Cytokine storm in COVID-19 PATIENTS is characterised by fever, cough and acute respiratory distress. The mortality rate of COVID-19 patients who were mechanically ventilated in 7 studies is about 60%...Laboratory studies showed that these patients had clinical features suggestive of hypercytokinemia and hyperinflammation associated with multi-organ failure

1. CYTOKINE STORM:
COVID-19 KILLER
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL, USA
A slide presentation for HealthCare Providers April 2020
Email: kevinng68@gmail.com

2. Mortality of COVID-19 patients on mechanical ventilation support:
April 9, 2020
https://www.rtmagazine.com/disorders-diseases/critical-care/icu-ventilation/early-data-on-ventilated-covid-19-patients-reveals-severe-mortality/

3. Outline of lecture: cytokine storm
▪ What is cytokine storm?
▪ What are cytokines
▪ Source of cytokines
▪ Functions of cytokines
▪ Clinical features of cytokine storm
▪ Current treatment
▪ Summary
https://www.cusabio.com/COVID-19-Cytokine-Storm

4. Synonyms for cytokine storm
▪ Cytokine release syndrome
▪ Systemic inflammatory response syndrome
▪ Macrophage activation syndrome,
▪ Hemophagocytic lymphohistiocytosis

5. What are cytokines?
▪ The word cytokine comes from two Greek words: cyto
meaning cell and kines meaning movement.
▪ Cytokines are produced by immune cells: mast cells,
macrophage, B lymphocytes, T lymphocytes and
endothelial cells, fibroblasts and stromal cells.
▪ Cytokines include chemokines, interferons,
interleukins, lymphokines, and tumor necrosis factors.
▪ Cytokines act through receptors on plasma membrane.
https://en.wikipedia.org/wiki/Cytokine
immune cellcytokines

6. Milestones in the history of cytokine storm
https://en.wikipedia.org/wiki/Cytokine_release_syndromeTGN1421=monoclonal antibody for CD28

7. Functional Classes of Cytokines
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140102/table/T2/?report=objectonly

8. Major groups of cytokines
▪ Major groups of cytokines:
▪ interferons
▪ Interleukins
▪ chemokines
▪ tumor necrosis factors
▪ growth factors.
▪ Most cytokines are “proinflammatory cytokine”.
▪ Proinflammatory cytokines promote an inflammatory response
in cells, whereas anti-inflammatory cytokines do the opposite.
https://www.cibdol.com/blog/666-cytokines-made-clear-in-500-words

9. Source of Cytokines
▪ Cytokines are produced by a broad range of cells:
▪ Neutrophils
▪ mast cells
▪ macrophages,
▪ B lymphocytes,
▪ T lymphocytes
▪ endothelial cells,
▪ fibroblasts, and
▪ various stromal cells;
▪ A given cytokine may be produced by more than one type of cell.
https://en.wikipedia.org/wiki/Cytokine

10. Structure and nomenclature of cytokines
▪ Small protein/peptide molecules
▪ Molecular weight 6 – 70 kDa
▪ Short half-life in seconds
▪ Cytokines include the following:
▪ Interferons 3 types α, β, γ
▪ Interleukins 40 and more
▪ Chemokines 47
▪ TNF family 19 members
▪ Growth factors 4 classes
https://www.researchgate.net/figure/Representation-of-cytokine-structures-
A-The-structure-of-IL-1b-with-its-b-sheets-and_fig2_333912809

11. Cytokine receptors
https://www.sciencedirect.com/science/article/pii/B9780702068966000090

12. Major cytokines and their actions
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/

13. Functions of cytokines
▪ Act as chemical messengers
▪ Regulate immunity
▪ Regulate inflammation
▪ Regulate hematopoiesis

14. Mechanism of actions of cytokines
http://www.sbs.utexas.edu/sanders/Bio347/Lectures/2006/Lecture%2014%202006.htm

15. Multiple actions of cytokines: pleiotropy
http://www.sbs.utexas.edu/sanders/Bio347/Lectures/2006/Lecture%2014%202006.htm

16. Functions of major cytokines
▪ Interferon gamma:
▪ activator of macrophages
▪ Stimulator of NK cells and neutrophils
▪ iL-1β:
▪ Stimulate ACTH release
▪ iL- 2
▪ regulates the activities of white blood cells (leukocytes, often lymphocytes) t
▪ iL-4
▪ stimulation of activated B-cell and T-cell proliferation
▪ differentiation of B cells into plasma cells
▪ iL-6
▪ production of neutrophils in the bone marrow.
▪ stimulating acute phase protein synthesis
▪ It supports the growth of B cells and is antagonistic to regulatory T cells.
▪ iL-8
▪ induces chemotaxis in target cells, primarily neutrophils
▪ stimulates phagocytosis
▪ iL-10
▪ limiting host immune response to pathogen
▪ iL-12
▪ limiting host immune response to pathogen

17. Effects of cytokine and receptor interaction on infection outcome.
https://www.researchgate.net/figure/Mediators-of-the-cytokine-storm-and-
the-associated-phenotypes-with-infection-outcome-The_fig4_221888625

