Purinergic receptor ligands: the cytokine storm attenuators, potential therapeutic agents for the treatment of COVID-19.

The coronavirus disease-19 (COVID-19), at first, was reported in Wuhan, China, and then rapidly became pandemic throughout the world. Cytokine storm syndrome (CSS) in COVID-19 patients is associated with high levels of cytokines and chemokines that cause multiple organ failure, systemic inflammation, and hemodynamic instabilities. Acute respiratory distress syndrome (ARDS), a common complication of COVID-19, is a consequence of cytokine storm. In this regard, several drugs have been being investigated to suppress this inflammatory condition. Purinergic signaling receptors comprising of P1 adenosine and P2 purinoceptors play a critical role in inflammation. Therefore, activation or inhibition of some subtypes of these kinds of receptors is most likely to be beneficial to attenuate cytokine storm. This article summarizes suggested therapeutic drugs with potential anti-inflammatory effects through purinergic receptors.

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

Extracorporeal blood purification treatment options for COVID-19: The role of immunoadsorption.

The activation of the innate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.

The effectiveness of continuous renal replacement therapy in critical COVID-19 patients with cytokine release syndrome: a retrospective, multicenter, descriptive study from Wuhan, China.

BACKGROUND: Coronavirus disease (COVID-19) has spread rapidly since 2019. Approximately 15% of the patients will develop severe complications such as multiple organ disease syndrome related to cytokine release syndrome (CRS). Continuous renal replacement therapy (CRRT) can remove inflammatory cytokines through filtration or adsorption. We evaluated the effectiveness of CRRT in COVID-19 patients with CRS. METHODS: This retrospective, multicenter, descriptive study included 83 patients with CRS from three hospitals in Wuhan. RESULTS: In COVID-19 patients with CRS, the fatality rate was even higher in CRRT group (P=0.005). However, inflammatory markers such as C-reactive protein, neutrophil counts, and D-dimer decreased after CRRT (P<0.05). Results of Lasso model showed that tracheotomy (ß -1.31) and convalescent plasma (ß -1.41) were the protective factors. In contrast, CRRT (ß 1.07), respiratory failure (ß 1.61), consolidation on lung CT (ß 0.48), acute kidney injury (AKI) (ß 0.47), and elevated neutrophil count (ß 0.02) were the risk factors for death. CONCLUSIONS: Our results showed that although CRRT significantly reduced the inflammation, it did not decrease the fatality rate of patients with CRS. Therefore, the choice of CRRT indication, dialysis time and dialysis mode should be more careful and accurate in COVID-19 patients with CRS.

Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation.

Introduction: The mortality of coronavirus disease 2019 (COVID-19) is frequently driven by an injurious immune response characterized by the development of acute respiratory distress syndrome (ARDS), endotheliitis, coagulopathy, and multi-organ failure. This spectrum of hyperinflammation in COVID-19 is commonly referred to as cytokine storm syndrome (CSS). Areas covered: Medline and Google Scholar were searched up until 15th of August 2020 for relevant literature. Evidence supports a role of dysregulated immune responses in the immunopathogenesis of severe COVID-19. CSS associated with SARS-CoV-2 shows similarities to the exuberant cytokine production in some patients with viral infection (e.g.SARS-CoV-1) and may be confused with other syndromes of hyperinflammation like the cytokine release syndrome (CRS) in CAR-T cell therapy. Interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha have emerged as predictors of COVID-19 severity and in-hospital mortality. Expert opinion: Despite similarities, COVID-19-CSS appears to be distinct from HLH, MAS, and CRS, and the application of HLH diagnostic scores and criteria to COVID-19 is not supported by emerging data. While immunosuppressive therapy with glucocorticoids has shown a mortality benefit, cytokine inhibitors may hold promise as 'rescue therapies' in severe COVID-19. Given the arguably limited benefit in advanced disease, strategies to prevent the development of COVID-19-CSS are needed.

A case report of fulminant cytokine release syndrome complicated by dermatomyositis after the combination therapy with immune checkpoint inhibitors.

INTRODUCTION: Immune-related adverse events (ir-AEs) are increasingly becoming a concern, as immune checkpoint inhibitors (ICIs) are used more frequently. Herein, we present a case of fulminant cytokine release syndrome (CRS) complicated by dermatomyositis after the combination therapy with ICIs. PATIENT CONCERNS: A 70-year-old male developed dermatomyositis during the course of treatment with two ICIs, nivolumab and ipilimumab. He was treated by steroid pulse therapy, but the effect was limited. Afterwards, he had acute-onset high fever, hypotension, respiratory failure, impaired consciousness, renal failure, and coagulation abnormality at the same time. C reactive protein (CRP), creatinine kinase (CK), D-dimer, and ferritin levels were considerably elevated: CRP, 24 mg/dL; CK, 40,500 U/L; D-dimer, 290 µg/mL; ferritin, 329,000 ng/mL. DIAGNOSIS: CRS induced by ICI combination therapy. INTERVENTIONS: Given that high fever and elevated CRP level indicated potential sepsis, an antibiotic was used until the confirmation of negative blood cultures. All the simultaneous acute symptoms were supposed to be CRS. He was admitted to the intensive care unit (ICU), and temporary intubation and hemodialysis were needed. Immunosuppressive therapy was reinforced by mycophenolate mofetil together with steroid, and plasma exchange was performed for the elimination of abnormal proteins. OUTCOMES: The patient's clinical symptoms and laboratory parameters gradually improved and he was discharged from the ICU in a month. CONCLUSION: Fulminant CRS can be induced by ICI combination therapy. As the initial symptoms of CRS resemble sepsis, it is important to consider CRS as a differential diagnosis and to initiate immunosuppressive therapy early when needed. In steroid-resistant cases, early introduction of other immunosuppressive therapy and plasma exchange can be effective.