Ankara, Turkey – Research finds a cytokine storm and use of anakinra resulting in reduction in oxygen requirement and improvements in inflammatory markers and ferritin.

Case report: Cytokine storm and use of anakinra in a patient with COVID-19
Priyanka Nemchand, Hassan Tahir, Rapti Mediwake, Jeffrey Lee

“We present a case of a 50-year-old man with COVID-19 infection and acute respiratory distress syndrome as a result of a cytokine storm and use of anakinra, an interleukin 1-receptor antagonist that is normally used in the treatment of autoinflammatory disorders in adult patients. They saw a reduction in oxygen requirement and improvements in inflammatory markers and ferritin. Although They cannot determine its clinical efficacy from one case study, it may have a positive effect on the proinflammatory state that is associated with cytokine storm in COVID-19 infection.”

“COVID-19 can present from mild infection with fever and shortness of breath to severe interstitial pneumonia progressing to acute respiratory distress, multiorgan failure and death. COVID-19-associated pneumonia and ARDS have raised questions about the possible role of a cytokine storm in pathogenesis of SARS-CoV-2. Non-specific symptoms make it difficult to differentiate whether sepsis from bacteraemia is present, which can lead to delayed treatment. Our patient presented with persistent fever despite antibiotics, and deteriorating hypoxia, and extremely high inflammatory markers including ferritin and CRP.”

“Cytokine storms were earliest described in haemophagocytic lymphohistiocytosis in relation to rheumatological conditions and following T cell immunotherapy (rituximab and alemtuzumab). They present similarly with fever, general malaise and fatigue but furthermore diarrhoea, vascular leakage, cardiomyopathy, lung injury and the synthesis of acute phase proteins. Activated immune cells, most importantly macrophages and epithelial cells, release high levels of IL-6, IL-10 and tumour necrosis factor-α (TNF-α).”

“Respiratory symptoms such as cough and tachypnoea can progress to ARDS. Laboratory abnormalities that are common include cytopenias, elevated creatinine and liver enzymes, deranged coagulation, hyperferritinaemia and a high CRP.”

“How COVID-19 manifests pulmonary symptoms is not fully understood yet; however, it is thought to act similar to SARS-CoV-1 by acting on angiotensin-converting enzyme 2 receptor on alveolar epithelial cells activating IL-1B resulting in an inflammatory response in the lungs that leads to ARDS. More recently, cytokine storm has been implicated in viral infections such as avian influenza (H5N1) and SARS-CoV with the release of IL-10, IL-1B, IL-6, INF, TNF, chemokines and signs of acute lung injury progressing to ARDS with infiltration of monocytes and macrophages and spillover of cytokines into the systemic circulation, producing systemic sepsis, as defined by persistent hypotension, hyperthermia or hypothermia, leucocytosis or leucopenia, and thrombocytopenia.”

“In cytokine storms, IL-1B appears to be one of the main proinflammatory cytokines. Anakinra, an antagonist of IL-1 receptor (IL-1R), inhibits the release of IL-1B from macrophages and blockage of IL-1R has been associated with reversal of acute lung injury in avian influenza.”

“During the COVID-19 pandemic, there are emerging case report and cohort studies demonstrating beneficial effects of anakinra. San Raffaele Hospital, a tertiary healthcare centre in Milan, conducted a retrospective cohort study on the use of anakinra in patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU. Treatment with high-dose anakinra was safe and associated with clinical improvement. Seventy-two per cent of patients did not require mechanical ventilation and reduced CRP after 21 days. Multiple clinical trials are underway for the use of anakinra in COVID-19 pneumonia.”

“In our patient, there was reduction in the cytokine storm evidenced by a reduction in ferritin, fever and WCC after 2 days of anakinra. After 7 days, there was a significant reduction in oxygen requirement from 55% to 25% and an improvement in chest imaging with the consideration of extubation. However, he fatally suffered from sagittal sinus thrombosis that resulted in brainstem injury and death. There are reports of a higher incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia. There are several theories for hypercoagulability; the release of cytokines, as seen in COVID-19, can increase the liver’s production of clotting factors. A cohort of patients in ICU were found to have raised fibrinogen and platelets with normal prothrombin time (PT) and Activated Partial Thromboplastin Time (APPT) suggesting systemic inflammation and hypercoaguabilty as opposed to other conditions such as disseminated intravascular coagulopathy.18 19 Our patient had a resolution of fibrinogen, peaking at 9.0–4.8g/L after 7 days of anakinra.”

“Our case suggests that the administration of anakinra in SARSCoV-2-induced cytokine storm contributed to a significant clinical improvement. Anakinra is a cost-effective treatment in comparison with other potential biological treatments currently under clinical trials.20 21 It also has a potentially safe side-effect profile. We suggest that earlier identification of patients developing cytokine storm and COVID-19 infection with monitoring of biomarkers (rising ferritin, CRP) and treatment with IL-1R antagonist anakinra may help prevent the sequelae of COVID-19 complications.”