Flu, SARS, Ebola and Cytokine Storms

World War I was one of the deadliest conflicts in human history. An estimated 18 million combat personnel and civilians were killed during the war which began in July 1914 and continued until November 1918.

At the beginning of the final year of World War I, an even bigger human catastrophe hit the planet. From January 1918 until December 1920, a flu pandemic swept the globe. Over 500 million people are thought to have been infected worldwide.

The death toll from this influenza pandemic was staggering. We will never know the actual number of those who died globally and the range of estimates is very broad. Somewhere between 30 and 100 million people are estimated to have died worldwide from the flu in just three years. Taking the middle number, that is three to four times the number of deaths from the flu as from the Great War.

The social impact worldwide of the 1918 influenza pandemic was profound with so many young adults dying within days and sometimes even hours of being infected. Both rich and poor were equally affected. There were shortages of workers in factories and food production, healthcare and basic services. Widows, widowers and orphans were suddenly everywhere.

In early 1918, the U.S. was mobilizing to send the main contingent of its forces to Europe to join the fight against the Central Powers. Around one third of these military personnel, more than a million men, went down with flu and 30,000 of them died as a result of their infection without ever reaching the Western Front. It is estimated that almost 700,000 Americans died from influenza from 1918 to 1919.

Countries that were at war, particularly Germany, Britain, France and the USA, had censors that did not allow reports on the flu pandemic in their own countries to be published as it was considered damaging to morale. The press in those countries were however permitted to report on the flu outbreak in Spain where King Alfonso XIII was gravely ill from influenza (he later recovered.)

Spain was neutral during World War I so the news from that country was not censored. Because of the King of Spain’s illness and with most of the reports on the flu outbreak coming from Spain, in 1918 it became known as Spanish flu. Even though the whole world was equally affected, with most of the news reports on the influenza illness and deaths coming from Spain, it was thought at the time that Spain had been particularly hard hit.

So what made this influenza outbreak so deadly? Most flu viruses produce symptoms which are often deeply unpleasant but not deadly for the average healthy adult. Those at most risk are usually the very young, because of an underdeveloped immune system which struggles to fight infection, those individuals with health issues that leave them with a compromised immune system and the very old because the immune system weakens with age.

With the 1918 flu pandemic, unlike other flu outbreaks, it was not the very young, the very old and the sick that were most at risk, but young, previously healthy adults. The stronger the individual’s immune system, the greater the chance of death. This particular strain of flu — influenza A (H1N1) avian (bird flu) — caused the infected individual’s immune system to go out of control in what has come to be known as a cytokine storm.

Cytokines (pronounced sigh-toe-kyne) are proteins involved in cell signaling — cells communicating with each other. They are a critical component of the body’s immune system response and in fighting infection. With certain infections and conditions however, the immune reaction runs out of control with often fatal results. This is known as a cytokine cascade or a cytokine storm.

In a cytokine storm, cellular messages are sent out to attack a specific intruder. As a result, more cytokine response signals are sent and repeatedly in a positive feedback loop. This creates an immune system stampede in ever growing numbers. The healthier the individual and the stronger their immune system, the more robust the response and the more damaging it is to the host.

This amplified immune response was what made the 1918 Spanish flu pandemic so deadly. In common with other types of the flu, the immune response was concentrated in the lungs. The overwhelming immune response destroyed lung tissue and caused the lungs of the infected host to fill with liquid. 

On top of the inflammation and fluid in the lungs of those infected, this strain of the flu virus weakened the lungs and bronchial tubes creating the perfect breeding ground for bacterial pneumonia. Breathing became increasingly difficult and for many victims, death soon followed. 

Cytokine storms were also implicated in the deadly SARS (severe acute respiratory syndrome) outbreak from 2002 / 2003 in which 10% of the thousands infected with the virus died, and more recently with the Ebola virus disease outbreaks.

The largest Ebola virus outbreak occurred from 2014 to 2015 with almost 30,000 people infected and 40% dying as a result. Ebola virus disease is different from SARS, at least initially. The Ebola virus first interferes with the body's cell messaging system so that the cells that would normally identify an intruder and signal an immune response are unaware of its presence. This stealth approach allows the virus to rapidly replicate and body organs are soon infected.

The cells of these organs rapidly begin to die and the virus enters the bloodstream. Only then does the immune system recognize the virus along with the dead organ cells of the host. The ensuing immune response, a cytokine storm, is so powerful that other normal processes are overwhelmed, particularly blood clotting. This leads to severe internal bleeding, a catastrophic drop in blood pressure and inevitably death for those affected in this way.

What are the chances that the Spanish flu could appear once again as a global pandemic? Most experts agree that it is very unlikely. Some of those alive today have some residual immunity to the 1918 virus, H1N1 viruses circulate widely and current flu vaccines contain an H1N1 component.

A repeat of the 1918 Spanish flu pandemic from that specific strain is not a worry to scientists. But a naturally occurring mutation creating an influenza sub-type for which humans have no immunity is a very real cause for concern.

As we can see, there are many different ways that humans can encounter disease. Viruses and bacteria and various toxins enter the body by diverse ways and often overcome our usual layers of self-protection. On the other hand, viruses responsible for SARS and influenza trigger excess response of various components of our immune system which can be as deadly as no response.

Occasionally the drugs we use to treat a condition can have side effects that are so subtle they escape recognition for many years, leaving behind untold thousands of damaged patients. Statins are no different, leaving behind tens of thousands of victims of muscle weakness, incapacitating fatigue, diabetes and neuropathy.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

January 2016

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