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

Imran Mansoor Raza1 , Zubia Zaman1, Yamna Waseem2

  1. Student, 3rd Year MBBS, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
  2. Student, 5th Year MBBS, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan

Corresponding Author: Imran Mansoor Raza, Student, 3rd Year MBBS, Dow Medical College, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, 74200, Pakistan. Contact Author
Twitter: @imranr_14

Submission: Apr 18, 2020
Acceptance: Dec 05, 2020
Published: Mar 10, 2021

© Author(s) (or their employer(s) 2021. Re-use permitted under CC BY. No commercial re-use. Published by Pak J Surg Med.

Article Citation: Raza IM, Zaman Z, Waseem Y. Cytokine Storm Syndrome, a potential cause of death in COVID-19 patients?. Pak J Surg Med. 2021;1(4):e139. doi: 10.37978/pjsm.v1i4.139

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SARS-Cov-2 has infected more than three million people worldwide.[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 most prevalent.[2] With constantly evolving research regarding its pathophysiology, possible treatment regimens, and trials for potential vaccines in progress, the field of medicine is subjected to new data concerning the current global pandemic.

Cytokine storm syndrome (CSS) consists of uncontrolled systemic inflammation, vascular instability, multi-organ failure, and death.[3] Despite usually occurring in a younger population, CSS affects all age groups in COVID-19.[4] Patients with severe COVID-19 may present with CSS and develop secondary hemophagocytic lymphohistiocytosis (sHLH), which causes acute respiratory distress syndrome (ARDS).[5] A study was conducted in Wuhan, China on 41 COVID-19 patients with a median age of 49 years. All critically ill patients admitted to the intensive care unit (n=14) including those who died, recorded high levels of cytokines in their plasma, suggestive of CSS.(4) CSS illustrates elevated levels of pro-inflammatory cytokines including interleukin IL-6, IL-8, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF). A similar cytokine surge was also observed in previous SARS-CoV and MERS-CoV epidemics.[6] CSS manifests an increase in biomarkers including erythematosus sedimentation rate (ESR), serum ferritin, liver enzymes, D-dimers, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels, which serve as a basis for its diagnosis. Lymphocytopenia with reduced NK cells and T cells accompanied with splenic atrophy has also been reported in severe COVID-19. Proportionally increased cytokine levels with COVID-19 severity sheds light through a different perspective on the management and treatment of the disease.[7]

Moreover, cytokine surge is mediated by catecholamines using the alpha-1 adrenergic receptor (⍺1-AR) pathway which can be blocked using ⍺1-AR antagonists (e.g. prazosin), thus illustrating its potential use as a prophylactic inhibitor for COVID-19. In a retrospective analysis of 13,125 male (age 45-64) ARDS patients where five percent of them (n=655) previously used α1-AR antagonists, results showed that the latter had a lesser ratio of needing mechanical ventilation with a 36% lower incidence of death compared to non-users.[6]

Limitations to these therapies insist on the need for increased clinical trials which can be used to evaluate their effectiveness in the prevention of CSS in COVID-19 patients. We believe that critically ill patients of COVID-19 should be tested for hyper-inflammation using laboratory trends and HScore (used to diagnose CSS) to distinguish the subgroup of patients for whom immunosuppressive drug therapy could help improve mortality.[8]


  1. WHO. Coronavirus disease 2019 (COVID-19) Situation Report – 97 [Internet]. 2020 [cited 2020 Aug 12]. Available from:
  2. 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.
  3. 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.
  4. 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.
  5. 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:
  6. 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:
  7. 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.
  8. 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.

Author CRediT

IMR: Conceptualization, Investigation, Methodology, Project Administration, Writing – original draft, Writing – review & editing
ZZ: Writing – original draft
YW: Writing – original draft

Conflict of Interest

The Authors Declared No Conflict of interests.


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Editorial Team

This article has been subjected to extensive editing and double blind peer review process. The following editors were involved in editing of this article;

Lead Editor: MI Anwar
Editor: AA Sheikh, A Sarfraz, A Anwer, A Pervez, K Zahra, M Ahmed
Proof: J Siddiq
Bibliography: A Anwer

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