Cytokine storm syndrome is one of the most important cause of mortality in severe COVID-19 cases. It can be treated if diagnosed in time and life of a patient can be saved.

1. Cytokine syndrome
in COVID-19
Presenter: Dr. Sonam Aggarwal
Moderator: Dr. Suraj Chawla

2. Contents
• Background
• What are cytokines?
• What is Cytokine storm/ syndrome?
• Cytokine storm in COVID-19
• Difference between COVID-19 Cytokine Syndrome and Conventional
Cytokine Syndrome
• Treatment of COVID- 19 Cytokine Syndrome
• Conclusion
• References

3. Background
• Coronavirus disease 2019 (COVID-19), which is caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has globally
spread to an ongoing pandemic since the first case of infection was
reported in 2019 in China.
• The initial symptoms of COVID-19 mainly include fever, cough,
myalgia, fatigue, or dyspnea.
• In the later stages of the disease, dyspnea may occur and gradually
develop into acute respiratory distress syndrome (ARDS) or multiple
organ failure.

4. • The severity of COVID-19 is associated with an increased level of
inflammatory mediators :
• Interleukin (IL)-2
• IL-7,
• IL-10,
• Tumor Necrosis Factor (TNF),
• Granulocyte Colony Stimulating Factor (G-CSF),
Cytokines
• Monocyte Chemoattractant Protein-1 (MCP1; also known as CCL2),
• Macrophage Inflammatory Protein 1 alpha (MIP1α; also known as CCL3),
• CXC-chemokine ligand
Chemokines
C-reactive protein
Ferritin
D-dimers

5. What are cytokines?
• Cytokines are small glycoproteins produced by various types of cells
throughout the body.
• Various functions of cytokines are:
control of cell proliferation and differentiation processes,
autocrine, paracrine and/or endocrine activity
regulating immune and
inflammatory responses.

6. • The specific actions of some of these important cytokines are as
follows:

7. Cytokine Actions Types
Colony-
stimulating factors
(CSFs)
Tumor necrosis
factor (TNF)
•Associated with inflammation
•Participate in amplification cascade that can promote
inflammatory responses
•Plays an important role in the cytokine storm
•Excessive production can lead to chronic inflammatory and
autoimmune diseases
•Granulocyte CSF (G-CSF)
•Macrophage CSF (M-CSF)
•Granulocyte-macrophage CSF (GM-
CSF)
TNF-a

8. What is Cytokine storm/syndrome?
• Cytokine storm is a fast-developing, life-threatening, clinical condition
in which the there is overproduction of inflammatory cytokines and
excessive activation of immune cells.
• It leads to complicated medical syndromes such as persistent fever,
nonspecific muscle pain, and hypotension, capillary leak syndrome,
DIC, ARDS, hemophagocytic lymphohistiocytosis (HLH), multiorgan
failure, and death if treatment is not adequate.
• Therefore, the timing of diagnosis and treatment of Cytokine storm
could be life-saving.

9. Yang L. et al. The signal pathways and treatment of cytokine storm in COVID-19. Signal transduction and targeted therapy (2021)
6:255.

10. Cytokine storm in COVID-19
*Yang L. et al. The signal pathways and treatment of cytokine storm in
COVID-19. Signal transduction and targeted therapy (2021) 6:255.
SARS-CoV-2 enters epithelial cells and cause damage
Elevated levels of pro-inflammatory cytokines
Activate immune system to release more cytokines
Cytokine storm
Leads to complicated medical syndromes and death

11. Difference between COVID-19 Cytokine
Syndrome and Conventional Cytokine Syndrome
COVID-19 Cytokine Syndrome
• It involves more inflammatory
cytokines
• Lymphopenia commonly observed in
patients of COVID-19 Cytokine
Syndrome
• Treatment of COVID-19 Cytokine
Syndrome is more challenging,
because blocking inflammatory
cytokine function without effective
anti-viral drug support may
exacerbate the infection.
Conventional Cytokine Syndrome
• Involves less inflammatory
cytokines
• Lymphopenia less frequent in
patients
• Treatment is less challenging when
compared.

12. Treatment of COVID- 19 Cytokine Syndrome
Cytokine Action Inhibitor/ Antagonist
drug
IL-6 Serves as a prominent activator of the JAK/STAT3 pathway in the
inflammation
Siltuximab, Sirukumab
Tocilizumab, Sarilumab
IFN-γ IFN-γ exerts a predominant effect on protective immunity against bacterial and viral
infections through the activation of JAK1/JAK2 complex
Emapalumab
TNFα TNFα can activate the NF-κB signaling pathway to induce the expression of several
pro-inflammatory and anti apoptotic genes through its receptor TNFR1
Infliximab, Adalimumab
Etanercept
IL-1β IL-1β exerts positive effects on the migration of immune cells to inflamed tissues Canakinumab,
Anakinra
IL-2 IL-2 plays crucial roles in the expansion and differentiation of CD4+ T, CD8+ T,
NK, and other cells through the IL- 2R–JAK–STAT5 signaling pathway.
Ustekinumab
IL-7 Increase of IL-7 may be a feedback mechanism in response to the lymphopenia in
patients with severe/critical COVID-19.
Secukinumab

13. Intravenous
immunoglobulin,
Corticosteroid,
Traditional medicine
Target multiple
cytokines and pathways
Dexamethasone
Methylprednisolone

14. Conclusion
• Cytokine storm is a life threatening condition in COVID-19 and it can
be treated only if diagnosed timely.
• IL-6 levels are important marker for early detection of Cytokine storm.
• To treat COVID-19 Cytokine storm, several biologic interventions
specifically targeting inflammatory cytokines or related signaling
pathways have been clinically evaluated.

