BOOK REVIEW: Influenza, The Hundred-Year Hunt to Cure the Deadliest Disease in History

BOOK REVIEW by Roger Ham 3/26/20

INFLUENZA The Hundred-year hunt to cure the deadliest disease in history

Book Author: Dr. Jeremy Brown, Touchstone 2018

  • ISBN-10: 1501181254
  • ISBN-13: 978-1501181252

(Dr. Brown is an Emergency Room doctor who is now the Director of the Office of Emergency Care Research at the NIH.)

This book was published on the 100th anniversary of the deadly 1918 Influenza pandemic which killed 675,000 Americans and 50 million or more people worldwide. It is estimated that 1/3 of all humans on Earth contracted the flu and roughly 10% of those died. Reporting and statistics at the time were very sketchy and inaccurate. For comparison, in recent years there have been, on average, 30-50 thousand deaths per year in the US from influenza.

1918 Flu Deaths
U.S. Life Expectancy

Outbreaks have occurred at unpredictable intervals over centuries.

In spite of the work by Pasteur and others in the late 1800’s to develop the “germ theory” of disease, medicine was in many respects, still barbaric. In the early 1900’s, bloodletting was still used by many doctors as well as enemas with mercury and other toxic compounds to “treat” flu and other diseases. Even inhaling toxic fumes like nitric acid was promoted as a prophylactic. Aspirin was the new “wonder drug”, but it was not well understood and was often administered at fatal doses.

Anyone capable of paying for courses was admitted to US medical schools, regardless of qualifications, and most doctors graduated without ever seeing a patient. Bacteria were mistakenly believed to be the cause of flu because they were present in patients’ lungs, but this was later found to be a secondary bacterial infection, not the flu itself,which was only determined to be a virus in 1933. It was not until 1939 that the influenza virus could actually be imaged, and due to it’s incredibly small size, only with the aid of an electron microscope.

It is debatable whether viruses should be considered “alive”, because they are nothing more than a envelope containing genes which take over the machinery of healthy cells, and act like a copy machine, making millions of more virus particles.The virus contains no nucleus, no mitochondria to make energy, no ribosomes to build proteins, no lysosomes to export waste and toxins.

The flu virus is a hollow ball containing 8 viral genes of ribonucleic acid (RNA). The shell contains proteins on the surface in the form of spikes and pitchforks. The spikes are Hemagglutinin (the H in H1N1) and the pitchforks are Neuraminidase (the N in H1N1). There are 16 different heagglutinins and 9 different neuraminidases for a possible total of 144 different combinations, H1N1 being the most common.

The spikes allow the flu virus to attach to and break into the lung cell, where the genes are released and hijack the rna and protein synthesizing machinery of the cell to produce millions of new viruses. The newly manufactured flu viruses then migrant back to the cell membrane where the pitchforks break the cell membrane and allow the new viruses to infect other lung cells or get coughed into the air to infect new hosts.

The making of millions of copies of the virus genes and proteins by the host cell allows for extensive errors, or mutations. While the majority of mutations are nonfunctional, some viable mutations can confuse or disable our body’s normal immune response to foreign pathogens. This sort of small mutation is called “antigenic drift” and is the reason that a new flu vaccine has to be formulated every year and why your relative immunity doesn’t carry over from one year to the next. In effect, you are being exposed to a new flu virus every year.

The second type of alteration in the virus gene occurs when two different strains (including animal strains) of flu are reproducing within the same cell simultaneously and can combine to form an entirely different strain. This is called “antigenic shift”. So called “novel” viruses like COVID-19 arise through this mechanism and because we have never been exposed to this new virus, we are much more vulnerable. The SARS outbreak in 2002 may have involved a bat virus being transmitted to civit cats and then to humans. The MERS virus involved a camel virus being transmitted to humans. A camel virus that could not originally infect human cells mutated in an environment where camels and humans lived closely together. It is thought that the “wet markets” in Wuhan may have been where the COVID-19 virus originated.* In these markets, common in Asia, not only is local wildlife sold and slaughtered, but animals from all over the world are confined, slaughtered and handled by humans. Animals that never lived together naturally are exposed to each other’s diseases and viruses, increasing the potential for a species jump to other animals and humans. In 1997, a small mutation in an avian flu virus in Hong Kong made transmission to humans possible. Six of 18 people working directly with chickens were infected. The contagiousness and lethality of any virus is a combination of factors—how it is transmitted to new hosts, how long can a host be contagious before symptoms appear, does the virus kill the host and, if so, how quickly. The most “successful” viruses , like the common cold, create mild symptoms and the host can continue to spread the virus to others indefinitely.

Our immune system responses:

Phagocytes are non-specific and attach “pathogens” of all sorts.

Antigen-presenting cells target specific viruses or bacteria. They in turn present a building block of the pathogen (like a protein) to helper T cells which reproduce vastly and remain on guard for years. This is why you only need to be vaccinated for chicken pox once.

