Cause of Cytokine Storms

When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.[2] Normally, the body keeps this feedback loop in check. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs. If a cytokine storm occurs in the lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.

The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors). Both pro-inflammatory cytokines (such as Tumor necrosis factor-alpha, Interleukin-1, and Interleukin-6) and anti-inflammatory cytokines (such as interleukin 10 and interleukin 1 receptor antagonist) are elevated in the serum of patients experiencing a cytokine storm.[3]

Cytokine storms can occur in a number of infectious and non-infectious diseases including graft versus host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS).[4] Cytokine storm may also be induced by certain medications. The experimental drug TGN1412 caused extremely serious symptoms [5] likely due to a cytokine storm[6] when given to six participants in a Phase I trial.

The first reference to the term cytokine storm in the published medical literature appears to be by Ferrara et al.[7] in GVHD in February 1993.

Pandemic Deaths

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 50 to 100 million people.[1] In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Hong Kong also indicated this as the probable reason for many deaths during the SARS epidemic in 2003.[8] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[9]

Recent reports of high mortality among healthy young adults in the 2009 swine flu outbreak has led to speculation that cytokine storms could be responsible for these deaths, since the Swine Flu results from the same influenza strain as the 1918 pandemic.[10] However, the Centers for Disease Control and Prevention (CDC) has indicated that symptoms reported from this strain are similar to those of normal seasonal flu,[11] with the CDC stating that there is “insufficient information to date about clinical complications of this variant of swine-origin influenza A (H1N1) virus infection.”[11] Cytokine storm has also been implicated in hantavirus pulmonary syndrome.[12]

In 2006, a medical study at Northwick Park hospital in England almost resulted in the deaths of 6 volunteers.[5] Parexel, a German company, in one of its own documents, wrote about the trial and said TGN1412 could cause a cytokine storm – the dangerous reaction the men experienced.

Free radical scavengers

Preliminary data from clinical trials involving patients with sepsis-induced ARDS have shown a reduction in organ damage and a trend toward improvement in survival (survival in ARDS is approximately 60%) after administering or upregulating a variety of free radical scavengers (antioxidants).

Ultraviolet radiation and vitamin D (to prevent infection)

An inverse association between exposure to the sun and upper respiratory tract infections was first proposed in 1926 by Smiley, who theorized that seasonality of infection was caused by “disordered vitamine metabolism in the human…directly due to a lack of solar radiation during the dark months of winter.”[1] Studies of Dutch[2] and Russian[3] subjects have also indicated a correlation of ultraviolet light exposure and relative absence of infection. However, the seasonality of infections such as influenza may also be explicable by other factors. For example, low absolute humidity favours the survival of the influenza virus.[4] A review by authors from the University of Maryland School of Pharmacy suggested that while low-dose vitamin D supplementation was unlikely to be harmful, “sensible sun exposure” was “an inexpensive and enjoyable way” to ensure healthy levels of vitamin D.

A study published in the Archives of Internal Medicine found that people with the lowest blood vitamin D levels reported having significantly more recent colds or cases of the flu chronic respiratory disorders, especially those who had pre-existing respiratory ailments.[6][7] A report in the American Journal of Clinical Nutrition reported that children who took vitamin D3 supplements daily in winter were 42% less likely to get infected with seasonal flu than those who were given a placebo.[8][9] Mongolian schoolchildren who drank vitamin D fortified milk during winter reported having fewer colds than those who received non-fortified milk.[10] Another study found no effect of vitamin D supplementation on the incidence or severity of upper respiratory tract infections.[11] Authors of one of the positive studies also stressed that their results would need to be confirmed in clinical trials before vitamin D could be recommended to prevent infections.