Cytokine Storm Syndrome, a potential cause of death in COVID-19 patients


  • Imran Mansoor Raza Dow University of Health Sciences
  • Zubia Zaman
  • Yamna Waseem



pandemic, coronavirus, COVID-19, cytokine storm, cytokine storm syndrome


COVID-19 pandemic caused by SARS-CoV-2 has infected more than two million people worldwide accounting for more than 130,000 mortalities. [1] Its mortality rate of 3.4% is driven by lower respiratory tract infections such as pneumonia, septic shock, multiorgan failure and acute respiratory distress syndrome (ARDS), the latter being the leading cause of mortality. [2] With constantly evolving research regarding the virus’s pathophysiology, possible treatment regimens and trials for potential vaccines having been undergone, the field of medicine is subjected to new data concerning the cause and cure of the current global crisis.


Cytokine storm syndrome (CSS) is a hyperinflammatory state characterized by a fulminant and fatal hypercytokinemia with multiorgan failure. CSS occurs due to the virus’s ability to activate an uncontrolled immune response leading to local and systemic crisis. [3] Hyper-inflammation in COVID-19 illustrates elevated levels of pro-inflammatory cytokines including interleukin (IL)-6, IL-8, tumor necrosis factor-?, and granulocyte-macrophage colony-stimulating factor (GM-CSF). [5] Similar, fulminant cytokine production by lung macrophages and pneumocytes was observed in previous SARS-CoV and MERS-CoV epidemics. [4] Clinical features of CSS include unremitting fever, hyperferritinemia and elevated cytokine levels as well as pulmonary involvement (including ARDS). Data from a retrospective, multicenter study from China indicated hyperferritinemia and hypercytokinemia in COVID-19 patients suggestive of mortalities due to virus related hyperinflammation. [4]


Proportionally increased cytokine levels with the severity of COVID-19 sheds light through a different perspective on the management and treatment of the disease. A multicentre, randomized controlled trial of tocilizumab (IL-6 receptor blocker, used for CSS), has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China (ChiCTR2000029765), reporting significantly reduced fever and improved respiratory function. [5] Moreover, surge in cytokines is in turn mediated by catecholamines. The latter enhances IL-6 production through alpha-1 adrenergic receptor (?1-AR) signaling. It was concluded that ARDS patients with prior use of ?1-AR antagonists like prazosin in the year before their diagnosis were about less likely to need to be placed on a ventilator after their diagnosis.[4] This encourages its use as a prophylactic inhibitor for COVID-19.


We believe that critically ill patients of COVID-19 should be tested for hyperinflammation using laboratory trends (hyperferritinemia, low platelet count, low erythrocyte sedimentation rate) and the HScore (used to diagnose CSS) to distinguish the subgroup of patients for whom immunosuppressive drug therapy could help improve mortality. [5]


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WHO. Coronavirus disease 2019 (COVID-19) Situation Report – 97 [Internet]. 2020 [cited 2020 Aug 12]. Available from:

Ruan Q, Yang K, Wang W, Jiang L, Song J. Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Jun;46(6):1294–7.

Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012 Apr;59(2):329–44.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England). 2020 Feb;395(10223):497–506.

Lorenz G, Moog P, Bachmann Q, La Rosée P, Schneider H, Schlegl M, et al. Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients. Sci Rep [Internet]. 2020;10(1):18277. Available from:

Konig MF, Powell M, Staedtke V, Bai R-Y, Thomas DL, Fischer N, et al. Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome. medRxiv [Internet]. 2020 Jan 1;2020.04.02.20051565. Available from:

Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020 May;214:108393.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Vol. 395, Lancet (London, England). 2020. p. 1033–4.




How to Cite

Mansoor Raza, I., Zaman, Z., & Waseem, Y. (2021). Cytokine Storm Syndrome, a potential cause of death in COVID-19 patients. Pakistan Journal of Surgery and Medicine, 1(4), e139.