A hyperinflammation clinical risk tool, HI5-NEWS2, stratifies hospitalised COVID-19 patients to associate risk of death and effect of early dexamethasone in an observational cohort.

BACKGROUND: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION: Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.

Secondary haemophagocytic lymphohistiocytosis in hospitalised COVID-19 patients as indicated by a modified HScore is infrequent and high scores do not associate with increased mortality.

A significant proportion of COVID-19 patients show evidence of hyperinflammation (HI), of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation and diagnosed with HScore. Using a COVID-relevant modification of the HScore (%HScore), we set out to determine the prevalence of sHLH in 567 COVID-19 inpatient cases.The overall incidence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% if calculated at any time during admission. This small cohort as defined by %HScore showed no excess mortality compared with the whole cohort. Overall, %HScores were lower in older patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211, odds ratio 0.99).Our study demonstrates that a modified version (%HScore) of the conventional sHLH scoring system (HScore) does not enable risk stratification in people hospitalised with COVID. We propose further work is needed to develop novel approaches to predict HI and improve trial stratification for HI directed therapy in people with COVID-19.