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Epidemic Influenza

PROF. HEWLETT'S interesting article in NATURE for October 24 may justify the statement of a few facts collected during the last quarter of a century. Dealing with the Registrar-General's returns for London and considering twenty deaths per week as epidemic if this number or more, is maintained for successive weeks, there have been twenty-eight epidemics since the reassertion of the complaint in 1890. Of these there have only been two, in the years 1910 and 1911, with fewer deaths than 100. The only years in the epoch without influenza being epidemic are 1896 and 1901. The most serious epidemics since 1890 occurred in, 1891, 1892, and 1899–1900, in each of which there were in London upwards of 2000 deaths. In recent years the most serious epidemic occurred in 1908 with a total of 1961 deaths, hut the summer and autumn epidemics of the present year bid fair to be at least as severe.

Deadly Diseases

In the world of human afflictions, the general public often overlooks influenza, considering it an unwanted guest that must be endured during the winter months. But few diseases match the year-in, year-out power of this deadly viral infection. Each year it takes the lives of about 37,000 people in the United States and between 250,000 and 500,000 worldwide. While that toll is significant enough, influenza always has the potential to turn far more lethal, because the viruses can mutate rapidly into new strains. To public health officials, flu tops the list of diseases that could cause a pandemic — a global epidemic.

Influenza got its name in the 1700s from an Italian folk word that attributed colds, cough, and fever to the influence of the stars. Highly contagious, the flu virus passes through the air via water droplets from coughing and sneezing. The organism can survive for hours outside the body. A person infected with flu remains contagious for about a week, beginning one day before symptoms show up.

With its generalized symptoms, the flu mimics the initial stages of many diseases, including the common cold. Flu can be clinically determined by a throat culture and blood test, but by the time results arrive, symptoms may have already run their course. Antiviral drugs can be effective if taken within two days of the start of symptoms.

The flu usually causes fever, body aches, and intestinal problems, as well as upper respiratory tract infections in about 5 percent to 15 percent of the population. Up to 50 million Americans get the flu each year. On average, adults lose three workdays a year as a result. The flu can turn deadly in combination with bacterial pneumonia, an opportunistic infection that attacks flu-weakened lungs. Severe illness affects between three million and five million people each year. The flu is particularly hard on the elderly, who account for 90 percent of the deaths.

Historians believe it was influenza that plagued Greece in 430 B.C.E. During the Peloponnesian War, and that it also ravaged Charlemagne's army in 876 C.E. The first recorded appearance, though, came in New England in 1647, where residents colorfully dubbed the unknown affliction as the "jolly rant," the "new acquaintance," and the "grippe."

New strains of flu arise early each year, and world health officials hurry to identify them in order to develop an effective vaccine. Because the virus mutates so often, immunity doesn't carry over from one year to the next. A flu pandemic sparked by a particularly virulent strain has typically occurred a few times each century, and no one can predict which strain in which year might have global impact. Constant vigilance and early action by global public health authorities is essential because vaccines take six months to produce, test, and distribute — too long to ward off a pandemic once it has taken hold. Another constraint is that at present, vaccines are grown in fertilized eggs, and at any given moment, the number of eggs available in the world is limited. New methods of vaccine production not dependent on eggs are crucial.

Experts agree that another flu epidemic is not only inevitable, but also likely to happen soon. Three times during the 1900s a sub-strain of flu underwent a major genetic change, leading to pandemics: The worse occured in 1918, and there were serious but less dangeours pandemic strains in 1957 (The Asian Flu) and in the 1968 (The Hong Kong Flu). Health officials fear a repeat of the Great Spanish Influenza of 1918, in which an estimated one billion people came down with the disease. Between 21 million and 50 million died — several times the total number of deaths in all of World War I, which ended the year the epidemic began. In the United States alone, 550,000 lost their lives to the disease. Busy gravediggers sang as they worked: "I had a little bird/ Its name was Enza/ I opened the window/ And In-Flu-Enza." As mysteriously as the Spanish flu appeared, it disappeared, leaving health workers to wonder if and when it might return.

A more severe form of human influenza, one that attacks not just the respiratory system but every tissue of the body, can originate in birds, chickens, and pigs. Until 1997, this so-called avian flu hadn't been known to strike humans. But that year in Hong Kong, 18 people came down with severe respiratory disease at the same time a widespread avian flu outbreak hit poultry. Investigations showed that the virus had jumped from birds to humans — the first known instance of that happening.

Within days, Hong Kong authorities destroyed the entire poultry population — about 1.5 million birds — a response that may have averted a pandemic. This avian-to-human transmission of the flu alarmed health officials, and subsequent years have seen minor outbreaks of avian flu in humans elsewhere, including the Netherlands and Vietnam. The real danger is if the avian flu strain evolves from a disease that humans catch from animals to a disease that humans can spread to other humans. The antiviral drug Tamiflu™ may be helpful in fighting symptoms for human victims, and many nations are trying to secure supplies in the event of a large-scale outbreak.

Meanwhile, a new vaccine against the avian flu virus, made by the pharmaceutical company Sanofi Pasteur, has proved effective in 115 volunteer subjects when given in two large doses. While this is hopeful news, critics point out that the large amounts needed mean that the hundreds of millions of doses required to fight a pandemic could never be produced with existing production methods. Vaccines that work at much lower doses are still urgently needed.

Whether the next pandemic originates in humans or birds, its effects will likely be dramatic. An estimated two million to seven million people could die, with tens of millions requiring medical attention. One nightmare scenario: A single person becomes infected with both common and avian flu, allowing the genetic material to mix. The resulting strain would doubtlessly be as lethal as it is contagious.

The key to containing all pandemics is fast action by global health authorities. Western nations stockpile antiviral drugs to protect their own citizens. But rather than combating a virus already spreading globally, health officials suggest rushing drugs and vaccines to the source of the infection and quarantining the area. The goal is to keep the disease from spreading beyond these areas where it breaks out.

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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).

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