**13. Cytokine storm as cause of mods**

The cytokine storm caused by COVID-19 has been proposed to be associated with the severity of COVID-19 which is multisystem inflammatory syndrome [30, 93, 94]. The early symptomatic presentation of COVID-19 mainly include fever, cough, myalgia, fatigue, or may have dyspnoea. With the progression of disease in later course, dyspnoea may worsen in susceptible host to acute respiratory distress syndrome (ARDS) or multiple organ failure (MOF) [95]. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) is known to be associated with a cytokine storm like many other infectious diseases [95, 96].

One of the major reasons for the deaths in this infection is suspected to be due to the "cytokine storm" [also called "cytokine storm syndrome"(CSS)]. Cron and Behrens bring the current knowledge of CSS. They define that "cytokine storm" is an activation cascade of auto-amplifying the production of cytokines due to dysregulated host immune response. The triggering factors for the host immune response may be due to infections, rheumatic disorders, malignancy, etc [97]. It is also thought that cytokine storm is a systemic inflammatory response to infections and drugs and leads to excessive activation of host immunity which further leads to activation of pro-inflammatory cytokines [98].

Cytokine Release Syndrome (CRS) is a similar entity which is mainly due to acute systemic inflammatory syndrome characterized by multiple-organ dysfunction (MOD). It has been said that chimeric antigen receptor (CAR)-T-cell therapy would be helpful to differentiate CRS from a cytokine storm [98]. For patients with COVID-19, C-reactive protein (CRP), and other inflammatory cytokines and chemokines are markedly elevated in the intensive care unit (ICU) patients [99, 100]. Many studies showed link between pro-inflammatory cytokines, especially interleukin 6 (IL-6), with the severity of illness in COVID-19 [30, 101–103]. Increased D-dimer levels are also found in severe disease [104]. The higher concentration of cytokines also has a poor prognosis in COVID-19 [102, 105]. Activation of both innate and adaptive immune responses by SARS-CoV-2 infection can lead to dysregulated inflammatory responses which ultimately results into the cytokine storm [106]. Furthermore, the cytokine storm leads to apoptosis of epithelial cells and endothelial cells, and dysfunction of endothelial cells causing vascular leakage and, finally, result in ARDS, MODS and other severe syndromes, and even death [107].

Many therapies are targeted to reduce the cytokine storm which can results in one of the life-saving measures in severely ill COVID-19 infection. Out of many therapies, Corticosteroids, Hydroxychloroquine (HCQ ) and chloroquine (CQ ) and Tocilizumab (TCZ) (IL-6 Inhibitor) are widely used in the recent past. Corticosteroids inhibit the host inflammatory response and suppress the immune response and pathogen clearance [108]. In a retrospective study of 401 patients infected with SARS-CoV, the rational use of corticosteroids shortened hospital stays and reduced the mortality of seriously ill patients without complications [109]. In view of their in vitro antiviral effects and anti-inflammatory properties, CQ and its analogue HCQ are most potential therapies against COVID-19. CQ and HCQ can reduce CD154 expression in T cells and suppress the release of IL-6 and TNF53 [110]. TCZ, an IL- 6 receptor (IL-6R) antagonist, can inhibit cytokine storms by blocking the IL-6 signal transduction pathway [111].

#### **14. Sepsis and Multi-Organ Dysfunction Syndrome (MODS) in COVID-19**

Patho-physiology of SARS-CoV-2 infection is complex and is known to involve activation of the immune and hematologic systems [112–118]. Endotoxin and tumor necrosis factor-alpha (TNF-alpha) trigger the production of interleukin-6 (IL-6) and IL-8, which is followed by the cytokine storm. Further events lead to activation of the coagulation cascade through endothelial and tissue factor (TF) pathways, as well as systemic inflammatory activation [94, 112]. Moreover, SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE-2) receptors, which are widely distributed. not only in lung alveolar epithelial cells and oro-nasopharyngeal mucosa but also in the endothelium as well as vascular smooth muscle cells, in the brain, in the gut and in peripheral organs such as liver and kidney [113]. This suggests that the clinical spectrum of COVID-19 is not limited to local pneumonia, but rather represents a multisystem illness with involvement of different organs and potential for systemic complications [113]. It seems that the highly pathogenic SARS-CoV-2 is associated with rapid virus replication and a tendency to infect the lower respiratory tract, resulting in an elevated response of IL-6-induced severe respiratory distress.

Most SARS-CoV-2 infected patients admitted to ICU showed a dysregulated host response characterized by hyperinflammation, alterations in coagulation, and dysregulation in the immune response that further contribute to MODS, like occurs in sepsis [114, 115]. Due to virus infection and to MODS in some cases, many patients with severe COVID-19 meet the Third International Consensus Definitions for Sepsis (SEPSIS-3), which define sepsis as "a life-threatening condition that

*COVID-19 and Multiorgan Dysfunction Syndrome DOI: http://dx.doi.org/10.5772/intechopen.99676*

arises when the body's immune response to infection damages the host's own tissues" [116]. Also, when performing specimen cultures in septic patients from a COVID-19 cohort, about 80% of patients had no bacterial or fungal infection and so viral infection would seem to be the only reason for sepsis which was reported in 50% of their 191 COVID-19 patients. This retrospective study from Wuhan reported Sequential Organ Failure Assessment (SOFA) score of 5·65 on admission [36]. SOFA score may increase on day 3 to 7as reported in one series of 50 patients of bacterial and malarial sepsis [117]. It may be due to release of mediators that there may be upward trend of SOFA score, development MODS and in mortality in sepsis patients who has unfavourable outcome. COVID-19 sepsis which can be called as viral sepsis or secondary sepsis which can be hospital acquired; may worsen the clinical phenotypes of these critically ill COVID-19 patients [118].
