COVID-19 is a viral infection. As we have noted[1]
previously, the virus starts off an immune response by binding with TLR7, a
toll like receptor in the invaded cell. It then sets off a massive set of
cytokine releases. As we have also noted[2]
when the immune system is triggered there can be massive cytokine storms.
Namely the release of massive amounts of immune related molecules which can run
havoc in the body.
As we get to better understand COVID-19 and its dynamics we
apparently are seeing is more as a massive immune reaction and less as a
classic viral disease. Let us briefly examine this observation.
As Vaninov had recently noted:
Not all patients with COVID-19 develop the same symptoms,
but the immunological determinants of a poor prognosis are unknown. In this
preprint article, Yang, Y et al. followed a cohort of 53 clinically moderate
and severe patients; they conducted a multiplex screen for 48 cytokines and
correlated these results with lab tests, clinical characteristics and viral loads.
They found a marked increase of 14 cytokines in patients with COVID-19 compared
with healthy controls. Continuously high levels of three of these cytokines
(CXCL10, CCL7 and IL-1 receptor antagonist) were associated with increased viral
load, loss of lung function, lung injury and a fatal outcome. These observations
offer key insights into the immunopathology of COVID-19 and provide new avenues
for prognosis and therapy.
The implication seems to be to find therapeutics which may
be counter-intuitive, namely immune repressors. Thus the classic virologist may
have to be replaced by the immunologist, those dealing with immunotherapy. For
example in the use of CAR-T cells, we can create these cytokine storms. Not
always, but often enough to have some concerns.
As Tisoncik et al note:
Inflammation associated with a cytokine storm begins at a
local site and spreads throughout the body via the systemic circulation. Rubor
(redness), tumor (swelling or edema), calor (heat), dolor (pain), and “functio
laesa” (loss of function) are the hallmarks of acute inflammation. When
localized in skin or other tissue, these responses increase blood flow, enable
vascular leukocytes and plasma proteins to reach extravascular sites of injury,
increase local temperatures (which is advantageous for host defense against
bacterial infections), and generate pain, thereby warning the host of the local
responses. These responses often occur at the expense of local organ function,
particularly when tissue edema causes a rise in extravascular pressures and a
reduction in tissue perfusion. Compensatory repair processes are initiated soon
after inflammation begins, and in many cases the repair process completely
restores tissue and organ function. When severe inflammation or the primary
etiological agent triggering inflammation damages local tissue structures,
healing occurs with fibrosis, which can result in persistent organ dysfunction.
The multi-organ attack seems to be now a part of COVID-19
and results in significant co-morbidities.
As Tisoncik et al note:
Cytokines are a diverse group of small proteins that are
secreted by cells for the purpose of intercellular signaling and communication.
Specific cytokines have autocrine, paracrine, and/or endocrine activity and,
through receptor binding, can elicit a variety of responses, depending upon the
cytokine and the target cell. Among the many functions of cytokines are the
control of cell proliferation and differentiation and the regulation of
angiogenesis and immune and inflammatory responses
They list the major class of cytokines as follows:
|
Type
|
Action
|
|
Interferons
|
Regulation of innate
immunity, activation of antiviral properties, antiproliferative effects
|
|
Interleukins
|
Growth and differentiation
of leukocytes; many are proinflammatory
|
|
Chemokines
|
Control of chemotaxis,
leukocyte recruitment; many are proinflammatory
|
|
Colony Stimulating Factors
|
Stimulation of
hematopoietic progenitor cell
proliferation and
differentiation
|
|
Tumor Necrosis Factors
|
Proinflammatory, activates
cytotoxic T lymphocytes
|
The following are common in a cytokine storm:
Interferons: The interferons (IFNs) are a family of
cytokines that play a central role in innate immunity to viruses and other
microbial pathogens (45, 75). They are classified into three major types (types
I, II, and III) on the basis of their receptor specificity.
Interleukins: IL-1α
and IL-1β are
proinflammatory cytokines that mediate the host response to infection through
both direct and indirect mechanisms. Among their biological functions, these
cytokines increase acute-phase signaling, trafficking of immune cells
to the site of primary infection, epithelial cell
activation, and secondary cytokine production.
CSFs: Colony-stimulating factors (CSFs), such as granulocyte
macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating
factor (M-CSF), and granulocyte colony stimulating factor (G-CSF), stimulate
hematopoietic progenitor cell proliferation and differentiation.
Colony-stimulating factors are also associated with inflammation, and there is
evidence that these factors may be part of a mutually dependent proinflammatory
cytokine network that includes IL-1 and tumor necrosis factor (TNF)
TNF: Tumor necrosis factor (TNF) is perhaps the best known and
most intensely studied of the proinflammatory cytokines, and it plays a
prominent role in the cytokine storm literature. The name “tumor necrosis
factor” was first used in 1975 for a cytotoxic serum factor capable of inducing
tumor regression in mice (23), which soon thereafter was reported to play a
role in the pathogenesis of malaria and sepsis (14, 30, 31). TNF is now
considered a central cytokine in acute viral diseases, including those caused
by influenza virus, dengue virus, and Ebola virus.
As Mehta et al note regarding this syndrome in previous
viral attacks:
As during previous pandemics (severe acute respiratory
syndrome and Middle East respiratory syndrome), corticosteroids are not
routinely recommended and might exacerbate COVID-19-associated lung injury. However,
in hyperinflammation, immunosuppression is likely to be beneficial. Re-analysis
of data from a phase 3 randomised controlled trial of IL-1 blockade (anakinra)
in sepsis, showed significant survival benefit in patients with
hyperinflammation, without increased adverse events A multicentre, randomised
controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine
release syndrome), has been approved in patients with COVID-19 pneumonia and
elevated IL-6 in China (ChiCTR2000029765). Janus kinase (JAK) inhibition could
affect both inflammation and cellular viral entry in COVID-19.10 All patients
with severe COVID-19 should be screened for hyperinflammation using laboratory
trends (eg, increasing ferritin, decreasing platelet counts, or erythrocyte
sedimentation rate) and the HScore11 (table) to identify the subgroup of
patients for whom immunosuppression could improve mortality. Therapeutic
options include steroids, intravenous immunoglobulin, selective cytokine
blockade (eg, anakinra or tocilizumab) and JAK inhibition.
We believe that a rethinking of the COVID-19 treatments in
this context can have a significant advantage.
References
1. Leonard and Schreiber, Cytokines, CSHL Press, 2018
2. McGarty, A Primer for COVID-19, March 2020, https://www.telmarc.com/Documents/White%20Papers/173Corona.pdf
3. McGarty, CAR-T Cells and Cancer, October 2016, https://www.researchgate.net/publication/309419224_CAR_T_Cells_and_Cancer
4. Mehta et al, COVID-19: consider cytokine storm syndromes and immunosuppression,
Lancet, March 28, 2020
5. Tisoncik et al, In the Eye of the Cytokine Storm, MMBR, Microbiology
and Molecular Biology Reviews, March 2012
6. Vaninov, In the Eye of the COVID-19 cytokine storm, Nature
Reviews, Immunology, 6 April, 2020
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