What is influenza?

Causes and Symptoms

Influenza viruses
are members of the orthomyxovirus group and are usually spherical or elliptical bodies 80–120 nanometers in size. The core of the virus is a nucleocapsid consisting of matrix or structural proteins, various nonstructural proteins or enzymes, and ribonucleic acid (RNA). The central core is surrounded by an envelope that is studded by two types of surface antigens, rod-shaped trimeric spikes of hemagglutinins and mushroom-shaped tetrameric projections of neuraminidases. Frequent changes in these two antigens produce the waves of influenza, also known as flu or grippe, in people who have no immunity from prior exposure to new strains. When the changes are small, they are referred to as antigenic drift; when they are large, they are called antigenic shift. There are sixteen hemagglutinin and nine neuraminidase subtypes, and all are known to infect birds. Influenza A maintains a reservoir in waterfowl and shorebirds and can infect domestic poultry, horses, pigs, and humans, but influenza B and C viruses principally infect humans. During the past century, H1N1, H2N2, and H3N2 subtypes of influenza A have been the predominant viruses circulating in the human population, and of the 144 possible antigenic combinations these are the only t that have become adapted to human hosts. When antigenic shift occurs, new hemagglutinin and neuraminidase antigens arise to which the population has no immunity. These large changes in the viral surface antigens occur every ten to thirty years, whereas smaller changes (antigenic drift) in the existing circulating subtypes appear every one to three years. Antigenic shift produces epidemics or pandemics, and antigenic drift results in outbreaks or less widespread epidemics.

Influenza epidemics are associated with excess morbidity and mortality. The excess morbidity is calculated by comparing rates of pneumonia- and influenza-associated illness with seasonally expected rates calculated from nonepidemic years. Similarly, excess mortality is determined by comparing pneumonia- and influenza-related deaths to an expected seasonal baseline rate. During epidemics, the attack rate in unvaccinated populations is 10 to 20 percent but may be as high as 40 to 50 percent. These effects were observed in dramatic fashion during the 1918 (H1N1, Spanish), 1957 (H2N2, Asian), and 1968 (H3N2, Hong Kong) influenza A pandemics of the twentieth century. While not associated with pandemics, influenza B virus is capable of causing severe disease, especially in elderly or immunologically impaired individuals. Influenza C is associated with only mild respiratory disease. In temperate climates, influenza is usually a seasonal illness of the winter months. Colder weather and low humidity facilitate transmission, and indoor crowding and school attendance may also contribute to the spread of virus.

The infection is acquired by the transfer of virus in infected respiratory secretions to mucosal surfaces. Aerosols, both large and small droplets from sneezing and coughing, and direct contact are all responsible for viral transfer. The virus attaches to and penetrates the cells lining the respiratory tract and, through a variety of mechanisms, produces cell death. In the hours preceding cellular destruction, however, new viral particles manufactured by the influenza-infected cell are released to infect nearby cells and continue the infection. Viral shedding in respiratory secretions begins about twenty-four hours before the onset of symptoms and continues for five to ten days.

Influenza infection elicits both local (mucosal) and systemic antibodies as well as T-cell lymphocyte responses. Mucosal antibodies of both the IgA and the IgG type have been demonstrated in nasal secretions, and IgA antibodies help protect the cells of the upper respiratory tract from infection. Systemic antibodies against the hemagglutinin antigen are capable of neutralizing the virus infectivity, while those against the neuraminidase antigen decrease the release of virus from infected cells. If there has been no prior exposure to the particular virus subtype, through either infection or vaccination, then antibody response takes two weeks to develop and peaks at four to seven weeks. Contribution of the T-cell response is less well understood but appears to reduce both the duration of illness and the viral replication.

