THERAPEUTIC IMPLICATIONS OF CYTOKINE STORM

As we now know that the high viral load in the beginning followed by exaggerated immune response later is responsible for severe covid-19. This leads to ARDS- primary cause of death, along with multiple organ dysfunction. The understanding of the cytokine storm provides key information regarding key theoretical therapeutic interventions. These therapeutic interventions that can suppress the excess immune response through various mechanisms. Today I will discuss about few such pharmacological agents.

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The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19Q. Ye, B. Wang and J. Mao / Journal of Infection 80 (2020) 607–613

 

IFN-gamma

Use –

Can stimulate alveolar epithelial cells for their action against virus by stimulating certain antiviral genes

It can inhibit IFN-α/β secretion and inhibit excess activation of macrophage-monocyte.

It can inhibit excess neutrophils

Disadvantages

Should be used in early in the disease course.

Late administration has no advantage.

 

Corticosteroid therapy

Potent anti-inflammatory agent

It can be very useful if administered during cytokine storm at 1-2 mg of methylprednisolone for not more than 3-5 days

Disadvantages

If used early can stimulate the viral replication by inhibiting host immunity

At high doses can increase viral replication.

Thus, appropriate dose at appropriate time is important.

 

Intravenous immunoglobin (IVIG)

Use:

Since IVIG have immunomodulatory and immunesubstitive action, it can have theoretical benefit.

Further studies are required.

Disadvantages:

IVIG therapy increases the risk of thrombosis in covid-19 patients

IL-1 antagonist

Anakinra is an IL-1β antagonist which inhibits the IL-1, an important cytokine in the pathway of cytokine storm.

Although there have been case reports about its use and benefits, animal studies and RCTs have to be done to prove its actual effectiveness.

IL-6 Antagonists

IL-6 is another key cytokine in the cytokine storm. Tocilizumab, an IL-6 antagonist, has been shown to be effective in infection related cytokine in the past. There are case reports of its use and benefits but RCTs are yet to be done and published before we can use it as a therapeutic modality.

 

TNF-inhibitors

At present, TNF blockers have not been suggested in the treatment of patients with COVID-19, but the efficacy of TNF blockers in treatment of patients with COVID-19 deserves further exploration.

 

IFN-α/β antagonist

Late administration of these cytokines is effective to suppress the inflammatory response.

 

Chloroquine/Hydroxychloroquine

These antimalarials inhibit the TNF and IL-6 cytokines. WHO has warned against the use of these drugs in covid-19 due to significant side effects.

 

Ulinastatin

It is a natural anti-inflammatory agent which prevents the damage to the endothelium by inhibiting the inflammatory cytokines.

It has been used in acute pancreatitis and acute circulatory failure.

It inhibits IL-6, TNF and IFNs.

It is better than corticosteroids as it has no immune inhibitory action.

 

Eritoran

It is a Toll like receptor 4 antagonist which inhibits production of chemokines, cytokines and oxidized phospholipids.

 

Stem cell therapy

Mesenchymal Stem Cell can inhibit the abnormal activation of T lymphocytes and macrophages, and induce their differentiation into regulatory T cell (Treg) subsets and anti-inflammatory macrophages, respectively.

It can also inhibit the secretion of pro-inflammatory cytokines, such as, IL-1, TNF- α, IL- 6, IL-12, and IFN- γ, thereby reducing the occurrence of cytokine storms.

Blood purification therapy:

Cytokines and other proinflammatory mediators can be removed by plasma exchange, artificial liver and early renal replacement therapy.

Chemokine antagonist, Sphingosine 1 phosphate agonist and agents that reduce vascular permeability can have beneficial anti-inflammatory action in cytokine storm associated with covid-19.

What is the role of anticoagulant in covid-19?

Since there is higher incidence of venous thromboembolism in covid-19 patients, prophylactic anticoagulants like low molecular weight heparin and unfractionated heparin are routinely administered.