Cytokine storm

Scientists have known since March 2020 that there are two types of immune reactions involved in severe COVID-19 disease. One is immunodeficient, or a poor immune system that is unable to fight the virus. The other is what some scientists have called immunopathological, or sickness caused by the immune response. A cytokine storm is the result of the latter.

Researchers think that two things happen at the beginning of a cytokine storm in COVID-19:

• The Th 1 response by the helper T-cells is muted and the immune system doesn't release enough C8+ cells for adequate antiviral activity.
• Instead, more interleukins—including TNF-⍺, IL-6 and IL-10 are produced in the body.

Here’s what happens when a respiratory virus like SARS-CoV-2 attacks the cells in the air sacs (alveoli) in our lungs:

• The virus enters the cell undetected. But once it starts making copies of itself, the cell realises there’s been an invasion.
• The macrophages (white blood cells that kills pathogen by eating them) inside the alveoli start destroying the virus. Simultaneously, they send out cytokines to call for help from other immune cells.
• Neutrophils, another type of white blood cells that normally circulate in the blood, respond by entering the cell and releasing pro-inflammatory substances like leukotrienes, PAF, oxidants and proteases.
• The leukotrienes cause inflammation and constrict the airways (bronchoconstriction). They also encourage the production of more mucus and fluids. This causes difficulty in breathing.
• Fibroblasts, another type of white blood cell present inside the alveoli cells, release more cytokines. They also start making pro-collagen, which is turned into collagen (the most abundant protein in our body, collagen is present in all our tissues) for scarring or patching up the alveoli with fibres. Instead of helping, this scarring compounds the problem.
• As inflammation occurs and the cell allows white blood cells to rush in, fluid builds up in the cells. Tiny blood clots form in the capillaries (tiny blood vessels) next to the affected air sac.
• Meanwhile, the macrophages are still releasing cytokines like TNF-⍺, IL-1, IL-6 and IL-8.
• The wall of the air sac (alveoli) and endothelium or outer wall of the blood vessels passing close to the air sacs suffer damage. This is because of the sheer volume of white blood cells and fluid passing through for repair. Once these walls break down, fluid leaks from the capillaries into the air sacs.
• This buildup of proteins and fluids in the lungs appears as ground-glass opacity in a CT scan.

Cytokines are mainly proteins produced by our immune cells (like macrophages, neutrophils and lymphocytes including T-cells, B-cells and NK cells) to talk to each other. There are many different types of cytokines, with their specific roles and production module. The following are the main types of cytokines uncovered by researchers so far:

• Interleukins: There are more than 40 types of Interleukins (ILs) which are divided according to their jobs and the receptors that they attach to. Examples include IL-1 alpha, IL-1 beta, IL-2, IL-6, IL-8 and IL-29. These interleukins perform jobs like the activation of immune cells, cell differentiation, and signalling the production of even more cytokines.
  According to “Into the Eye of the Cytokine Storm”, published in the Microbiology and Molecular Biology Reviews journal of the American Society for Microbiology, cytokines “increase acute-phase signalling, trafficking of immune cells to the site of primary infection, epithelial cell activation, and secondary cytokine production”.
  You might have heard of interleukins in the context of death by COVID-19. Indeed, IL-6, a proinflammatory cytokine, has been found to be closely linked to severe illness in COVID-19. (more on this in a later section)
• Tumour necrosis factor: Tumour necrosis factor or TNF cytokines are linked to negative outcomes in many viral diseases, including Ebola virus disease and dengue fever.
  Of these cytokines, TNF-⍺ is well-known for its role in sepsis. Sepsis is basically an over-the-top immune response to an injury, infection or insult that often results in multiple organ damage. The world over, more people die from sepsis each year than cancer.
  Excess TNF production is also linked to autoimmune diseases and some chronic diseases. Indeed, TNF inhibitors are sometimes prescribed to people with conditions like inflammatory bowel disease and Crohn's disease.
  According to researchers, these proinflammatory cytokines activate cytotoxic T cells.
• Interferons: These cytokines help the body fight viruses and other pathogens. Interferons (IFNs) are responsible for what is known as innate immunity (or the immunity that we are born with) as well as adaptive immunity (the immunity we gain throughout our life, from fighting infections).
  In the case of a viral infection like COVID-19, IFN gamma activates the immune system’s macrophages (a type of white blood cells that destroys pathogens by eating them), triggers inflammation and regulates what is known as the Th1 cell response. Helper T cells (Th cells) are a part of the immune system. The Th1 response is crucial for releasing C8+ cells which release specific antivirals to fight the disease.
• Chemokines: These cytokines are responsible for the movement of cells according to chemical stimuli (chemotaxis). These proteins recruit leukocytes to come and fight the infection.
• Colony-stimulating factors: These proteins are responsible for the production of macrophages and granulocytes (both are types of white blood cells) among other functions.

