Identification of Novel Factors Leading to Activated Macrophage Expansion in COVID19 and Related Conditions to Guide Targeted Intervention

Purpose:

The primary purpose of this research is to identify an early warning for hyperinflammation in COVID19 so that interventional trials of anti-inflammatory agents can target this sub-group.

Background Mortality from SARS-CoV-2 infection causing COVID-19 is estimated to be 3.7% globally. The principal cause of death due to COVID-19 is respiratory failure due to acute respiratory distress syndrome. Early reports have suggested that a subgroup of individuals suffer a hyperinflammatory state with a high mortality which is associated with high levels of IL-6 and CRP. Recent randomised controlled trial data has shown that the anti-inflammatory agent dexamethasone can reduce mortality in severe COVID-19 in an unselected COVID-19 cohort. Whilst impressive, these results suggest that if the anti-inflammatory interventions could be targeted early to individuals with hyperinflammation, even greater benefit in mortality may be seen, and this approach may additionally reduce the morbidity of COVID-19 by preventing escalation to high dependency and intensive care. The purpose of our study is to identify hyperinflammation early because there are specific therapies which are in clinical use which treat hyperinflammation.

Hyperinflammation has been previously described secondary to acute infection and termed cytokine release syndrome / cytokine storm (CRS / CS), macrophage activation syndrome (MAS), macrophage-cytokine self-amplifying loop (MCSAL) and secondary haemophagocytic lymphohistiocytosis (sHLH). Viral infections are the commonest cause of sHLH, and symptoms of hyperinflammation resemble those of general sepsis, therefore hyperinflammation has generally been under-recognised at an early stage leading to a high mortality. Blockade of the key pathways in hyperinflammation such as IL-1 have been shown to be effective in sepsis triggered cases without increased adverse events . Early data in a single arm open label study of 21 severely ill COVID-19 patients with increased IL-6 expression, showed that inhibition of IL-6 signaling with tocilizumab caused rapid clinical improvement in 75% of cases, with some improvement in all cases .

During COVID19 infection, the initial viral invasion of epithelial tissues causes direct cytotoxic damage but subsequently progresses to an inflammatory response at 7-10 days. While an inflammatory response is likely to be needed to eliminate virus, there is a risk of ongoing activation with inflammatory mediators causing end organ damage. Therefore, it seems that targeting hyperinflammation (e.g. IL-6) during acute SARS-CoV-2 infection requires the timing of blockade to be finely balanced to avoid early on impairment of host antiviral responses. Similarly, intervening too late is likely to show minimal benefit. Due to the urgency, despite this uncertainty, clinical trials to address the effectiveness of anti-IL-6 are already underway with Tocilizumab (ClinicalTrials.gov Identifier: NCT04317092, REMAP-CAP, RECOVERY) and Sarilumab (ClinicalTrials.gov Identifier: NCT04315298). The entry criteria for the UK trials of such interventions have largely been unselected, ie not specifically targeting individuals who have hyperinflammation.