Pathophysiology of severe COVID-19

The global pandemic of covid-19 has taken many lives. Although the mortality rate is around 3-4% many people get admitted to ICU for severe symptoms. The leading cause of mortality is ARDS- acute respiratory distress syndrome.

It has been found that severe covid-19 develop a phenomenon called cytokine storm. It is a condition characterized by dysregulated immune response of human body. The damage in the patient is not due to the virus but because of excessive and inappropriate response by human immune system. The excess activation of innate and acquired immune system results in secretion of large amounts of cytokines, chemokines and complement activation. It has also been found that there is excess thrombin activation with widespread thrombus formation leading to DIC.

This phenomenon of cytokine storm has been previously explained in other immune dysregulated conditions. Influenza infections and EBV infection are associated with cytokine storm. Familial and secondary Hemophagocytic lymphohistiocytosis (HLH) has similar excess cytokine release. Macrophage activation syndrome in Juvenile idiopathic arthritis and malignancy also exhibit similar phenomenon.

Cytokine release syndrome is a similar condition that occurs after treatment of certain malignant conditions.   

Pathophysiology of cytokine storm in Covid-19.

The cytokine storm in covid-19 results in severe disease and multisystem inflammatory syndrome in children.

After sars-cov-2 infection in an individual there are 2 phases that a human body goes through.

Phase 1

In cases of mild to moderate disease - antiviral mechanism of body is able to suppress the viral replication with development of protective antibody.

In severe cases the antiviral mechanism – the dendritic cells, macrophage monocyte system is unable to secrete cytokines and chemokines in the early phases because of which the viral action and replication is not countered. This enables the virus to directly damage the respiratory epithelium known as direct cytopathic effect.

However, in Phase 2, in severe cases there is excess secretion of the proinflammatory mediators and cytokines in other words there is delay release of these inflammatory cytokines which should have been ideally present during Phase 1.

The delayed activation of dendritic cells releases large amounts of IFN-gamma, IFN-β/α which further activates macrophages and neutrophils. The activated macrophages release IL-1β, IL-6, TNF, chemokines like CCL2, CCl5 etc., These chemokines and cytokines result in further activation of monocyte-macrophage, neutrophils and complement cascade. These cells accumulate in lungs causing direct damage to parenchymal cells, pulmonary endothelial cells with resulting inflammation. All this contribute to pathogenesis of ARDS in lungs. Similar damage occurs in other organs as well. These chemokines, cytokines also degrade T-cells thus inhibiting viral clearence.

The cytokine storm is also associated with activation of coagulation cascade. The activation of thrombin not only promotes clot formation by activating platelets and by converting fibrinogen to fibrin, it also exerts multiple cellular effects and can further augment inflammation via proteinase-activated receptors (PARs), principally PAR-1.

The anticoagulants, such as antithrombin III, tissue factor pathway inhibitor, and the protein C system keep thrombin formation in check. During inflammation, all three of these control mechanisms can be impaired, with reduced anticoagulant concentrations due to reduced production and increasing consumption. This defective procoagulant–anticoagulant balance predisposes to the development of micro thrombosis, disseminated intravascular coagulation, and multiorgan failure—evidenced in severe COVID-19 pneumonia with raised d-dimer concentrations being a poor prognostic feature and disseminated intravascular coagulation common in non-survivors.

 

 Clinical and laboratory characteristics

 

Cytokine release syndrome-Shimabukuro-Vornhagen et al. Journal for ImmunoTherapy of Cancer (2018) 6:56 https://doi.org/10.1186/s40425-018-0343-9

The laboratory characteristics are as follows

Cytopenia- Lymphopenia is the characteristic of covid-19.

Hypertriglyceridemia

Hyperferritenemia

Elevated liver enzymes

Raised CRP and ESR

Raised IL-6 can be assessed in lab which indicates inflammation with immune dysregulation.

Since the characteristics of cytokine storm are similar to secondary HLH, the H-score used in sHLH has been used to diagnose and monitor the severe covid-19 hypercytokinemia.

 

The understanding of pathogenesis of the cytokine storm is important as it provides key information about the therapeutic modalities that can be applied. I will update about the possible therapeutic modalities in my next blog.