1918 Flu pandemic

The first reports of a contagious respiratory infection were in the Spring of 1918 from Kansas, Northern France, England and China. Since no one knew what caused these respiratory infections, descriptions and identification were very difficult. The first wave of cases was mild and few died. Given the carnage of WWI, these deaths were barely noticed and under-reported due to wartime censorship. One unusual and alarming observation was the higher mortality rate among young, healthy adults. Usually children with less developed immune systems and older people with weaker immune systems were at greater risk.

By June, the flu season seemed to be over.

In the Spring of 1918, the US had 110,000 troops in Europe and over 1 million by the Summer. US military camps as well as tenement housing in US cities had the high density of people that makes transmission very efficient. Camp Devens, 30 miles west of Boston was home to 45,000 troops. On Sept. 8, an outbreak began which quickly grew to 100 deaths per day. In less than a month, 14,000 became ill and 750 died. Camp Dix in NJ, as well as camps in Kansas, California and Georgia, had similar outbreaks. At Camp Dodge in Iowa, 2 cases grew to 12,000 in 6 weeks and then ended suddenly.

Flu Deaths — W Curve

One particularly horrific story emerged in Philadelphia, home to 1.7 million people and the Philadelphia Naval Shipyard’s 45,000 sailors. After the arrival of two infected sailors, within two weeks 900 were sick. In a show of patriotic support for the US troops fighting in Europe, a “Liberty Loan” parade was scheduled for Sept. 28. Despite warnings, the parade went ahead and 100,000+ people crowded on the streets to watch. As a result, 100’s of people died per day. Eyewitnesses report seeing friends healthy one morning and hearing of their death the next day. The epidemic in Philadelphia peaked in mid-October and suddenly abated.

In Alaska, native tribes had little exposure or antibodies, and when the flu hit, the casualties were extremely high. Death rates of 50% were seen and one small village saw 72 of its 80 residents die. The frozen bodies of some of these Alaskan victims would play an important part in our understanding of the flu 60 years later. By the Spring of 1919, 675,000 Americans had died (approx. 0.7% of the US population).

There are various hypotheses about why the 1918 flu was so deadly.

1—A surface protein prevented the production of interferons to alert the immune system. This led to lethal viral pneumonia.

2—If the 1918 flu virus didn’t kill you, secondary bacterial pneumonia could. With no antibiotics available, strep. and staph. infections caused the majority of deaths.

3—An overreaction by the immune system caused massive inflammation of the lungs. Messenger proteins (cytokines) caused a “cytokine storm”. Healthy cells scabbed over and fluids filled the lungs. While this could explain the higher death rates among 20-40 year-olds, who would have strong immune systems and hence a stronger overreaction, this age group’s higher death rate remains a major unsolved question about 1918.

4—High transmission rates in the crowded tenements and military camps.

Years of war undoubtedly left millions undernourished and with compromised immune systems. Today, less than 0.1% of flu victims die. In 1918, it was around 2.5%. Within that single year, the US life expectancy dropped from 51 to 39 years.

In 1920, it was determined that flu was smaller than a bacteria, but it wasn’t until 1933 that it was identified as a virus. Despite being such a deadly killer, it was extremely difficult to culture and study the flu. Literally, the only thing researchers could get the virus to grow in was the amniotic fluid of developing chicken embryos. Once the virus could be grown in large quantities, it could be killed and injected into people as a vaccine. The killed virus could not cause infection, but would trigger the immune response that would protect against any future infection by a live flu virus. The first electron microscope image of the flu was taken in 1939; penicillin was first developed around 1942, and the first flu vaccine was achieved in 1944. Vaccines and antibiotics to halt the secondary bacterial infections have saved countless lives since.

20th Century Mortality

Since 1918, we have had several “near misses” in terms of epidemics:

1957 H2N2 outbreak. Human and avian flu virus. 10% of Hong Kong’s 2.5 million people became sick. Believed to come from ducks in bird markets in China, it eventually killed around 2 million worldwide. (68,000 in the US), mostly people with underlying heart or lung disorders. 60% of school children became ill. By 1957 the availability of antibiotics and vaccines gave physicians two powerful weapons to fight the pandemic. 40 million doses of vaccine were produced utilizing fertilized chicken eggs by the end of 1957.

1968 H3N2 A new avian flu emerged in Hong Kong with it’s vast open chicken and duck markets. The H2 surface protein was replaced by H3 while the rest of the genome remained unchanged. This similarity led to some immunity. One million deaths occurred worldwide.

1976 Swine flu. On Feb. 4, an Army private at Fort Dix, NJ collapsed and died. This swine flu was an H1N1 type similar to 1918. There were calls for mass vaccination and despite fears of a backlash, Pres. Gerald Ford accepted the advice of his health care advisors and ordered the mass vaccination of the entire population rather than risk a pandemic. The “failure” of the virus to kill anyone else caused a huge scandal.

1997 Avian flu . In Hong Kong, only a few people died because 1.5 million chickens were slaughtered quickly. The virus could only be transmitted from the meat of an infected bird to the person handling it, not by person-to-person transmission.