After an incubation period of one to two days, the illness has an abrupt onset, with chills, fever, myalgia (muscle pain), headache, and anorexia (appetite loss). Ocular symptoms may be prominent, with tearing, burning, and pain with eye movement. Nasal stuffiness and discharge, dry cough, and sore throat are often present. The fever is usually 100 to 104 degrees Fahrenheit on the first day and gradually decreases to normal over the following two to three days, but it may last up to a week. The cough and general feeling of malaise may last for as long as six to eight weeks, even though the acute illness typically resolves in seven to ten days.

Pneumonia is the most important complication of influenza. There may be primary viral pneumonia, secondary bacteria pneumonia, or a combination of both. Autopsies of fatal cases during the 1918 influenza pandemic revealed each of these three varieties of pneumonia in about equal numbers. Primary viral pneumonia more commonly strikes patients with chronic cardiovascular or pulmonary disease; however, new pandemic strains, such as H1N1 influenza, have caused pneumonia in healthy children and young adults. A return of fever during the second week of illness may herald the onset of secondary bacterial pneumonia. This complication is more common in patients with underlying cardiovascular or pulmonary disease and in the elderly. While Richard Pfeiffer originally found Haemophilus influenzae as the most common bacterial pathogen, staphylococci and streptococci are the most dominant today. Less common complications
include myositis, myocarditis, toxic shock, encephalitis, Guillain-Barré syndrome, and Reye’s syndrome.

The influenza virus may be isolated for specific diagnosis and sensitivity testing from nasal swabs or washes, throat swabs, and sputum. Viral cultures usually grow within three days, and special stains combined with specific antibody are then used to identify strains. Susceptibility testing of virus to antivirals is performed in only a few research laboratories. The property of hemagglutination has also been used to identify the virus using a hemagglutination inhibition assay. Currently, the diagnostic “gold standard” is the polymerase chain reaction
(PCR), which employs molecular methodology and can discriminate between subtypes. PCR testing is demanding, time-consuming, and expensive. A variety of colorimetric rapid tests to facilitate diagnosis and treatment of influenza A and B are available, and while the results are available in fifteen to twenty minutes, they are able to correctly identify only 40 to 70 percent of influenza patients.

Treatment and Therapy

Four antiviral drugs that are effective against various strains of influenza are currently available for treatment. Amantadine and rimantadine block the ion channel of the matrix protein M2. This ion channel is necessary for acidification of the nucleocapsid, allowing viral RNA to be transported to the nucleus of the invaded cell, which can then be directed to replicate virus. These drugs work to block the ion channels of influenza A and are administered orally. Zanamivir and oseltamivir inhibit neuraminidase, which assists the virus in entering host cells and also enables the newly replicated virus to exit the cell. Neuraminidase cleaves sialic acid from cell wall glycoprotein. Oseltamivir is administered orally, but zanamivir must be given as an aerosol as it is not absorbed from the gastrointestinal tract. These last two medications are effective against both influenza A and B.

All these antivirals must be administered early in the course of illness in order to be effective. They are most efficacious during the first twenty-four hours and lose their efficacy after forty-eight hours. However, therapy after forty-eight hours, while not altering the course of the disease, does reduce viral shedding and infectivity. Furthermore, they have been shown to be useful only in the treatment of uncomplicated influenza.

Widespread usage of these antivirals has resulted in mutations conferring resistance in some influenza A subtypes. For example, the circulating “seasonal” H1N1 virus is resistant to both neuraminidase inhibitors but retains susceptibility to the M2 ion channel blockers, while the reverse was true for the 2009 H1N1 pandemic strain. Specific antiviral treatment must be targeted to the current strain of influenza A or B producing disease in order to be effective.

Antivirals may be used to prevent or ameliorate infection with influenza virus. As with treatment, prophylaxis must be tailored to the specific influenza strain to circumvent resistance. Prophylaxis is often employed during outbreaks to prevent disease during the two weeks following influenza vaccination until the previously susceptible individuals can develop protective antibodies. Antiviral prophylaxis has been shown to be effective for prolonged periods as well.

