Allergies Don’t Cause a Fever — At Least, Not Directly

Genetics Of The Influenza Virus

The name "influenza" is derived from the Latin word for "influence," and the pathogens that cause this disease are RNA viruses from the family Orthomyxoviridae. The genomes of all influenza viruses are composed of eight single-stranded RNA segments (Figure 1). These RNAs are negative-sense molecules, meaning that they must be copied into positive-sense molecules in order to direct the production of proteins.

There are three basic types of influenza viruses: A, B, and C. Influenza B and C viruses only infect humans, so novel antigens are not introduced from other species. Only influenza A viruses infect nonhuman hosts, and a reassortment of genes can occur between those subtypes that typically infect animals and those that infect humans, resulting in antigenic shift and potential pandemics. Epidemics of seasonal influenza occur due to influenza A or B viruses.

As in all viruses, the genome of an influenza virus particle is encased in a capsid that consists of protein. The influenza A capsid (Figure 2) contains the antigenic glycoproteins hemagglutinin (HA) and neuraminidase (NA); several hundred molecules of each protein are needed to form the capsid. These proteins are the parts of the virus that are recognized as foreign by a host's immune system, thus eliciting an immune response. Because many different subtypes of the influenza A hemagglutinin and neuraminidase proteins exist, the human immune system is frequently challenged with new antigens. For example, point mutations in the HA and NA genes can lead to changes in antigenicity that allow a virus to infect people who were either infected or vaccinated with a previously circulating virus. This phenomenon is referred to as antigenic drift. In addition to humans, other animals can be infected with or serve as a reservoir for influenza, and outbreaks have been seen in poultry, pigs, horses, seals, and camels (Hayden & Palese, 1997). When a strain is named, the host (if not human), the location where the virus originated, the strain number, the year of isolation, and the HA/NA subtype are all included in the name.

Figure 2: Electron micrograph of influenza A virus particles.

The genome of influenza A viruses consists of eight single-stranded RNA segments, and the viral particle has two major glycoproteins on its surface: hemagglutinin and neuraminidase.

With the HA and NA genes, the influenza A genome contains eight genes encoding 11 proteins. These proteins include three RNA polymerases that function together as a complex required by the virus to replicate its RNA genome. Interestingly, these polymerases have been shown to have high error rates due to a lack of proofreading ability, which leads to high mutation rates in replicated viral genomes and therefore rapid rates of viral evolution. This high rate of mutation and evolution is one source of influenza virus genetic diversity. The influenza genome also encodes additional structural proteins necessary to form the capsid, the nucleoprotein (NP), and the proteins NS1 (nonstructural protein 1) and NS2/nuclear export protein (NEP), whose roles are still being investigated. Still other proteins encoded by the viral genome include membrane proteins M1 and M2 (which are needed for nuclear export and several other functions) and, of course, HA and NA (which play roles in viral attachment and release from host cells, respectively).

Due to the segmented nature of the influenza genome, in which coding sequences are located on individual RNA strands, genomes are readily shuffled in host cells that are infected with more than one flu virus. For example, when a cell is infected with influenza viruses from different species, reassortment can result in progeny viruses that contain genes from strains that normally infect birds and genes from strains that normally infect humans, leading to the creation of new strains that have never been seen in most hosts. Moreover, because at least 16 different hemagglutinin subtypes and nine different neuraminidase subtypes have been characterized, many different combinations of capsid proteins are possible. Of these subtypes, three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) have caused sustained epidemics in the human population. Birds are hosts for all influenza A subtypes and are the reservoir from which new HA subtypes are introduced into humans (Palese, 2004).

The Spanish Flu

What can the 1918 Flu epidemic teach us about COVID-19, asks Professor Marc Zimmer.

CC Magazine: The Spanish Flu didn't start in Spain. Why did the Iberian country get stuck with the name?

Marc Zimmer: It's commonly believed that the 1918 pandemic started in Camp Funston, Kansas. The camp hospital received its first influenza victim on March 4. By April, 30 of the 50 largest cities in the United States, most in close proximity to military bases, reported increased deaths. It spread to England, France, Germany and Spain. Spain was the only country hit by the virus that was not involved in World War I; therefore it was the only country to report the true extent of the pandemic. This resulted in the mistaken belief that the 1918 flu originated in Spain.

CC: The Spanish Flu was the last pandemic. How does it compare to the COVID-19 outbreak?

MZ: The 1918 flu pandemic haunts all epidemiologists. It's estimated that between 50 million and 100 million people died. The world is more prepared now and science has dramatically advanced. However, the U.S. Response to COVID-19 shows there are some important lessons we haven't learned. COVID-19 isn't like the flu. It's its own beast. It's caused by a coronavirus, not an influenza virus, and there are many differences to the 1918 flu. But there are also similarities. In 1918, we hadn't yet developed drugs or vaccines for the flu. This is also true for COVID-19. In addition, the 1918 flu virus was a spillover virus. Like COVID-19, it came from nonhuman hosts and no one had immunity to this new virus.

