How serious is a cytokine storm in Covid-19?
Dispelling the myth around ‘cytokine storm’ is the need of the hour, and will help temper down the use of corticosteroids.
As of June 2021, the number of confirmed Covid-19 cases has topped 170 million across the globe with about 3.75-million deaths reported to WHO. Much of the mortality has been attributed to a “cytokine storm” syndrome in patients with Covid-19 pneumonia. Cytokines are inflammatory proteins produced by cells of the body in response to any illness. Cytokines play an important role in the immune response. An overactive cytokine response, a phenomenon known as the “cytokine storm” can harm the patient by causing tissue damage. Although not clearly defined, the cytokine storm has been believed to be the hallmark of Covid-19.
The misapprehension around “cytokine storm” has led to first, repeated measurements of C-reactive protein (CRP) and interleukin-6 (IL-6) in the blood as markers of disease severity; and second, irrational exuberance in use of corticosteroids such as prednisone, prednisolone or dexamethasone to quell the cytokine storm. Use of corticosteroids in Covid-19 patients with mild to moderate disease, sometimes for as long as 1-2 months, is unwarranted, and not supported by scientific or clinical evidence. In fact, inappropriate use of corticosteroids appears to be prime cause for the unfolding epidemic of mucormycosis. Because of its profound implications the myth of “cytokine storm” merits a closer look. The compelling evidence that “cytokine storm” is fiction rather than reality comes from a number of recent studies outlined below.
First, Mudd and colleagues from St. Jude Children’s Research Hospital and Washington University School of Medicine at St. Louis, US have compared the immune responses in patients with Covid-19 versus flu(1). The research included 168 adults with Covid-19, 26 adults with flu and 16 healthy volunteers. More than half of the flu patients were hospitalized, 35% in the ICU, and 8% of those hospitalized died. As for Covid-19 patients, more than 90% of the Covid-19 were hospitalized, about half required admission to intensive care unit, and 23% of those who were hospitalized died. Only 7 out of the total of 168, that is 4% of Covid patients met the definition of cytokine storm. Patients with cytokine storm syndrome had individual cytokine levels as much as 10 to 100 times higher than the average. But when researchers included age and other factors, Covid-19 patients had lower overall cytokine levels than flu patients. Overall, the average patient with Covid-19, even patients with moderate-to-severe disease, had less inflammation than the average patient with flu. The lack of hyperinflammation in most Covid-19 patients does not mean they had less disease. It appears that in most cases the disease was not caused by broad hyperinflammation and cytokine storm. Second, scientists from Radboud University in the Netherlands compared cytokine levels in critically ill people with Covid-19 to those in patients with bacterial infection, trauma, and aftermath of cardiac arrest(2). The results convincingly showed that the circulating cytokine concentrations in Covid-19 patients were not higher, but rather lower, compared to other diseases. Third, scientists from University of California, San Francisco have collated and compared IL-6 levels as reported in five previous studies of severe
Covid-19 patients, and three studies of adult respiratory distress syndrome (ARDS) not related to Covid(3). The IL-6 levels in patients with severe Covid-19 were about 0.5 to 10% of the levels in not-covid ARDS.
Dispelling the myth around “cytokine storm” is the need of the hour, and will help temper down the use of corticosteroids. Physicians across India have gotten accustomed to prescribing corticosteroids across the spectrum of Covid-19 disease severity, including in early disease. Corticosteroids need to be reserved for the sickest amongst the sick in the intensive care unit, and under close physician supervision. The duration of corticosteroid treatment needs to be limited to a maximum of 10 days. When taken for such short periods steroids can be discontinued abruptly, without a need for gradually tapering the dose over days to weeks, a common but unnecessary practice. Abrupt discontinuation will prevent prolonged and severe suppression of the immune system by steroids and mitigate the risk of superinfections including mucormycosis. In Covid-19, pathways controlling the immune response promote corticosteroid production by the body itself. This suggests that most Covid-19 patients are perhaps already producing high levels of glucocorticoids possibly leading to the blunted immunity. These patients may need therapy to boost rather than further suppress their immune response by use of corticosteroids.
In conclusion, recent scientific research has provided unequivocal and compelling evidence that cytokine storm in the vast majority of Covid-19 patients is, in reality, merely a “storm in a teacup”. Rather than lifethreatening hyperinflammation, most adults with mild, moderate or severe Covid-19 have a suppressed immune response when compared to adults with influenza, commonly referred to as “flu”. While dexamethasone and other steroids are prescribed to treat cytokine storms, the drugs can backfire in patients whose immune response is already suppressed as happens to be case in more than 90% of Covid patients. The emerging evidence strongly cautions against use of steroids in all but the most severe cases of Covid-19. Irrational exuberance in use of corticosteroids such as dexamethasone may only further damage a beleaguered immune system and predispose to mucormycosis, commonly referred to as the black fungus.
Dr Ajay Gupta, MBBS (AIIMS), MD (AIIMS) is Clinical Professor of Medicine at University of California Irvine, USA; and inventor of two new US FDA approved drugs.
FOOTNOTES
1. P. A. Mudd et al., Distinct inflammatory profiles distinguish Covid-19 from influenza with limited contributions from cytokine storm. Science Advances 6, eabe3024 (2020).
2.M. Kox, N. J. B. Waalders, E. J. Kooistra, J. Gerretsen, P. Pickkers, Cytokine Levels in Critically Ill Patients With Covid-19 and Other Conditions. JAMA 10.1001/ jama.2020.17052 (2020). 3.P. Sinha, M. A. Matthay, C. S. Calfee, Is a “Cytokine Storm” Relevant to Covid-19? JAMA Internal Medicine 180, 1152 (2020).