Cytokine Storm in COVID-19

Background

A cytokine storm is a severe, overreactive inflammatory response, which can lead to multi-organ failure and eventual death. This process occurs when a large number of white blood cells are activated, release inflammatory cytokines, and then create a vicious loop in which more white blood cells are activated. Cytokine storms are associated with a wide number of conditions such as infections, autoimmune diseases, CAR-T therapy, and graft-versus-host disease.

There is accumulating evidence that the progression of COVID-19 to acute respiratory distress syndrome or fulminant myocarditis is through a cytokine storm mechanism.

Coronavirus Infections Lead to Early Cytokine Storm

Human coronaviruses replicate to high viral loads very early after infection. This leads to rapid activation of inflammatory cytokines and recruitment of macrophages and neutrophils into damaged tissue. The result is increased cell death, breakdown of vasculature, and impaired virus clearance.

This leads to acute lung injury which can rapidly progress to acute respiratory distress syndrome. This mechanism is why we see reports of young patients quickly progressing to respiratory failure a couple days after they have their first symptom of coronavirus. More detail about the pathophysiology of cytokine storm in coronaviruses is available here: https://link.springer.com/article/10.1007%2Fs00281-017-0629-x

Early cytokine storm leads to acute lung injury, respiratory failure, and death after coronavirus infection.
Source: Channappanavar and Perlman. Seminars in Immunopathology 2017

Cytokine Storm in Severe COVID-19

There are several reports that suggest now that patients with severe COVID-19 have an inflammatory cytokine storm. Ruan et al. showed that patients who died from COVID-19 have elevated C-reactive Protein and Interleukin-6 levels compared to those who recovered. https://link.springer.com/article/10.1007/s00134-020-05991-x

Source: Ruan et al. Intensive Care Medicine 2020

This was confirmed by Zhou et al, who showed that patients requiring ICU admission had increased levels of IL-6 and CM-CSF, which in turn create more pathogenic Th1 cells, a type of inflammatory white blood cell. Source: https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa041/5804736?searchresult=1

Patients with severe COVID-19 infection had greater inflammatory marker levels (IL-6 and GM-CSF)
Source: Zhou et al. National Science Review 2020

Repeated overactive, inflammatory cytokine activation eventually leads to T cell exhaustion, which decreases our ability to fight infection and may be the reason why some infected individuals take so long to recover.

T cell exhaustion after cytokine storm in patients with COVID-19
Source: Zhou et al. National Science Review 2020.

In Zhou et al’s experience, the patients in the ICU with features suggestive of worsening cytokine storm had greater C-reactive protein, lower albumin, greater ALT/AST, and greater lactate dehydrogenase levels. These are relatively easy values we can track daily in patients.

Increased CRP, ALT/AST, LDH and decreased albumin in COVID-19 patients in the ICU
Source: Zhou et al. National Science Review 2020.

Summary

Patients with COVID-19 infection are prone to early cytokine storm, leading to ARDS. We should be on the look out for patients that have elevated inflammatory markers or liver function enzymes.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s