Cytokine storm syndrome and COVID-19 mortality

The SARS-CoV-2 responsible for the ongoing pandemic causes ARDS and COPD. The disease’s progression is observed through different stages with different sets of medications in the specific stage. It has a 6.4% rate of mortality, according to statistics. Autopsy results on the non-survivors indicate elevated levels of IL-6 and the ‘cytokine storm syndrome’ as a possible reason for death. Previous outbreaks of SARS and MERS also suggest the same. A potential treatment would be the administration of IL-7 (anti-inflammatory), which has the opposite effect of IL-6 (pro-inflammatory).

Typical immune response to infections

Under the event of a typical infection, various cells of the immune system act to kill the pathogen. This activation is a response of PAMPs and PRRs. The PRRs–Pattern recognition Receptors — recognize different molecules (Pathogen Associated Molecular Patterns (PAMPs)), which characterize the invading pathogens. 

The binding of PAMPs to PRRs triggers an inflammatory response resulting in activation of signaling pathways and pro-inflammatory cytokines and chemokines. These cytokines are the signaling molecules. 

The first cytokines released are IL-1β and TNFɑ. They recruit WBCs, neutrophils, monocytes, macrophages, and natural killer cells to the site. This is the innate response. Furthermore, these cells’ activity releases Interleukin-6, which provokes a T and B-cell response (adaptive immunity). 

Meanwhile, IL-6 also makes the lining of vasculature and organs permeable to facilitate transport. As a result, all the fighting cells accumulate at the stimulation site, leading to mild localized inflammation. The system then starts secreting anti-inflammatory cytokines to turn off the response and return to a healthy state. Without this signal, the pro-inflammatory response escalates, resulting in multi-organ failure.

What is a cytokine storm?

When our immune system enters hyperactivity, it can lead to irreversible tissue damage. Usually, the anti-inflammatory system works just fine, but sometimes it fails and spirals out of control. As a result, the obedient soldiers turn into an unruly fighting mob, leading to an overdrive. 

Since this hyperactivity is a response of rampaging cytokines through the bloodstream, it falls under the umbrella term ‘cytokine storm syndrome,’ which is highly fatal. Dysregulation of pro and anti-inflammatory responses is a characteristic symptom. There are dozens of these messengers all signaling the immune system to calm down and rev-up at the same time. 

The immune system cannot stop itself, and the immune cells move to different locations from the site of stimulation damaging healthy tissues and organs.

The blood vessels open up to facilitate transport, but since IL-6 can increase vascular permeability, they can get so leaky that fluid builds up in the lungs, and blood pressure drops. Moreover, the clotting factors secreted by vascular cells further coagulate the pathway resulting in micro thrombosis. 

Many regions in the bloodstream clog up, closing the gates for blood flow to other cells. Due to a lack of oxygen and nutrient supply, they start to die. When organs don’t get enough oxygen, you may go into a shock, coma, or increase the risk of permanent organ damage or death. Other symptoms include neural complications like headaches and seizures. All the symptoms are due to tissue death in various organs like kidneys, intestine, liver, heart, and brain.

Though there is no diagnostic test, a few tests can signal that a storm is underway– for instance, a high C-reactive protein level and elevated IL-6 levels are inflammation indicators and warning signs of a cytokine storm.

Signs of Cytokine storm syndrome

A cytokine storm release is also a consequence of hemophagocytic lymphohistiocytosis (HLH) disease (persistent activation of T-cells and NK cells). Though blood destruction is not always a result of HLH, the boundaries between the clinical manifestations of HLH and CSS are blurred. 

The symptoms of HLH can serve as warning signs of CSS– enlarged liver and spleen, hypercoagulation, liver dysfunctions, and hyperferritinemia. Ferritin is the primary form of iron stored in the body. Though identifying and recognizing the warning sign is challenging, it is life-saving. It should be suspected when there is unremitting fever and signs of elevated inflammatory response without any clinical infection. 

This hyperactivity is influenced by various factors, including the auto-immune response, in which your system identifies your own cells as invaders. Various genetic factors also increase susceptibility. Besides, mutations in genes can encourage the immune cells to keep fighting, further releasing a massive amount of cytokines. 

Also, viruses such as Epstein Barr virus (targeting neural cells) can trigger CSS. However, there are also records of CSS in previous viral outbreaks like influenza, MERS, and SARS, including the current outbreak– SARS-CoV-2.  

Signs in severe COVID-19 patients

In severe COVID-19 patients, elevated levels of lymphocytes in the lungs (the target organ) and low levels in the spleen and liver indicate immune overdrive. On a prolonged level, it can lead to cell death in the spleen and liver, worsening it. A commonly diagnosed condition in COVID-19 victims is ARDS (Acute respiratory distress syndrome). Besides, the non-survivors expressed scattered degeneration of neurons, alongside the enlarged liver, edema, and kidney hemorrhage. 

Conclusively, elevated IL-6 is a potential CSS marker. 

Moreover, the hypercoagulability also explains the D-dimer levels diagnosed in severe conditions. D-dimer is a protein by-product found in the blood after the degradation of a blood clot. However, elevated procalcitonin–also suggests CSS– is an indication of secondary bacterial infection. 

Treatment for cytokine storm syndrome

The first solution to quiet down this response is steroids, but researchers are not sure if steroids act conventionally or have severe side effects in COVID-19. There are other medications that can interfere with the cytokines. The list includes tocilizumab, sarilumab, and anakinra, which can help block the pathway acting as cytokine inhibitors.

If your own immune system is killing you, then you need to make a quick decision to treat the condition. The doctors must come up with a new medication plan that alleviates the cytokine storm and also kills the pathogen that caused it. Besides, it is best to catch the storm before its first appearance using specific diagnostic tests and a complete blood picture. 

Related: How T-cells and B-cells act? How does a vaccine train them?

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