Article Type : Research Article
Authors : Harfouch RM
Keywords : Cytokine storm syndrome (CSS); Coronavirus SARS-CoV-2; Characteristics
Cytokine storm syndrome (CSS) is a serious condition induced by a cascade of cytokine activation, characterized by general systemic inflammation, hyperferritinaemia, haemodynamic instability and multiple organ failure (MOF). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan China, at the end of 2019, and rapidly developed into a global pandemic. This infection causes a dramatic increase of inflammatory cytokines in patients, suggesting the development of cytokine storm in some critical illness patients. Here, we summarize the pathogenesis, clinical manifestation of CSS, and highlight the current knowledge about the recognition and diagnosis of CSS in COVID-19.
The coronavirus SARS-CoV-2 has infected more than 250 million people causing death to over than 5 million, with a mortality rate of approximately 2% worldwide. Many patients who die from COVID-19 suffer from hyper-inflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome . Only anti-inflammatory treatment have improved survival in these patients, although the antiviral Remdesivir was shown to reduce the length of hospital stay for COVID-19 patients . The greatest survival benefit has been found with immunosuppressive glucocorticoids when given to those with an oxygen requirement. However, in the absence of an oxygen requirement or substantial systemic inflammation, patients treated with glucocorticoids may fare worse than those who receive standard care. For survival benefit, the selection of patients and timing of the administration of glucocorticoids is critical. Optimal treatment is earlier use of targeted anti-cytokine therapy to prevent CSS, without increasing viral replication .
Cytokine storm syndrome (CSS) is characterized
by immune dysregulation due to continuous activation of lymphocytes and
macrophages, secretion of large amounts of cytokines including IL-1?, IL-1?,
IL-6, IL-18 and TNF-? and finally, overwhelming systemic inflammation and
multi-organ failure with high mortality . The term CSS was first used to
describe the hypercytokinemia in graft after allogeneic stem cell transplant.
Many viral, bacterial and parasitic infections can cause CSS such as
Epstein-Barr virus (EBV) and Mycobacterium tuberculosis, which cause
pathological immune activation characterized by elevated cytokines mainly
interferon-? (IFN-?) and soluble interleukin-2 receptor (sIL-2r) in patients
with immune defects . Levels of inflammatory cytokines IL-6, IL-8, MCP-1 and
TNF? are significantly increased in COVID-19 plasma. Detailed correlation
analysis revealed strong associations between some of the endothelial derived
markers but only weak associations with age or general inflammatory parameters
such as CRP. Fibrinogen levels correlate with increased P-selectin. In
addition, plasma levels of IL-8 were strongly associated with circulating vWF
levels. Local as well as systemic, circulating inflammatory markers coincide
with various markers revealing endothelial activation and damage in COVID-19
The pathogenesis of CSS has not been fully
known. Previous studies have shown that the development of CSS involves the
imbalance of pro-inflammatory and anti-inflammatory mechanisms and the
interaction of a variety of cells and cytokines, resulting in immune regulation
disorder, causing a series of clinical manifestations. Previous studies have
shown that a variety of cytokines can be markedly increased in patients with
CSS, which may vary according to the heterogeneity of the disease background.
In the setting of influenza virus-related CSS, a previous study found that
patients infected with H5N1 had higher levels of monocyte chemoattractant
protein 1 (MCP-1), interferon-gamma-induced protein-10 (IP-10) and IL-8 than
patients infected with seasonal H1N1 influenza . Moreover, previous studies
also confirmed that cytokines played an important role in the pathogenesis of
severe CoV infection. The serum proinflammatory cytokines (IFN-?, transforming
growth factor-? (TGF-?), IL-1, IL-6, IL-12) in severe SARS patients were
significantly higher than those with mild to moderate symptoms, and serum
proinflammatory cytokines (IFN-?, IL-6, IL-8) in severe MERS patients were
significantly increased as well .
