Unit 3 Project Fall 2012

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Posted on 25 May 2013 03:26

Cytokine Storms and the Influenza Virus

Imagine for a moment that you are young Michael Wind, a six-year-old child, one of six siblings, living in Brooklyn in October of 1918. As you look out your window, you notice how deserted the streets of New York are. After all, for the time being, all public gatherings have been banned. Schools, churches, and theaters have all been shut down. You hear a knock on the door to your apartment, but you refuse to leave your room. Although you try to drown out the sounds, you hear your mother’s closest friend yelling at your father. “How could you not have told me that she was sick?” you hear her scream. Your father solemnly answers that she was fine only yesterday. Your mother’s corpse lies in the other room, yet another life claimed by the influenza pandemic. The rest of your family is now at risk for infection, and even if you survive, you realize that the only destination left for you is the orphanage.

As you can see from the narrative, the influenza pandemic of 1918 struck with unprecedented virulence, taking the lives of formerly healthy, young adults within hours of contracting it. By the end of the pandemic, anywhere from 30 to 50 million people had died, which was approximately 3% of the world’s population at the time. This death toll was significantly higher than even that of World War 1, which claimed the lives of approximately 8 million soldiers in combat related deaths. The question then arises: What made this particular influenza strain so much more deadly than normal influenza strains? It is first important to understand the characteristics of the more traditional influenza strains.

As defined by Mayo Clinic, influenza is spread through, coughing, sneezing, and the exchange of bodily fluids. Once the virus enters the body, it attaches itself to a host cell and injects its genetic material into the cell. The injected nucleic acids use the cell’s own reproductive mechanisms to replicate viral nucleic acids, and new viruses are produced. In the final stage of this lytic cycle, (lysis, meaning the breaking down of a cell), the newly formed viruses burst out of the cell and use the outer membranes of the host cells to create their own protein coat, killing the host cell in the process. Most commonly the influenza viruses begin by attacking the protective cells of the respiratory track. This often weakens the immune system and paves the way for bacterial infections of the lungs and pneumonia. It is not the influenza itself that kills, but rather the secondary infections that kill. This is why traditional deaths by influenza occur primarily among the very young, the elderly, and those with compromised immune systems.

The influenza strain in 1918 did not follow these traditional trend lines. As you can see from the graph of death rates by age, the virus in 1918 was especially potent among healthy, young adults with very strong immune systems. So how can we explain this statistic? How was this virus able to turn a healthy and strong immune system against someone? The answer lies in the concept of the cytokine storm. A cytokine storm, in the simplest of terms, is an overreaction of the body’s immune system. As Angela Petrosino Johnson of the Northwest Ohio Consortium for Public health puts it, “A cytokine storm is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors)”. When confronted with a foreign threat, the immune system triggers the release of cytokines (small, protein molecules used in intercellular communication) that can trigger both pro-inflammatory and anti-inflammatory responses. The deadly interplay between these cytokines causes the cytokine storm. As you can see from the diagram entitled “The Mechanism of the Cytokine Storm Evoked by an Influenza Virus”, the process begins with a macrophage that has been infected by the virus. The infected macrophage releases viral proteins that activate previously inactive T-cells (a group a white blood cells responsible for cell-mediated immunity). These activated T-cells cause the uncontrolled release of cytokines that lethally interact in the lungs, causing the storm. Victims of cytokine storms often find themselves suffering from ARDS (acute respiratory distress syndrome). ARDS occurs when lung inflammation begins to inhibit gas exchanges, often resulting in multiple organ failure from lack of oxygen. This is often the cause of death attributed to cytokine storms.

So how do we know that the severity of the 1918 pandemic can be attributed to cytokine storms? After all, the disease occurred during a time in which humans did not fully understand the world of microbiology, not to mention the concept of a cytokine storm. Evidence lies in a study conducted by Professor Yoshihiro Kawaoka, a professor of virology at the University of Wisconsin. Kawaoka and his team exposed monkeys to a resurrected strain of the virus found in preserved tissues from the victims in 1918. They found the monkeys’ response to be much more drastic than even they had expected. In an experiment that was supposed to last twenty-one days, the monkeys had to be used euthanized after only eight days because of ethical guidelines. They exhibited extreme pain and difficulty breathing. Michael Katz, a co-author in the study, claims, “It was the robustness of the immune system that helped victimize them.” Katz also said that in contrast to normal influenza, in which immune response gradually fades, “the innate response [exhibited by the monkeys] stayed up and didn’t go down”. This can largely be attributed to the fact that the virus is such a good replicating virus. As the virus keeps replicating, it is able to affect more of the immune system and ultimately cause the cytokine storm. The cytokine storm that resulted essentially caused the monkeys to drown themselves.