A cytokine storm is a kind of self-perpetuating release of inflammatory proteins or the inability to regulate inflammation for some reason. These proteins or cytokines invite white blood cells into the damaged area for repair. Though this starts out as a helpful and restorative process, it turns dangerous with the sudden and excessive production of too many proinflammatory cytokines. The blood vessels, which allow proteins to pass through to repair tissues, eventually become leaky. The immune cells start to attack healthy cells. And if this situation is left unchecked, there is wide-ranging damage to the organs.

The NIH National Cancer Institute in the US defines a cytokine storm thus: “A severe immune reaction in which the body releases too many cytokines into the blood too quickly.... Sometimes, a cytokine storm may be severe or life threatening and lead to multiple organ failure. Also called hypercytokinemia.”

According to the institute, the outward signs of a cytokine storm include:

• High fever
• Redness
• Swelling
• Nausea
• Extreme fatigue
• Purpuric rash

A doctor may also be able to detect organomegaly (enlarged organs), especially the liver and spleen, in an examination.

Cytokine release syndrome is a side-effect of immunotherapy. It is also characterised by the excessive production of cytokines. Some of the symptoms associated with cytokine release syndrome are:

• Loss of appetite or anorexia
• Myalgia or muscle pain
• Joint pain or arthralgia
• Nausea and vomiting
• Headache
• Skin rash
• Diarrhoea
• Rapid breathing or tachypnea (a healthy adult breathes 12-20 times per minute)
• Low blood oxygen levels (hypoxemia) which can be measured with a pulse oximeter
• Fast heartbeat (tachycardia)
• Low blood pressure (hypotension)
• Elevated D-dimer (Read more: D-dimer test)
• Difficulty in blood clotting (hypofibrinogenemia and bleeding)
• Azotemia or buildup of excess nitrogen-based compounds like creatinine and urea in the blood—this could signal some damage to the kidney
• Transaminitis or the presence of liver enzymes (transaminases) in the blood could indicate a liver problem
• Hyperbilirubinemia, or too much bilirubin in the blood, could also be a sign of a liver problem or jaundice
• Altered mental state
• Confusion or delirium
• Difficulty finding the right words (frank aphasia)
• Hallucinations
• Altered gait, or difficulty walking
• Seizures

A cytokine storm caused by hemophagocytic lymphohistiocytosis (HLH), a rare complication of HIV/AIDS, presents with:

• Fever
• Enlarged spleen (splenomegaly)
• Enlarged liver
• Abnormal complete blood count: The neutrophil count could be less than 1,000 per microlitre (µL) of blood, haemoglobin could be less than 9 g/dL and platelet count could be under 100,000.
• High triglyceride levels (over 265mg/dL) in the blood (hypertriglyceridemia) or low fibrinogen levels in the blood (hypofibrinogenemia; under 150 mg/dL).
• Hemophagocytosis
• Neurological signs like ataxia (difficulty in walking straight), altered mental state and seizures.
• Bleeding gums and loose teeth
• Rashes and easy bruising
• Abdominal pain
• Vomiting
• Diarrhoea
• Loss of appetite (in babies, this is seen as a loss of interest in feeding)

While the trigger for a cytokine storm could be a bacterial infection, viral infection, injury, infection after surgery, etc., the exact cause for it is unknown. Some scientists say that some people may be genetically predisposed to having an out-of-proportion immune response.