Influenza vaccines are about 80 percent effective in preventing or reducing illness from the viruses included in the vaccine. The seasonal vaccines for the 2012–2013 season contained two influenza A strains (an H1N1 and an H3N2) plus an influenza B strain. These strains were selected for inclusion by a panel of experts based upon new strains isolated from patients during the later portion of the preceding influenza season to allow sufficient time for the next vaccine to be produced. Virus for inclusion in all these vaccines is grown in chicken eggs and then purified to minimize any contaminating proteins from the chicken egg. Nevertheless, they should not be given to individuals with a prior history of egg allergy. Each of the vaccines is available as a killed injectable preparation or an attenuated live virus nasal preparation. The nasal vaccine is approved only for immunocompetent individuals aged five to forty-nine years. Influenza vaccines are highly recommended for populations at risk for severe or complicated influenza, such as the elderly, patients with underlying cardiopulmonary disease, and pregnant women. Influenza vaccines are also recommended for health care workers to maintain the caregiving workforce and reduce transmission to patients.

Treatment of complicated influenza is mainly supportive by ensuring fluid and electrolyte balance and adequate respiration. In severe cases with pneumonia, mechanical ventilation may be necessary. If secondary bacterial pneumonia occurs, then antibacterial therapy with agents directed against likely pathogens, especially Staphylococcus aureus, must be administered.

Lastly, because influenza is spread by both aerosols and direct contact, frequent hand washing and the use of masks can prevent or reduce the spread in households and hospitals.

Perspective and Prospects

Epidemics of influenza have been noted to recur every one to three years for at least four hundred years. Such an epidemic prompted Robert Pfeiffer to microscopically identify and cultivate an organism in the purulent sputa of patients with influenza in 1892. This gram-negative bacterium was known as the Pfeiffer influenza bacillus and was thought to be the causative agent of influenza. This organism would later be named Haemophilus influenzae in honor of this historic association.

The 1918 influenza pandemic resulted in 21 million deaths worldwide and 549,000 in the United States. Pfeiffer’s bacillus could not be consistently isolated from influenza patients during this pandemic, and researchers began to question whether this was the true etiologic agent. In 1932, an American, Richard Shope, was able to transmit swine influenza to other animals using filtered nasal secretions, suggesting a viral, rather than bacterial, etiology. A year later, Wilson Smith and colleagues in England employed similar techniques to transmit human influenza virus from the 1932 epidemic to ferrets. After passage in ferrets, the filtrable agent was injected into mice, producing a pneumonia that resembled that seen during the 1918 pandemic. Smith also demonstrated that sera taken from convalescent influenza patients could neutralize the agent and prevent it from causing disease in ferrets.

While Smith had demonstrated that human influenza was caused by a virus, this association was dependent on transmission to an animal host. An Australian, Sir MacFarlane Burnet, discovered how to cultivate influenza virus in embryonated chicken eggs in 1936. This breakthrough enabled the virus to be grown in quantities that facilitated further study and the development of a protective vaccine in 1944.

The isolation of influenza A by Smith was followed by isolation of another strain of influenza virus from a patient in Puerto Rico by Thomas Francis in 1935. This strain, known as PR-8, served as the prototype for influenza disease worldwide in the 1930’s. However, in 1940 a strain of influenza was isolated from a patient during an outbreak that could not be neutralized by antisera from other influenza A strains, and this virus was named influenza B. An influenza outbreak in 1946 led to the discovery that a vaccine made from PR-8 was not protective against this new strain of influenza A; an antigenic shift had occurred. In 1949, a third type, influenza C, was noted.

In 1941, George Hirst observed that influenza virus caused the hemagglutination of red blood cells and, after standing at room temperature, the agglutinated cells would begin to disaggregate, suggesting that the virus was breaking free. Indeed, after about one hour, all the virus could be eluted from the surrounding fluid and the red blood cells were not longer agglutinable. Hirst believed that the virus had altered the red cell surface to make the cells no longer be able to be agglutinated. It was subsequently shown that a glycoprotein of the red cell membrane contains neuraminic acid which was split off by an enzyme of the influenza virus (neuraminidase).