The cytokine storm in COVID-19 may have some differences from the cytokine storms in other clinical settings. Remarkably, the autopsy findings revealed that the lymphoid tissues and organs had been destroyed in COVID-19 patients, which is very unusual from CSS in sepsis and CAR T-cell therapy. Spleen atrophy and lymph node atrophy are observed in patients with COVID-19, whilst in other CSS-related diseases, lymphadenopathy and splenomegaly are more common. However, the specific mechanisms for these differences remain unclear and need to be further clarified . Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses, which have caused two large-scale pandemics in the last two decades, SARS and MERS . Spike (S) proteins of coronaviruses, including the SARS-CoV, facilitate viral entry into their target cells via the interaction with functional cellular receptor identified as angiotensin-converting enzyme 2 (ACE2), which is highly expressed in alveolar epithelial cells, vascular endothelial cells, intestinal epithelial cells and renal proximal tubular cells. Functionally, ACE2, belonging to the ACE family, inactivates angiotensin II (Ang II) and generates angiotensin 1–7, a biologically active heptapeptide characterized by a potent vasodilator function. It has been demonstrated that the binding of the coronavirus spike protein to ACE2 leads to the down-regulation of ACE2, which in turn results in excessive production of vasoconstrictor Ang II and reduced production of vasodilator angiotensin 1–7.
Ang? also plays the role as a proinflammatory
cytokine via angiotensin receptor 1 (AT1R). The AngII-AT1R axis further activates NF-?B and
metalloprotease 17 (ADAM17), which stimulates the production of the mature form
of epidermal growth factor receptor (EGFR) ligands and TNF-?. The activation of
both NF-?B and STAT3, which in turn activate the IL-6 amplifier (IL-6 Amp), a
mechanism for the hyper activation of NF-?B by STAT3, will lead to a hyper
inflammatory state, resulting in increased pulmonary vascular permeability
. A retrospective study also found higher plasma concentrations of IL-2,
IL-7, IL-10, IP-10, MCP-1, MIP-1a and TNF-? in intensive care unit (ICU)
patients compared with no severe patients, suggesting there might be a cytokine
storm in the body of severe patients .
There is no standard for the diagnosis of COVID-19 associated with CSS, and further clinical and laboratory investigations are needed. Hee is a basic principle for consideration of CSS in COVID-19:
· A sudden or rapid progression with multiple organ involvement (such as liver, cardiac or renal injury)
· A significant decline of peripheral blood lymphocyte counts
· The significant elevation of systematic inflammatory indicators (such as CRP, serum ferritin, erythrocyte sedimentation rate)
· The elevation of multiple cytokines, such as IL-1?, IL-2R, IL-6, IFN-?, IP-10, MCP-1 and TNF-?.
keep highly alert on the possibility of CSS under these circumstances. However,
given that CSS is a highly heterogeneous disease and may present with
unspecific syndromes, the diagnosis of CSS in COVID-19 is very challenging and
the development of a specific diagnostic test that helps to make the diagnosis
of CSS earlier is a high priority for future research . The inflammatory
disorders in COVID-19 have been reported in many clinical studies. The COVID-19
causes a decrease of lymphocyte count and an increase of C reactive protein (CRP),
especially in severely ill patients. The major subsets of the T lymphocytes (T
cell) (CD3+ CD4+ T cell and CD3+ CD8+ T cells) are reduced in the COVID-19 and
are significantly lower in the severe cases. The results of the other immune
cells, the B cell and natural killer (NK) cell, have more inconsistency in
recent researches. IL-6 was observed increased .
The clinical, immunological, and pathologic
features of COVID-19 have something in common with SARS and MERS. All the
viruses can cause lymphopenia and influenza-like symptoms in the early stage.
SARS and COVID-19 do not lead to the elevation of TNF-?, but the increase of
IL-6 and IL-10 is more common in COVID-19. The IL-6 plays a crucial role in the
pathologic of COVID-19, including the chemotaxis of neutrophils and lymphocyte
necrosis. Importantly, COVID-19 is more able to cause cytotoxic lymphocytes