CC: What lessons do we still need to learn from the 1918 flu pandemic?

MZ: COVID-19 originated in China. Its heavy-handed quarantines may have saved thousands of U.S. Lives. Although we may have wasted the advantages given to us by the Chinese, we need to pay it forward to our neighbors in the southern hemisphere and slow the spread in the U.S. To mitigate resurgences of the virus and to prevent future pandemics, global cooperation is required. Withdrawing from the World Health Organization and blaming China won't help. It will antagonize our allies, which may further weaken our medical supply chains and endanger our epidemiological early-warning systems.

CC: We've been told to practice social distancing. Where did that come from?

MZ: The first cases of 1918 flu among civilians in Philadelphia were reported on Sept. 17, 1918. Authorities downplayed their significance and on the 28th the city held the largest parade in its history: the "Liberty Loan Drive," a massive gathering designed to get people to subscribe to war bonds. This provided the newly arrived virus a feast of victims, resulting in a tenfold higher death rate due to the flu than was observed in the more careful St. Louis over the same period.

CC: Does the Spanish Flu inform us about how the COVID-19 pandemic ends?

MZ: In 1918, the U.S. Army requested George Soper—who discovered Mary Mallon, or Typhoid Mary, an asymptomatic carrier of typhoid—to investigate the flu pandemic. He found that the complete isolation of flu patients was the only way to control the outbreak and that "the disease is carried from place to place by persons, not things or by the general atmosphere, as was once supposed. Its rapidity of spread is due to its great infectivity, short period of incubation, missed cases and absence of timely precautionary measures. The epidemics stop themselves ... Either by the exhaustion of the susceptible material, by a reduction in the virulence of the causative agent, or both." Despite this knowledge, and although public health officials advocated keeping a distance, not everyone adhered to the advice—with deadly consequences. Sound familiar?

Marc Zimmer is the Jean C. Tempel '65 Professor of Chemistry. He teaches a new course, "COVID-19: Diseases Without Borders." He is the author of the soon to be released The State of Science (Prometheus Press, 2020).

Illustration by Miles Ladin '90

Inside The Swift, Deadly History Of The Spanish Flu Pandemic

Scientist Johan Hultin traveled to Brevig Mission, Alaska, a town of a few hundred souls in the summer of 1997. He was searching for buried bodies, and Alaska's frozen ground was the perfect place to find them. Digging through the permafrost—with permission from the town's authorities—he eventually uncovered a woman who died almost 80 years previously and was in a state of excellent preservation. Hultin then extracted samples of the woman's lung before reinterring her. He intended to use this to decode the genetic sequence of the virus that had killed this Inuit woman along with 90 percent of the town's population.

Brevig Mission was just one place that was part of a global tragedy, one of the worst ever to befall humanity: the influenza pandemic of 1918-19. The outbreak of this influenza virus, also known as Spanish flu, spread with astonishing speed around the world, overwhelming India, and reaching Australia and the remote Pacific islands. In just 18 months at least a third of the world's population was infected. Estimates on the exact number of fatalities vary wildly, from 20 million to 50 million to 100 million deaths. If the upper end of that estimate is accurate, the 1918 pandemic killed more people than both World Wars put together. (Get the facts on influenza.)

The first official cases of the 1918 Spanish flu pandemic were recorded at the U.S. Army's Camp Funston, Kansas, where this emergency influenza ward held treated patients.

SPL/AGE FOTOSTOCK

War and pestilence

Several closely related viruses cause influenza, but one strain (type A) is linked to deadly epidemics. The 1918-19 pandemic was caused by an influenza A virus known as H1N1. Despite becoming known as the Spanish flu, the first recorded cases were in the United States in the final year of World War I. (Explore the memorials of World War I.)

A magnified view of the H1N1 virus responsible for the 1918 pandemic.

SPL/AGE FOTOSTOCK

By March 1918 the United States had been at war with Germany and the Central Powers for 11 months. During that time America's small, prewar army had grown into a vast fighting force that would eventually send more than two million men to Europe. (How the United States entered World War I.)

American forts experienced a massive expansion as the entire nation mobilized for war. One of these was Fort Riley, Kansas, where a new training facility, Camp Funston, was built to house some of the 50,000 men who would be inducted into the Army. It was here in early March that a feverish soldier reported to the infirmary. Within a few hours more than a hundred other soldiers had come down with a similar condition, and more would fall ill over the following weeks. In April more American troops arrived in Europe and brought the virus with them. The first wave of the pandemic had arrived. (What is the difference between an epidemic and a pandemic?)