Similar characteristics to that of the viral strain in 1918 were seen in the strain of avian (bird) influenza that was brought to the media’s attention in 2005. Although the virus has had difficulty in spreading from bird to human and also from human to human, the mortality rate of those who have been infected by the H5N1 virus has been obscenely high. The WHO reports that as of September 2012, out of 608 confirmed cases of avian influenza, 359 of them died as a result of the virus, approximately a 60% mortality rate. If this viral strain ever reached epidemic proportions, the results would be devastating to the human population. A study conducted by M. Chan and his team at the University of Hong Kong confirms that the lethality as a result of the virus is attributed to cytokine storms. Chan and his team exposed lung tissue to the virus in vitro and analyzed the resulting serum produced. He found that the particular avian influenza virus was a very potent inducer of pro-inflammatory cytokines, confirming that cytokine storms are associated with the lethality of this virus as well. Bird flu patients ultimately die from ARDS, in a similar fashion to those who died in the 1918 pandemic.

Thus the question arises: How can we prepare for the next pandemic? The fact that the recent avian influenza virus strain operates in such an eerily similar fashion to the pandemic strain of 1918 leads scientists to believe that the next strain of pandemic influenza could arise at any moment. Dr. Michael T. Osterholm writes about the possibility of a future pandemic and ways to prevent it, or at least reduce its effects. Acknowledging the fact that human population has grown to almost three times the size it was in 1918, he states that even a relatively mild influenza outbreak today could kill millions, let alone a virus with a 60% mortality rate such as the bird flu. His primary suggestions on combatting such a virus are heavily focused on the production of vaccinations. Now that we generally know how pandemic influenza strains operate, it is now time put our efforts into finding some sort of solution. Osterholm first suggests funding basic research on the ecology and biology of influenza viruses in order to work on early intervention and risk assessment of potentially deadly strains. He then suggests replacing the current egg-based manufacturing process for vaccinations with cell-cultured production of vaccinations, allowing for higher, faster yields of vaccine. Lastly he feels that it is necessary to create the sufficient industrial capacity to produce the necessary amount of vaccination quickly in the case of a massive pandemic. While some steps have been taken to control the severity of cytokine storms (such as the drug Tamiflu), there is still yet to be a permanent solution to the problem. In the time being, all we can do is continue fund research in this particular field and follow the guidelines that Dr. Osterholm has mentioned in order to minimalize the effect of a massive pandemic as much as possible.

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Diagram A: Influenza Pandemic Mortality in America and Europe During 1918 and 1919
http://upload.wikimedia.org/wikipedia/commons/thumb/e/e2/Spanish_flu_death_chart.png/787px-Spanish_flu_death_chart.png

Diagram B: The Mechanism of the Cytokine Storm Evoked by an Influenza Virus
http://www.cytokinestorm.com/cytokine_storm.jpg

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Annotated Bibliography:

a) Mayo Clinic Staff. nd. Influenza. Mayoclinic.com. Retrieved November 17, 2012. http://www.mayoclinic.com/health/influenza/DS00081
b) (na). (nd). Pandemic Flu History. Flu.gov. Retrieved November 17, 2012. http://www.flu.gov/pandemic/history/index.html
c) Petrosino Johnson, Angela. (nd). Cytokine Storm and the Influenza Pandemic. Retrieved November 15, 2012. http://www.cytokinestorm.com/
d) (na). January 17, 2007. New Tests Reveal Why 1918 Flu Was So Deadly. Retrieved November 21, 2012. http://www.msnbc.msn.com/id/16670768/ns/health-cold_and_flu/t/new-tests-reveal-why-flu-was-so-deadly/#.ULqGoYUmxsO
e) M. Chan. November 11, 2005. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Retrieved November 25, 2005. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1318487/
f) Osterholm, Michael T. 5/5/2005. Preparing for the Next Pandemic. Retrieved November 17, 2012. http://www.nejm.org/doi/full/10.1056/NEJMp058068

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