Early Treatment of Cytokine Storm Syndrome in Covid-19

This proposal addresses the problem of preventing the very high mortality and morbidity associated with the development of Cytokine Storm Syndrome (CSS) associated respiratory failure in Covid-19 infection.

The first aim of this project is to determine whether rapidly assayed early clinical laboratory markers of CSS (eCSS: leucopenia, lymphopenia, and elevated ferritin, d-dimer, LDH, CRP, and AST/ALT) in patients admitted to the hospital with respiratory compromise in the setting of Covid-19 infection can accurately identify patients with CSS as defined by validated CSS case definitions (H-Score, aHLH-2004). Confirmation of eCSS predictive of evolving CSS will identify patients at risk for rapid deterioration of lung function and inform early initiation of treatment for CSS. Genotyping studies will also be performed on patients with confirmed CSS to determine whether perforin pathway mutations commonly present in CSS associated with other disorders are present. The second aim is to determine whether early treatment with rhIL-1Ra (anakinra) in patients admitted to the hospital with markers of CSS improves or prevents deterioration of respiratory dysfunction and prevents the development of respiratory failure requiring mechanical ventilation.

The active treatment group will receive anakinra 100 mg subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to 100 mg twice daily for the remaining 5 days.

The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to twice daily for the remaining 5 days.

The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days

The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days

Percentage of subjects discharged from hospital alive and who did not require intubation and mechanical ventilation

Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent

25% change (decrease) in noted baseline elevations of serum ferritin and CRP measured 48-72 hours after following initial dosing of anakinra/placebo.

Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 Hours.

Supplemental oxygen requirement to maintain oxygen saturation >90% stable or decreased without escalation of respiratory support measures (addition of CPAP, initiation of mechanical ventilation)

Percentage of participants requiring no more than 2 L/min nasal canula oxygen to maintain oxygen saturation >93% by Day 10

Normalization or ≥ 75% improvement by Day 10 (120 hours) in each (all) of the following laboratory CSS attributes elevated beyond the normal range at randomization: ferritin, d-dimer, CRP, and LDH.

Occurence of new bacterial or fungal or viral infection through the time of hospital discharge or Day 28.

Inclusion Criteria: 18 years old or older Molecular (pcRNA) diagnosis of SARS-CoV-2 infection Chest imaging studies consistent with Covid-19 pneumonia Hyperferritinemia (>700 ng/ml) History of fever >38 degrees C Any three of the following: Elevated d-dimer (> 500 ng/ml) thrombocytopenia (< 130,000/mm3) leucopenia (WBC <3500/mm3) or lymphopenia (<1000/mm3) elevated AST or ALT (> 2X ULN) elevated LDH (> 2X ULN) CRP > 100 mg/L Exclusion Criteria: Participation in other investigational treatment protocols for Covid-19 infection Culture confirmed active bacterial infection requiring antibiotic therapy On mechanical ventilation Previous known hypersensitivity reaction to anakinra Previous known hypersensitivity reaction to E Coli derived proteins Pregnant or breast-feeding females