Activation of the AIM2 Receptor in Circulating Cells of Post-COVID-19 Patients With Signs of Lung Fibrosis Is Associated With the Release of IL-1α, IFN-α and TGF-ß.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-ß. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-ß were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.

Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems.

Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.

Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-ß but Higher Levels of IL-1α and TGF-ß.

PURPOSE: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. PATIENTS AND METHODS: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. RESULTS: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-ß, but not of IFN-ß, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-ß, but higher IL-1α and TGF-ß. CONCLUSIONS: We found that higher IL-1α and TGF-ß and lower plasma levels of IFN-ß could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients.

Prevalence of Persistent Olfactory Disorders in Patients With COVID-19: A Psychophysical Case-Control Study With 1-Year Follow-up.

The purpose of this multicenter case-control study was to evaluate a group of patients at least 1 year after coronavirus disease 2019 (COVID-19) with Sniffin' Sticks tests and to compare the results with a control population to quantify the potential bias introduced by the underlying prevalence of olfactory dysfunction (OD) in the general population. The study included 170 cases and 170 controls. In the COVID-19 group, 26.5% of cases had OD (anosmia in 4.7%, hyposmia in 21.8%) versus 3.5% in the control group (6 cases of hyposmia). The TDI score (threshold, discrimination, and identification) in the COVID-19 group was significantly lower than in the control group (32.5 [interquartile range, 29-36.5] vs 36.75 [34-39.5], P < .001). The prevalence of OD was significantly higher in the COVID-19 group, confirming that this result is not due to the underlying prevalence of OD in the general population.

Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence.

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.

Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study.

To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses.

Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications.

The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.