Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.

Immunopathogenesis and treatment of cytokine storm in COVID-19.

/pdf/cytokine-storm-in-covid-19-immunopathogenesis-and-therapy-3ef3tqvb.pdf

Cytokine Storm in COVID-19: Immunopathogenesis and Therapy

The "sex gap" in COVID-19 trials: a scoping review.

http://www.trasci.com/article/S1473050222001057/pdf

Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.

/pdf/covid-19-sepsis-pathogenesis-and-endothelial-molecular-4b1f1pzvkr.pdf

COVID-19 Sepsis: Pathogenesis and Endothelial Molecular Mechanisms Based on "Two-Path Unifying Theory" of Hemostasis and Endotheliopathy-Associated Vascular Microthrombotic Disease, and Proposed Therapeutic Approach with Antimicrothrombotic Therapy.

/pdf/therapeutic-plasma-exchange-as-a-rescue-therapy-in-patients-5fdj4zeook.pdf

Therapeutic plasma exchange as a rescue therapy in patients with coronavirus disease 2019: a case series.

BACKGROUND
Increasing the number of COVID-19 patients raises concerns about the capacity of the health care system. This issue emphasizes reducing the admission rate and expediting patient discharge.


OBJECTIVE
This study aimed to develop a discharge protocol for COVID-19 patients based on the existing capacity of the healthcare system and to assess its post-discharge outcomes.


METHODS
This is a multicenter cohort study. All COVID-19 patients referred to selected medical centers in Qom, Iran, from Feb. 19 to Apr. 19, 2020, were target populations. Eligible patients were classified into a) the criterion group and b) the non-criterion group. Patients were followed up daily for 14 days after discharge by phone, and the required data was gathered and recorded in follow-up form. Univariate (chi-square and t-tests) and multivariate multiple (multivariate probit regression) analysis were used.


RESULTS
A total of 2775 patients were included in the study (1440 people in the criterion group and 1335 in the non-criterion group). Based on multivariate probit regression, death was statistically associated with discharge outside our criteria (p<0.001), rising age (p<0.001), and being male (p=0.019), and readmission were associated with discharge outside our criteria (p<0.001), rising age (p=0.009), and having the history of underlying diseases (p=0.003). Furthermore, remission had statistically significant associations with discharge based on our criteria (p<0.001), decreasing age (p=0.001), and lack of a history of underlying diseases (p<0.001).


CONCLUSION
Mortality and readmission were significantly lower according to our discharge criteria. Our designed criteria apply to less developed and developing countries due to the limited capacity and resources available in the health care system.

Discharge of Confirmed COVID-19 Patients Based on WHO or Regional Criteria? A Cohort Study.

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Therapeutic plasma exchange as a rescue therapy in patients with coronavirus disease 2019: a case series.

Discharge of Confirmed COVID-19 Patients Based on WHO or Regional Criteria? A Cohort Study.