Deadly speed

The Spanish flu strain killed its victims with a swiftness never seen before. In the United States stories abounded of people waking up sick and dying on their way to work. The symptoms were gruesome: Sufferers would develop a fever and become short of breath. Lack of oxygen meant their faces appeared tinged with blue. Hemorrhages filled the lungs with blood and caused catastrophic vomiting and nosebleeds, with victims drowning in their own fluids. Unlike so many strains of influenza before it, Spanish flu attacked not only the very young and the very old, but also healthy adults between the ages of 20 and 40.

Biologists at St. Bartholomew's Hospital in London are analyzing brain and lung tissue from victims of the 1918 pandemic as part of global efforts to understand the virus. Here, wax-mounted tissue samples sit on a list of children's names who fell victims to influenza in 1918.

SPL/AGE FOOTSTOCK

The principal factor in the virus's spread was, of course, the international conflict then in its last phase. Epidemiologists still dispute the exact origins of the virus, but there is some consensus it was the result of a genetic mutation that perhaps took place in China. But what is clear is that the new strain went global thanks to the massive and rapid movement of troops around the world.

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The drama of the war also served to obscure the unusually high mortality rates of the new virus. At this early stage, the illness was not well understood and deaths were often attributed to pneumonia. Strict wartime censorship meant that the European and North American press were unable to report outbreaks. Only in neutral Spain could the press speak freely about what was happening, and it was from this media coverage that the disease took its nickname.

Deadly Contact

Native Americans treat patients infected by European diseases in this 1591 engraving by Theodor de Bry.

GRANGER/ALBUM

Epidemics are as old as civilization: Signs of smallpox appear on 12th-century B.C. Egyptian mummies. Increased contact led to the spread of disease. In the sixth century A.D. The Plague of Justinian moved along trade routes, killing 25 million people across Asia, Africa, Arabia, and Europe. Eight centuries later, the Black Death wiped out 60 percent of Europe's population. When Europeans settled in the Americas in the 16th and 17th centuries, they introduced smallpox, influenza, and measles to the native peoples, killing an estimated 90 percent of the population. Here, Native Americans treat patients infected by European diseases in a 1591 engraving by Theodor de Bry.

The second wave

The overcrowded trenches and encampments of the First World War became the perfect hosts for the disease. As troops moved, so the infection traveled with them. The wave that had first appeared in Kansas abated after a few weeks, but this was only a temporary reprieve. By September 1918 the epidemic was ready to enter its most lethal phase.

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It has been calculated that the 13 weeks between September and December 1918 constituted the most intense period, taking the greatest number of lives. At least 195,000 Americans died in October alone. In comparison, total American military casualties for the whole of World War I came in at just over 116,000. Once again, it was the crowded military encampments where the second wave initially gained a hold. In September an outbreak of 6,674 cases was reported at Camp Devens, a military base in Massachusetts.

As the crisis reached its zenith, the medical services began to be overwhelmed. Morticians and gravediggers struggled, and conducting individual funerals became impossible. Many of the dead ended up in mass graves. The end of 1918 brought a hiatus in the spread of the illness and January 1919 saw the beginning of the third and final phase. By then the disease was a much diminished force. The ferocity of the autumn and winter of the previous year was not repeated and mortality rates fell.

Although the final wave was much less lethal than its predecessors, it was still able to wreak considerable damage. Australia, which had quickly enacted quarantine restrictions, managed to escape the worst of the flu until the beginning of 1919, when the disease finally arrived and took the lives of several thousand Australians.

The Spanish flu did not strike in Australia until 1919. Quarantine camps like this one, in Wallangarra, Queensland, were set up to treat and contain the illness.

PAUL FEARN/ALAMY/ACI

The general trend of mortality, however, was downward. There were cases of deaths from influenza—possibly a different strain—as late as 1920, but by the summer of 1919 health care policies and the natural genetic mutation of the virus brought the epidemic to a close. Even so, its effects, for those left bereaved or suffering long-term health complications, were to last decades.

Lasting impact

The pandemic left almost no part of the world untouched. In Great Britain 228,000 people died. The United States lost as many as 675,000 people, Japan some 400,000. The south Pacific island of Western Samoa (modern-day Samoa) lost one-fifth of its population. Researchers estimate that in India alone, fatalities totaled between 12 and 17 million. Exact data in the number of deaths is elusive, but global mortality figures are estimated to have been between 10 and 20 percent of those who were infected.

In 1997 the samples taken by Johan Hultin from the woman found in the frozen mass grave in Brevig Mission added to scientists'  knowledge as to how flu viruses mutate and spread. Drugs and improved public hygiene—in conjunction with international institutions such as the World Health Organization and national bodies such as the Centers for Disease Control and Prevention in the United States—put the international community in a much better position to meet the challenges of a new outbreak. However, scientists know a lethal mutation could occur at any time, and a century on from the mother of all pandemics, its effects on a crowded, interconnected world would be devastating.

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