Evidence shows that the cytokine storm raised by the immune system may be the main reason for COVID-19's killing ability. So what is a cytokine storm? How does it harm human bodies?
Cytokine storm, also known as cytokine storm syndrome (CSS) or hypercytokinemia, refers to the phenomenon that multiple cytokines, such as TNF-α, IL-1, IL-6, IL-12, IFN-α, IFN-β, IFN-γ, MCP-1, and IL-8, are rapidly and massively produced in the body fluid when the body's immune system is over-activated. This is an important cause of acute respiratory distress syndrome and multiple organ failure. Once a cytokine storm occurs, it can quickly cause single organ or multiple organ failure, and eventually becomes life-threatening.
The daily work of the immune system is to clear the infection, but if the immune system is activated to the limit or loses control, it will harm the host. An extreme immune attack is a cytokine storm.
The cytokine storm is a signal for help, and the purpose is to ask the immune system to fight tooth and nail at once. This kind of suicide attack can damage the virus, but will also leave a lot of wounds to the host. The blood vessels withstood the most important offensive, in which the cytokine storm makes the blood vessel wall easier to penetrate. Therefore arteries, veins, and capillaries all begin to leak blood and plasma. The cytokine storm also triggers a massive release of nitric oxide, which will further dilute the blood and destroy blood vessels. All of these factors combine to lower blood pressure to a dangerous level, so the patient does not die from blood loss, but from a symptom similar to severe septic shock.
The concept of cytokine storm first appeared in graft-versus-host disease (GvHD) in 1993. GvHD shows the symptom that immune cells in the transplant treat the host as a foreign body and attack the host cells. Later, humans gradually discovered that viruses (such as SARS virus and MERS virus) and bacterial infections can also cause cytokine storms. At this time, it is the patients' own immune cells that attack the host cells.
When SARS-CoV-2 infects humans for the first time, the human immune system has no ability to recognize this virus. Once the virus invades into normal cells, the immune system will not be able to distinguish between friends and foes. When the virus multiplies rapidly and the immune system becomes intolerable and chooses to work hard to clear the virus, a cytokine storm may break out. From this point of view, a virus's toxicity depends on how destructive the immune response it induces.
Human ACE2 stable cell line is frequently used in research of SARS-CoV-2 since studies have shown that SARS-CoV-2 enters the cell through angiotensin-converting enzyme 2 (ACE2), so the lung tissue with high expression of ACE2 and easy access has become the main invasion target of these viruses. After invading the lungs, the immune system sends a large number of immune cells to the lung tissue to kill the enemy, thus forming pneumonia, and some symptoms appear such as fever, coughing, and expiratory dyspnea.
However, because these immune cells are not capable of destroying the virus accurately, they can only attack indiscriminately and summon more immune cells to kill the enemy, leading to the result that more and more immune cells and cytokines gather together. Once a cytokine storm is formed, the immune system may not be able to kill these viruses, but it will definitely kill a large number of normal cells in the lungs, severely destroying the ventilation function of the lungs, and large white shadows will appear on the lung CT scan, which is known as "white lung". The patient will have respiratory failure until death from hypoxia.
The diagnosis of cytokine storm mainly depends on the detection of inflammatory factors in the blood. However, in fact, different viruses do not trigger cytokine storms through exactly the same mechanism, so they will cause different cytokine changes. For example, SARS-related cytokine storms are mainly related to IL1B, IL6, IL12, IFNγ, IP10, and MCP1, while MERS CoV-induced cytokine storms are mainly related to IFNγ, TNFα, IL15, and IL17. The performance of COVID-19 is different from the above two. On January 24, 2020, The Lancet published a retrospective study of 41 COVID-19 pneumonia in Wuhan University Zhongnan Hospital. In this study, compared with patients with mild symptoms, the expression levels of multiple plasma pro-inflammatory factors (IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, TNFα) in severe cases were significantly higher, and these inflammatory indicators suggested that cytokine storms occurred in patients with severe COVID-19.
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