18. Hospital Intensive Care admissions of patients with COVID-19:
Critical care issues (April 10, 2020)
https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-critical-care-issues?source=related_link

19. Clinical course and risk factors for mortality of adult inpatients with
COVID-19 in Wuhan, China:
a retrospective cohort study (03/11/2020)
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
n=137
n=54

20. Changes in laboratory markers from illness onset in
patients hospitalized with COVD-10 (03/11/2020)
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
D-dimer
iL-6
Pro-inflammatory
cytokine
Cardiac troponin
Lymphocyte count
serum ferritin
Lactate dehydrogenase

21. Severe effects of coronavirus-2 infection on host
+

22. Effect of severe COVID-19 on cytokines in patients
+
IL-1, IL-2, IL-4, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, macrophage colony-stimulating
factor (MCSF), IP-10, MCP-1, MIP-1α, hepatocyte growth factor (HGF), IFN-γ and TNF-α

23. Cytokines associated with corona virus infection
▪ Covid-19: IL2, IL7, IL-10, GSCF, IP-10, MCP-1,
MIP1A, TNF-α
▪ SARS: IFN-γ, IL-1β, IL-6, IL12A, IP10 and
MCP1,
▪ MERS: IFN-γ, IL15 and IL17A,TNFα
https://www.cusabio.com/COVID-19-Cytokine-Storm

24. Actions of iL-6
https://www.researchgate.net/figure/Summary-of-cellular-sources-and-actions-of-IL-6_fig2_26715128

25. Actions of TNF-α
https://www.jacionline.org/article/S0091-6749(07)01999-9/pdf

26. Functions and targets of major cytokines
https://www.researchgate.net/figure/General-function-cell-source-and-target-cells-of-cytokines-measured-in-this-study_tbl3_266484530

27. Mediators of the cytokine storm and the infection outcome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/
The diagram shows the functional roles of key cytokines and chemokines and their cognate
receptors in the development of the main clinical outcomes associated with the cytokine storm.

28. Diagnostic criteria for cytokine storm as established in the HLH-2004
protocol of the Histiocyte Society.
diagnosis can be established by fulfilling five of the eight proposed criteria
https://www.researchgate.net/figure/Diagnostic-criteria-for-hemophagocytic-lymphohistiocytosis-HLH-as-established-in-the_fig1_44658147

29. Clinical Features of Hospitalized COVID-19 Infected Individuals
& Their Relationship to Cytokine Storm Syndrome Criteria
https://www.the-rheumatologist.org/article/dont-forget-the-host-covid-19-cytokine-storm/https://www.ncbi.nlm.nih.gov/pubmed/16937360
8 criteria
3 criteria

30. Cytokine Storm Causes Direct Organ Injury
https://www.cusabio.com/c-20981.html

31. Human Acute Respiratory Distress Syndrome (ARDS).
Photomicrographs from the lungs of 2 different patients with ARDS,
stained with hematoxylin and eosin (H&E).
(A) [magnification, 200] The alveolar spaces are filled
with a mixed mononuclear/neutrophilic infiltrate, the
alveolar walls are thickened, and the septae are
edematous.
Note the presence of cellular debris and proteinaceous
material in the air spaces and
(B ) [magnification, ×400]).
In later stages:
(C)[magnification, ×200] and (D) [magnification, ×400]),
there is a fibroproliferative response with collagen
deposition in the alveolar walls (arrows). Note that the
alveolar epithelium has been replaced with cuboidal
cells (arrowheads).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/

32. How to Treat Cytokine Storm in COVID-19?
https://www.cusabio.com/COVID-19-Cytokine-Storm

33. Controversy on use of ACE inhibitor and ARB in
COVID-19
▪ Most patients with cardiovascular comorbidities take angiotensin‐converting enzyme
inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy.
▪ Severe acute respiratory syndrome coronavirus-2 (SARS‐CoV‐2) uses the
angiotensin‐converting enzyme-2 receptor (ACE-2) for entry into target cells.
▪ Ferrario et al reported that both ACEI and ARB could significantly increase mRNA
expression of cardiac ACE2.
▪ It was hypothesized that these drugs might play a role in the severe course of
COVID‐19 cases.
▪ However, no clinical‐epidemiological data have been put forward and it is unknown
whether the hypothesized mechanism plays a pivotal role in COVID‐19.
https://www.ahajournals.org/doi/10.1161/JAHA.120.016509

34. Summary
▪ Cytokine storm in COVID-19 is characterized by fever, cough,
acute respiratory distress and multi-organ failure.
▪ The total mortality of 1751 COVID-19 patients (7 reports) on
mechanical ventilation is 57%
▪ Cytokine storm is associated with activation of macrophages and
lymphocytes.
▪ Activation of the immune cells results in an explosive release of
pro-inflammatory cytokines especially iL-6 and TNF-α.
▪ The hypercytokinemia leads to a hyperinflammatory state.
▪ There is no specific treatment for cytokine storm at this time.
▪ The current treatment is mainly supportive and symptomatic.

35. ANY QUESTION?
Please contact
Kevin KF Ng, MD, PhD
Email: kevinng68@gmail.com