Circulating histones are associated with disease severity and coagulopathy in COVID-19

Background : COVID-19 has highlighted lethal consequences of cross-talk between coagulation, inflammation and innate immune processes. Hospitalised COVID-19 patients have evidence of immune cell death, which would result in the release of nuclear material, such as histones. Extracellular histones are associated with adverse clinical outcomes and our work has shown they are procoagulant, pro-inflammatory and can cause pulmonary thrombosis. We hypothesize that circulating histones play a central role in poor outcomes in COVID-19. Aims : We aim to determine the pathological role of circulating histones in disease severity, coagulation activation, inflammation and organ injury in COVID-19. Methods : One hundred and three COVID-19 patients were recruited at the Royal Liverpool University Hospital, in accordance with ISARIC/WHO Clinical Characterisation Protocol for Severe Emerging Infections in the UK. Inclusion criteria: (1) swab positive/ high likelihood of infection OR (2) fever ≥38°C, cough, dyspnoea/ tachypnoea. Circulating histones were quantified in patient plasma and patients were categorised into three groups based on severity of infection: mild (minimal symptoms/incidental finding), severe (dyspnoea/ hypoxia) and critical (respiratory failure/multi-organ failure). Results : Admission histone levels were significantly ( P < 0.001) elevated in patients with increasing severity of COVID-19 infection (Mild;2.00 μg/ml [0.68-6.62], Severe;9.75 μg/ml [3.61-21.88], Critical;23.37 μg/ml [11.35-30.02]). Histones were associated with a pro-coagulant (histones vs d-dimer;R = 0.596, P < 0.001) and proinflammatory phenotype (histones vs CRP;R = 0.730, P < 0.001, histones vs fibrinogen;R = 0.677, P < 0.001). Increased circulating histones were associated with organ dysfunction including hypoxia (oxygen saturations ≤93%;P = 0.008), raised bilirubin ( R = 0.568, P = 0.002) and elevated serum creatinine ( R = 0.508, P = 0.009). Patients with elevated histones required critical care admission ( P < 0.001), increased duration of mechanical ventilation ( R = 0.778, P = 0.022) and overall length of hospital stay ( R = 0.618, P < 0.001). Conclusions : Admission histone levels are associated with disease severity, coagulation activation, inflammation and organ dysfunction in COVID-19. This study indicates that elevated circulating histones might play a key role in the immuno-thrombotic pathogenesis of COVID-19.