hemorheological markers in acute inflammatory diseases

Dissertação para obtenção do Grau de Mestre em Genética Molecular e BiomedicinaAcute myocardial infarction (AMI), sepsis and rheumatoid arthritis (RA) are part of the inflammatory diseases’ group. Every year millions of people are affected and die because of them, all around the globe. In the past years our knowledge of these diseases has increased and a light on their pathophysiology has been shed, but there is still much more to be discovered. Biological markers that would make pre-disease diagnosis possible would change many of the outcomes for patients suffering from them. The aim of this study was to access the evolution of four hemorheological markers (erythrocyte deformability, erythrocyte aggregation, nitric oxide – NO and S-nitrosoglutathione – GSNO) in order to understand their behaviour in three types of inflammatory diseases. Four study groups were created: ST-elevation myocardial infarction (STEMI) group (15 patients), RA (25 patients), sepsis (14 patients) and the control group (CTR; 15 healthy volunteers). In STEMI group two different measurements were taken, one at time of hospital admission and the other after a month. In the sepsis group four measurements were taken throughout the internment in the Intensive Care Unit (ICU): admission, 24 hours, 72 hours after and discharge. Significant difference was observed in the 10s erythrocyte aggregation marker between the STEMI patients at hospital admission and CTR group. Significant differences of deformability, aggregation and GSNO were obtained upon comparison of sepsis patients (at all time-points) and CTR. In addition to this, the longitudinal changes of GSNO erythrocyte concentrations were significant. In conclusion, abnormal values for some of the studied hemorheological parameters were verified in inflammatory diseases, namely myocardial infarction (STEMI), sepsis and rheumatoid arthritis. The results seem to point out to a relation between inflammation and the hemorheological alterations

Overexpression of Gilz protects mice against lethal septic peritonitis

Sepsis in humans and experimental animals is characterized by an acute inflammatory response. Glucocorticoids (GCs) are widely used for the treatment of many inflammatory disorders, yet their effectiveness in sepsis is debatable. One of the major anti-inflammatory proteins induced by GCs is GILZ (Glucocorticoid-Induced Leucine Zipper, coded by the TSC22D3 gene). We found that TSC22D3 mRNA expression is downregulated in white blood cells of human sepsis patients. Interestingly, transgenic Gilz overexpressing mice (Gilz-tg) showed better survival rates in the cecal ligation and puncture (CLP) model of mouse sepsis. To our surprise, Gilz had only mild anti-inflammatory effects in this model, since the systemic pro-inflammatory response was not significantly reduced in Gilz-tg mice compared to control mice. During CLP, we observed reduced bacterial counts in blood of Gilz-tg mice compared to control mice. We found increased expression of Tsc22d3 mRNA specifically in peritoneal exudate cells in the CLP model, as well as increased capacity for bacterial phagocytosis of CD45 Gilz-tg cells compared to CD45 Gilz-wt cells. Hence, we believe that the protective effects of GILZ in the CLP model can be linked to a more efficient phagocytosis

Pentraxin 3 in cardiovascular disease

The long pentraxin PTX3 is a member of the pentraxin family produced locally by stromal and myeloid cells in response to proinflammatory signals and microbial moieties. The prototype of the pentraxin family is C reactive protein (CRP), a widely-used biomarker in human pathologies with an inflammatory or infectious origin. Data so far describe PTX3 as a multifunctional protein acting as a functional ancestor of antibodies and playing a regulatory role in inflammation. Cardiovascular disease (CVD) is a leading cause of mortality worldwide, and inflammation is crucial in promoting it. Data from animal models indicate that PTX3 can have cardioprotective and atheroprotective roles regulating inflammation. PTX3 has been investigated in several clinical settings as possible biomarker of CVD. Data collected so far indicate that PTX3 plasma levels rise rapidly in acute myocardial infarction, heart failure and cardiac arrest, reflecting the extent of tissue damage and predicting the risk of mortality

Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

: We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered

Blood Levels of Macrophage Migration Inhibitory Factor after Successful Resuscitation from Cardiac Arrest

Introduction: Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patient

Rheumatoid arthritis, multiple sclerosis and lupus: key points from the COVID-19 era

The purpose of this work was to analyse published data on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis (MS) and SARS-CoV-2 infection: susceptibility, post-infection autoimmune disease (AD) exacerbation, immunosuppressive therapies and long COVID. Supported by PICO strategy, two independent reviewers conducted the research in the PubMed/Medline database from January 2020 to June 2022 and included 16 articles on RA, 25 on MS and 12 on SLE. The quality assessment of the studies was performed using criteria from the National Institute of Health. Patients with RA or SLE had increased susceptibility to contracting SARS-CoV-2. It was higher in RA and increased with the patients’ comorbidities. For MS, susceptibility to SARS-CoV-2 was similar to the general population. Post-infection AD exacerbation occurred in AR, SLE and MS with an increased number of hospitalisations and deaths. Regarding therapies, in RA the use of glucocorticoids (GC) was associated with a worsening of the infection. A more severe clinical picture was associated with anti-CD20 in SLE and with anti-CD20 and methylprednisolone in MS. Considering long COVID, RA and SLE patients had a higher risk of complications opposite to MS patients. There was a higher susceptibility to SARS-CoV-2 infection in rheumatological diseases AR and SLE, exacerbated by age and comorbidities. For RA and MS, GC aggravated the infection and for SLE and MS anti-CD20 antibodies use. In all AD there was exacerbation and worsening of the clinical picture translated in long COVID, the latter with MS exception