Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines

Abstract

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.

Keywords: COVID-19; IFN-γ; IL-6; SARS; TNF-α; coronavirus.

Figure 1.

CS symptoms in COVID-19 and disease progression. Clinical symptoms of COVID-19 can be related to those associated with cytokine storm. Delayed detection of symptoms may lead to disease progression, with multi-organ involvement. It is difficult to manage and requires the admission of patients to ICU; intensive care is observed in about 5% of the infected population. Of the critically ill COVID-19 patients, the mortality rate is high, 40–50% [2,7].

Figure 2.

ACE2 expression in human tissues. SARS-Cov-2 uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. ACE2 RNA and protein expression were observed in the endocrine tissues, gastrointestinal tract, the kidney and urinary bladder, the liver and gallbladder in men and women [7].

Figure 3.

Prominent cytokine sources and their effect in COVID-19 pathogenesis. Immune cell sources of cytokines associated with cytokine storms; IFN-γ, TNF-α, IL-1 and IL-6 are depicted with their effects in the context of COVID-19 [7].

Figure 4.

Viral entry, replication and innate immune activation. Multiple distinct toll-like-receptors (TLRs) pathways are involved in SARS-CoV-2 pathogenesis. SARS-Cov-2 cellular entry and subsequent replication (a) may trigger the immune system by engaging multiple TLRs (b). The spike protein triggers TLR4, ssRNA activates TLR7 and dsRNA may lead to TLR3 activation. Following TLR activation, IRFs and NF-κB-dependent signalling pathways are activated leading to type I/II Interferons and pro-inflammatory cytokines [7].

Figure 5.

ARDS is acute condition occurring within 1 week of clinical insult, or the onset of respiratory symptoms, characterized by bilateral pulmonary immune infiltrates and severe hypoxaemia in the absence of cardiac failure or pulmonary edema. The condition is characterized by severity levels based on the PaO2/FiO2 ratio; mild (PaO2/FiO2 200–300), moderate (PaO2/FiO2 100–200), and severe (PaO2/FiO2 ≤ 100) [7].