2002 SARS (Severe Acute Respiratory Syndrome) About 8100 cases have been reported worldwide, with 774 deaths. Since 2004, there have been no reported cases. This virus is named SARS-COV-1. The new corona virus first reported in Wuhan, China is named SARS-COV-2 to reflect its similarity to the 2002 virus.

2009 Swine flu similar to 1918 and 1976 strains. It struck in the spring and summer, much like 1918. Sixty people died in Mexico in March 2009. It reached the US in April. The virus was determined to contain genetic material from an American swine flu, a European swine flu, an avian flu and a human flu. By June , there were 30,000 cases in 74 countries. The WHO declared a pandemic. This swine flu caused 50% of the flu cases in the US with deaths among both children and adults. Those over 65 years seemed immune, probably because of limited immunity caused by exposure to a similar strain in the past. One million were infected in the US, but most recovered. Then in August, there was a sudden surge. New drugs were being developed to attack the virus itself. The FDA approved an anti-viral drug, peramivir, although there was little evidence of effectiveness. The outbreak peaked in October, with 60 million cases in the US, but “only” 12,500 deaths. There was a lot of confusion and recriminations for mobilizing 60 million face masks, equipment and anti-viral medications from the Strategic National Stockpile (SNS). In the age of the internet and twitter, there was a great deal of fear-mongering and finger pointing. The WHO was attacked for even using the term “pandemic”, despite the fact that over one billion were infected with 150,000-575,000 deaths worldwide. 80% of all deaths were for people under 65 years of age, much different than for most flu outbreaks. As with many strains of influenza, this one continues to circulate as a seasonal flu, causing illness and death every year.

2012-15 MERS (Middle East Respiratory Syndrome). First reported in Saudi Arabia, it was the result of a species jump from dromedary camels to humans. While “only” 2500 cases have been reported worldwide, it caused great concern because the death rate is over 30% of those infected. SARS, MERS as well as the common cold are all corona viruses.

Resurrecting the virus

In 1994, Jeff Taubenberger,Chief of the Viral Pathogenesis and Evolution Section within NIH, found an original tissue sample from one 1918 victim and, after 5 years of work, was able to amplify four small fragments of the gene for the viral Hemagglutinin (HA) protein. This showed the 1918 flu was closely related to a swine flu, although it had avian flu characteristics as well. He needed more samples to confirm the results.

In 1951, a Swedish scientist, Johan Hultin, had exhumed 1918 victim bodies frozen in Alaskan permafrost in an attempt to directly study the 1918 virus, but no virus could be reproduced and the tissue could not infect animals. In 1997, at the age of 72, Hultin read about Taubenberger’s work and offered to try again. He returned to the Alaskan village of Brevig Mission and exhumed the body of an obese woman, whose body fat had insulated her organs during brief thaws of the permafrost. From these excellent tissue samples, the entire genetic code could be rebuilt. A multi-agency effort succeeded in rebuilding all eight of the 1918 genes. In addition to the 8 gene clone, others were created with 1, 3 or 5 genes. The complete clone was 100 times more deadly than the 5 gene version and the gene for the HA surface protein was key to its lethality.

If you go to YouTube and search for “We heard the bells”, you can watch an hour long documentary on the 1918 flu including extensive interviews with both Hultin and Taubenberger. The video is included below. The interview with Dr. Hultin begins at 19:01.

The 1918 flu virus also attracted neutrophils, special white blood cells, to the site of infection, which caused collateral damage to the healthy lung cells and lead to secondary bacterial infections. This lends support to the “cytokine storm” hypothesis.

The 1918 virus seemed to have been a bird virus which adapted to humans after spending time in another mammalian host. This perfect killer had just enough new proteins to be unrecognizable to the immune system. The HA from a bird virus caused an uncontrolled inflammatory response, but only killed after a few days, allowing enough time to replicate and spread to the lungs of new hosts. This report was published in 2005 and alarmed many scientists concerned about the danger of new pathogens developing.

In 2012 an H5N1 virus was genetically modified as part of “gain of function” experiments. These experiments were seen as dangerous—creating even more lethal viruses—and were stopped. In Dec. 2017, the White House lifted that ban.

Taubenberger, who probably knew more about the flu than anyone, said “I have been thinking heavily about the flu for twenty years and I know nothing”. While we know a great deal more than we did in 1918, we still have no truly effective means to fight influenza. Antivirals have been generally useless and current vaccines are a poor defense.

In 1999, a Strategic National Stockpile was created to store vaccines, antivirals, ventilators, masks, as well as material needed for earthquake, flood and other natural disaster relief. The contents of the SNS are classified because some of the materials would be used in chemical of biological warfare, so it is unclear how much this could add to our current medical mobilization. It is estimated that there are several thousand ventilators, which would make an important addition, but would still not be sufficient to deal with the huge spike in serious cases expected.

* The contention that the coronavirus jumped from at bat in the Wuhan meat market has now been challenged:

A colorized image of the 1918 virus taken by a transmission electron microscope (TEM). 

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