15. References
1.Yang L. et al. The signal pathways and treatment of cytokine storm in COVID-19.
Signal transduction and targeted therapy (2021) 6:255.
2. Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in
China: a systematic review and meta-analysis. J. Infect. 80, 656–665 (2020).
3. Henderson, L. A. et al. On the alert for cytokine storm: immunopathology in
COVID-19. Arthritis Rheumatol. 72, 1059–1063 (2020).
4. Mangalmurti, N. & Hunter, C. A. Cytokine storms: understanding COVID-19.
Immunity 53, 19–25 (2020).
5. Dagens, A. et al. Scope, quality, and inclusivity of clinical guidelines produced
early in the covid-19 pandemic: rapid review. BMJ 369, m1936 (2020).

16. 6. Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does not support
corticosteroid treatment for 2019-nCoV lung injury. Lancet 395, 473–475 (2020).
7. Group, R. C. et al. Dexamethasone in hospitalized patients with covid-19. N.
Engl. J. Med. 384, 693–704 (2021).
8. Wan, Y. et al. Receptor recognition by the novel coronavirus from Wuhan: an
analysis based on decade-long structural studies of SARS coronavirus. J. Virol 94,
e00127–20 (2020).

17. Thank you…

19. • Hospitalized patients
• with severe COVID-19 show high levels of IL-2, IL-7, IL-
• 10, G-CSF, TNF, CXCL10, MCP1, and MIP1α in serum
• [6], suggesting that severe COVID-19 is dictated as a cytokine
• release syndrome (CRS), which is a disorder induced
• by cytokine storms [12–14]. Among the elevated levels of
• inflammatory mediators in COVID-19 patients, the blood
• levels of IL-6 are noticeably higher in non-survivors compared
• to survivors [1, 2, 11, 34] and predict the need for
• mechanical ventilation [35].
• These findings have led to the hypothesis that the main
• cause of death of COVID-19 is ARDS with cytokine storms.

20. • Recent studies on COVID-19 infected patients have shown that these
individuals exhibit high levels of both pro-inflammatory cytokines,
which include IFN-g, IL-1B, IL-6 and IL-2, and chemokines.
• The connection between a cytokine storm and COVID-19 was made
when clinicians observed that intensive care unit (ICU) admitted
patients had higher levels of CXCL10, CCL 2, and TNF-a as
compared to COVID-19 patients that experienced less severe
symptoms and did not require admission to the ICU.

21. Corticosteroid treatment
• Corticosteroids are one of the most commonly used anti-inflammatory
drugs in the treatment of many inflammatory disorders.
• They exert immune regulatory effects by inhibiting the expression of
multiple pro-inflammatory cytokines and activation of various
immune cells.
• At the beginning of 2020, corticosteroid treatment in COVID-19 was
either contraindicated or not recommended, because of the statement
that no clinical data indicated a benefit from corticosteroid treatment.
• Moreover, it even increased the mortality and secondary infection
rates in SARS-CoV and MERSCoV.

22. • Like many other viruses, particularly SARS, MERS, and influenza, the
cytokine storm has been used as a warning sign for clinicians to
recognize disease escalation. When left untreated, the cytokine storm
by COVID-19 produces immune pathogenic damage that not only
leads to ARDS in many cases but can also further progress to
extensive tissue damage, organ failure, and death.

24. IL-6-STAT3 signaling is a potential cause of the ARDS via cytokine storms in
COVID-19 patients.

25. • Second, lymphopenia, although relatively less frequent in other CS,
was often observed in patients with COVID CS, suggesting that
COVID-CS may be mainly attributed to innate —rather than adaptive
immune cells.
• Finally, compared with bacterial infection-induced CS (e.g., sepsis),
the treatment of COVID-CS is more challenging, because blocking
inflammatory cytokine function without effective anti-viral drug
support may exacerbate the infection.

26. • In March 2020, the RECOVERY trials, one of the largest randomized,
controlled trials for COVID-19 treatments including ~15% of all
hospitalized COVID-19 patients in the UK, were launched.
• The dexamethasone arm enrolled 2104 patients receiving a low-to
moderate dexamethasone dose of 6 mg per day for 10 days and the
control arm comprised 4321 patients receiving standard care.
• Compared to the control group, dexamethasone treatment reduced the
28-day mortality by one-third in mechanically ventilated patients and
by one-fifth in patients receiving oxygen only, but not in patients with
no need for ventilated support.