Cytokine release syndrome can also be triggered by some medicines and therapies such as CAR-T therapy for cancer and other immunotherapies that uses our own immune system to fight potentially lethal diseases.

The health of a patient with cytokine storm syndrome can deteriorate very quickly. In the later stages, a cytokine storm can lead to organ damage including:

• Lung failure
• Acute respiratory distress syndrome or ARDS
• Kidney failure
• Heart failure
• Shock
• Multi-organ failure
• Death

Cytokine storm-linked complications have been identified as a cause of death in COVID-19.

Apart from the symptoms and the context, doctors may look at a few diagnostics to know whether someone could be in danger of a cytokine storm:

• C-reactive proteins: These proteins are released by the liver. Cytokine storm has been linked to raised levels of C-reactive proteins in the blood. (Read more: C-reactive protein test)
• Erythrocyte sedimentation rate: Doctors might order an erythrocyte sedimentation rate (ESR) test, as a sudden drop in ESR has been associated with a cytokine storm. 
• Procalcitonin: The procalcitonin test is more useful in cases where the cytokine storm is triggered by bacterial infections rather than viral infections. That said, it is often used for detecting sepsis.
• Elevated levels of the proteins serum amyloid A, ferritin and fibrinogen could also alert doctors that there's something wrong.
• Tests used to determine organ damage, starting with a complete blood count with differential and liver function test can help to detect the problem.
• Hypoalbuminemia: Researchers say hypoalbuminemia or low albumin levels in the blood could be a sign of blood leaking into nearby tissues as a result of cytokine-induced damage.
• With respect to COVID-19 linked cytokine storms, doctors are still looking for the foolproof test for it. This is obviously very important, as early detection could drastically reduce severe disease and death in COVID-19.
  Research on this is ongoing. For now, scientists say medical professionals should be looking at some of these diagnostics:
  • Neutrophils-to-lymphocyte ratio (NLR) is an early indicator of inflammation. If this is monitored in all COVID-19 patients, it may be possible to predict who might have severe disease. High NLR is also associated with poorer health outcomes and even mortality in heart disease and cancer
  • Neutrophil-to-CD8+ T cell ratio (N8R) is another early marker associated with severe COVID-19, according to some researchers.
  • Test the blood for known inflammatory markers and elevated levels of specific cytokines like IL-6
  • Look for the signs of tissue damage, especially acute kidney injury, heart damage and liver damage
  • Overactive blood clotting
  • Look at the H score, typically used to detect secondary haemophagocytic lymphohistiocytosis (HLH)—a complication of some viral infections that is characterised by hyper-inflammation. The H score is calculated on the basis of parameters like fever, enlarged organs (especially liver and spleen), the number of cytopenias, triglyceride levels, level of fibrinogen (a blood-clotting protein), the amount of ferritin and serum aspartate aminotransferase enzyme in the body, haemophagocytosis, and any pre-existing condition that suppresses the immune response.

The treatment depends on the cause. By now, doctors are more familiar with the cytokine storms caused by bacterial infections and cancer immunotherapy.

However, cytokine storms caused by viral infections are comparatively new territory. In the context of COVID-19, doctors are currently using immunosuppressants like the steroid dexamethasone, selective cytokine inhibitors, and anti-inflammatory drugs like the ones used to treat rheumatoid arthritis (example: tocilizumab which is also a known IL-6 inhibitor) to reduce the chances of severe illness and death in COVID-19 patients.