Cytokine storm syndrome: causes, symptoms, diagnosis, treatment, and prevention

Cytokine storm syndrome, also known as cytokine release syndrome (CRS), can cause multiple organ dysfunction syndrome.

Cytokine is a collection of a variety of small molecule proteins secreted by cells serving as intercellular signal transducers, such as interleukin (IL), interferon (IFN), chemokine, colony stimulating factor (CSF), and tumor necrosis factor (TNF). Cytokine spreads to the body with pathways of autocrine, paracrine, and endocrine, triggering various biological effects by the corresponding receptors on the binding cells, including regulation of cellular proliferation, differentiation, and migration. Interferon is a core cytokine of the body to resist virus infection, including type I interferon (IFN-α, IFN-β) and type II interferon (IFN-γ), generated by infected histiocytes and activated T cells, respectively.


Pathology

Infection causes inflammation by stimulating the immune response, which is a common means for the body to resist pathogens such as pathogenic bacteria and viruses. In this process, cytokines are essential. Cytokine can be divided into two categories, one is pro-inflammatory cytokine, such as IL1β, IL6, IL12, TNF, and IFN-γ, which can help activate dendritic cells, pro-inflammatory macrophages, neutrophils, effector T cells, and B cells, promoting the occurrence and development of inflammatory reactions, and the other is anti-inflammatory cytokine, such as IL4, IL10 , IL13, and TGF-β, which can help activate regulatory T cells (Tregs) and anti-inflammatory macrophages, regulating the inflammatory response, and neutralize the effects of pro-inflammatory cytokines.


Causes

During the invasion of viruses or immunologic dysfunction, the balance between pro-inflammatory cytokines and anti-inflammatory cytokines is destroyed. Constantly generated pro-inflammatory cytokines activate more immune cells aggregating in the site of inflammation. Numerous immune cells and various pro-inflammatory cytokines cause congestion, edema, fever, lesions, other secondary infections, and even systemic inflammatory response syndrome, eventually resulting in multiple organ failure, which is termed cytokine storm, caused by diseases or treatments.


Signs and Symptoms

The secretion of multiple cytokines is closely related to the clinical symptoms. Studies have shown that IFN-γ can cause fever, chills, headaches, dizziness, and fatigue. TNF-α can cause flu-like symptoms similar to that caused by IFN-γ, with fever, general malaise, and fatigue, and can also cause watery diarrhea, vascular leakage, cardiomyopathy, and lung injury. IL-6 can lead to vascular leakage, disseminated intravascular coagulation (DIC), and cardiomyopathy. Endothelial dysfunction can result in capillary leakage, hypotension, and coagulopathy.


Diagnosis

The condition is difficult to diagnose and mainly based on empirical therapies.


Treatment

Immune modulators, including glucocorticoids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor agonists, cyclooxygenase inhibitors, and antioxidants, anti-tumor necrosis factor treatment, intravenous immunoglobulin, angiotensin-converting enzyme inhibitors, CCR inhibitors, adenosine monophosphate-activated protein kinase agonists, OX40 mAb, cytokine signal transduction inhibitors, macrolide antibiotics, and free radical scavengers such as vitamin C and vitamin E can be administered.


Prevention

Researches have shown that cytokine release is related to catecholamines such as epinephrine, and limit of its synthesis can effectively control the occurrence of CRS and can reduce cytokine production and increase survival rates without affecting the therapeutic effect.

Tyrosine hydroxylase (TH), the key rate-limiting enzyme in catecholamine synthesis, can be antagonized by metyrosine (MTR), an antihypertensive medication in clinical practices.