Severe COVID-19 as a virus-independent immunothrombotic process.

We read with interest the Viewpoint by Dennis McGonagle and colleagues in which they question the strategy of universal immunosuppression in patients with moderate-to-severe COVID-19 because of a concern about ongoing alveolar viral replication in these patients. We believe that this concern is unwarranted, as the key pathology driving severe COVID-19 is not active viral replication in the pneumocytes, but rather antibody-dependent inflammation leading to immunothrombosis.

First, in COVID-19, there is evident temporal and spatial dissociation between active viral replication in the respiratory tract and the development of lung injury. Although initial viral loads are higher and duration of viral shedding is longer in patients who develop severe illness (when compared with those who do not), the viral load typically trends downwards from the time of symptom onset, irrespective of eventual illness severity. Culturable virus is typically absent by the second week after symptom onset, when patients progress to severe illness. Pathologically, there is a lack of topological correlation between the location of lung pathology and presence of the virus, suggesting tissue tolerance to viral multiplication and a mechanism of lung injury other than viral cytopathy. Supporting this interpretation, studies in humanised mice have shown that viral infection of alveolar cells is not necessary for severe COVID-19 to occur.

Second, as we have previously argued, the peripheral ground glass changes seen in patients with COVID-19, which typically appear in the later part of the first week of illness, represent pulmonary infarcts due to small-vessel immunothrombosis rather than viral alveolitis. Inhaled thrombolytics seem to resolve these radiological changes, which would be highly uncharacteristic of viral-induced alveolar injury. Consistent with this explanation, the characteristic silent hypoxaemia of COVID-19 indicates a predominant perfusion problem rather than a ventilation problem.

Third, the key determinant of severe illness appears to be antibody-dependent inflammation, a phenomenon that occurs due to abnormal fucosylation of antibodies specific for viral spike protein during the seroconversion phase of COVID-19 in susceptible patients. These aberrant antibodies are pro-inflammatory; they activate platelets and macrophages and disrupt alveolar endothelial integrity, promoting in-situ thrombosis in the lung vasculature. The temporal association of severe illness with the onset of humoral immunity is also explained by this phenomenon. Autoantibodies directed at phospholipids, possibly emerging through molecular mimicry or redox-related conformational changes of innate epitopes, could also play a prominent role in disease progression.

As the initial viral load determines the strength and duration of the antibody response, it might be prudent to avoid downregulation of the innate immune response by immunosuppression during the early viral replication phase. However, if there is evidence of disease progression to the immunothrombotic phase, key treatment strategies include immunosuppression and anticoagulation to suppress the aberrant antibody response and lung-centric microthrombosis. Once immunothrombotic lung injury is fully established, with diffuse alveolar damage manifesting as clinical acute respiratory distress syndrome, neither antiviral therapy nor immunosuppression is likely to modify the disease trajectory, and the management would essentially be supportive.

RNAaemia seen at this stage might not have implications for therapy, but rather might be a marker of disease severity and immune paralysis, portending poor prognosis.

We declare no competing interests.