A Clinical-Therapeutic Staging Proposal: Summary

The largest report of COVID-19 from the Chinese Centers for Disease Control and Prevention summarized findings from 72, 314 cases and noted that while 81% were of a mild nature with an overall case fatality rate of 2.3%, a small sub-group of 5% presented with respiratory failure, septic shock and multi-organ dysfunction resulting in fatality in half of such cases, a finding that suggests that it is within this group that the opportunity for life saving measures may be most pertinent.

It appears that there are two distinct but overlapping pathological subsets, first, the one triggered by the virus itself and the second, the host response. Whether immunocompetent or immunosuppressed, the disease tends to present and follow these two phases, albeit in different levels of severity.

It is important to distinguish at which stage the viral pathogenicity is dominant versus where the host-inflammatory response becomes dominant. A pre-print in the Journal of Heart and Lung Transplantation proposed a 3-stage classification system, recognizing that COVID-19 illness exhibits three grades of increasing severity which correspond with distinct clinical findings, response to therapy and clinical outcome.

Stage I (mild)–Early Infection:

For most people, this involves an incubation period associated with mild and often non-specific symptoms such as malaise, fever and a dry cough. During this period, SARS-CoV-2 multiplies and establishes residence in the host, primarily focusing on the respiratory system.

Treatment at this stage is primarily targeted towards symptomatic relief. Should a viable anti-viral therapy (such as remdesivir, hydroxychloroquine) be proven beneficial, targeting selected patients during this stage may reduce duration of symptoms, minimize contagiousness and prevent progression of severity. In patients who can keep the virus limited to this stage of COVID-19, prognosis and recovery is excellent.

Stage II (moderate)-Pulmonary Involvement (IIa) without and (IIb) with hypoxia (low-oxygen, shortness of breath, difficulty breathing):

In the second stage of established pulmonary disease, viral multiplication and localized inflammation in the lung is the norm. During this stage, patients develop a viral pneumonia, with cough, fever and possibly hypoxia.

CT reveals bilateral infiltrates or ground glass opacities. Markers of systemic inflammation may be elevated, but not remarkably so. It is at this stage that most patients with COVID-19 would need to be hospitalized for close observation and management.

Treatment would primarily consist of supportive measures and available anti-viral therapies such as remdesivir, hydroxychloroquine. In early stage II without hypoxia, the use of corticosteroids may be avoided. Though, once hypoxia ensues, it is likely that patients will progress to requiring mechanical ventilation, and in that situation, anti-inflammatory therapy with corticosteroids may be useful and can be judiciously employed.

Stage III (severe) –Systemic Hyperinflammation:

A minority of COVID-19 patients will transition into the third and most severe stage of illness, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. In this stage, markers of systemic inflammation appear to be elevated. Low helper, suppressor and regulatory T-cell counts are observed. Inflammatory cytokine and biomarkers (IL-2,6,7. TNFalpha, CRP, etc.), are elevated.

In this stage, shock, vasoplegia, respiratory failure and even cardiopulmonary collapse are discernable. Systemic organ involvement, even myocarditis, would manifest during this stage.

Tailored therapy in stage III hinges on the use of immunomodulatory agents to reduce systemic inflammation before it overwhelmingly results in multiorgan dysfunction. Corticosteroids in combination with cytokine inhibitors like tocilizumab (IL-6 inhibitor) or anakinra (IL-1 receptor antagonist) may be used. Intravenous immune globulin (IVIG) may also help modulate an immune system in such a hyperinflammatory state.

Overall, the prognosis and recovery from this critical stage of illness is poor, and rapid recognition and deployment of such therapy may have the greatest yield.

Siddiqu HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. Journal of Heart and Lung Transplantation. doi: 10.1016/j.healun.2020.03.012

– Dylan Gris wold

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