COVID-19 Hyperinflammation Syndrome (COV-HI): Protocol for a Rapidly Executed Cohort Study

Early information from the UK ICNARC (Intensive Care National Audit and Research Centre)- COVID-19 Study Case Mix Programme Database 27 March 2020 report that critical care unit admissions with COVID-19 totaled 775 patients of whom 79 patients have died, 86 patients were discharged alive from critical care and 609 patients were last reported as still being in critical care. It is imperative to reduce this high death rate. Emerging evidence from China, Italy and the US suggests that in a small subset of patients with severe COVID-19 respiratory disease there is a hyperinflammatory syndrome (COV-HI), which may be contributing to the high mortality and morbidity.

Terminology regarding hyperinflammation is heterogenous. When caused by genetic abnormalities in children it is called primary or familial haemophagocytic lymphohistiocytosis (fHLH). Secondary HLH (sHLH) is a hyperinflammatory process driven by infection, rheumatic disorders and malignancy (usually lymphoproliferative disorders). sHLH is termed macrophage activation syndrome (MAS) when associated with rheumatic disease, macrophage activation-like syndrome (MALS) in sepsis, and cytokine release syndrome (CRS) following immune effector cell therapies (haplo-identical allogeneic stem cell transplantation or CAR-T cell therapy). It is likely that such hyperinflammatory states lie on a spectrum and collectively the clinical phenomenon has been called cytokine storm syndrome (CSS) or hyperinflammation (HI).

Current diagnostic criteria for HI are based on fHLH (HLH-2004 guidelines) and the H score (a weighted composite generating a probability). Recently published management algorithms in adults are based on consensus expert opinion and clinical experience, extrapolated from paediatric literature in fHLH.

The HLH Across-speciality Collaboration (HASC) is a 162-strong group of clinicians/scientists who specialize in the management of patients with hyperinflammation. HASC member include Rheumatologists, Haematologists, Intensivists, Infectious Disease specialists, Immunologists, Virologists, Nephrologists and Gatroenterologists from both adult and paediatric backgrounds. Members of HASC have led the set-up of multidisciplinary team meetings (MDTs) to raise awareness of and manage hyperinflammatory illness, completed national audits to demonstrate hyperinflammation is often missed and have set up HLH registries and bioresources (https://research.ncl.ac.uk/ukhr/).

COVID-19 hyperinflammation (COV-HI): rationale for treatment and summary of available evidence In COVID-19 respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. ARDS is a late pre-terminal event in these patients but there is a reported clinical phenotype of severe COVID-19 where hyperinflammation complicates the respiratory failure, termed here COVID-19 hyperinflammation or COV-HI.