Molecular techniques have allowed researchers to completely map all eight segments of RNA comprising the influenza A genetic code. Using these techniques on preserved tissue samples from 1918 influenza victims has provided a complete map of this historic strain. It is now known that the genetic legacy of the 1918 virus has been passed on to the subsequent influenza strains causing human disease. Despite these advances, the origin of the 1918 virus remains a mystery, and its ability to cause severe disease with high mortality is still unexplained. These data have shown that the novel H1N1 strain associated with the 2009 pandemic is a fourth-generation descendant of the 1918 virus. It is also known that new pandemic influenza A strains can emerge from two different pathways. The first is for an avian virus to infect a person and become transmissible between human hosts. The second is by reassortment of the eight segments of influenza RNA in hosts, such as pigs, that become infected with multiple strains of influenza A with the emergence of a new pathogenic strain for humans. Such knowledge may help prevent the appearance of a new pandemic strain by altering farming practices and by removing infected domestic poultry or swine when new strains are detected.

In addition to the four specific anti-influenza drugs currently available, several other drug therapies are promising. There are three drugs that inhibit viral RNA. Ribavirin is an antiviral currently available for the treatment of hepatitis C that has activity against influenza, especially at higher dosages. A new experimental drug, viramidine, is a prodrug of ribavirin with activity against influenza and less toxicity than ribavirin. Favipiravir is another RNA inhibitor under investigation. Peramivir is a new neuraminidase inhibitor that can be given intravenously and may soon be available for the treatment of severely ill influenza patients.

Anti-influenza antibody therapies have been tried since 1918, when blood, plasma, and serum from survivors were given to severely ill patients with some successes. Pooled human immunoglobulin from convalescent patients or artificially generated antibodies are both promising therapies.

Vaccine manufacture and development have not progressed significantly in the last fifty years. Perhaps the threat of another pandemic will stimulate new research in ways to produce vaccine strains in large quantities using methods other than chicken egg growth and harvesting. There is also continued hope that a conserved influenza antigen, rather than the ever-changing hemagglutinin and neuraminidase antigens, might yield a protective vaccine.

During the 2012–2013 flu season, a strain of avian influenza A, H7N9, developed in China and infected humans, with 131 cases and 32 deaths reported by the World Health Organization as of May 16, 2013. Very little is known so far about the strain or how it is transmitted, but researchers are studying animal-to-human and human-to-human transmission routes.

Bibliography

Beigel, John, and Mike Bray. “Current and Future Antiviral Therapy of Severe Seasonal and Avian Influenza.” Antiviral Research 78 (2008): 91–102.

Carson-DeWitt, Rosalyn. "Influenza (Flu)." Health Library, September 30, 2012.

Centers for Disease Control and Prevention (CDC). "Seasonal Influenza (Flu)." Centers for Disease Control and Prevention, May 17, 2013.

MedlinePlus. "Flu." MedlinePlus, May 17, 2013.

Morens, David M., Gregory K. Folkers, and Anthony S. Fauci. “What Is a Pandemic?” Journal of Infectious Diseases 200 (2009): 1018–1021.

Morens, David M., Jeffrey K. Taubenberger, and Anthony S. Fauci. “The Persistent Legacy of the 1918 Influenza Virus.” New England Journal of Medicine 361 (2009): 225–229.

Preidt, Robert. "HealthDay: Flu Vaccine Safe for Kids with Crohn's, Colitis: Study." MedlinePlus, May 6, 2013.

Treanor, John T. “Influenza Viruses, Including Avian Influenza and Swine Influenza.” In Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John F. Bennett, and Raphael Dolin. 7th ed. Philadelphia: Churchill Livingstone/Elsevier, 2009.

World Health Organization/GIP. "Number of Confirmed Human Cases of Avian Influenza A(H7N9), Reported to WHO (Report 6)." World Health Organization: Influenza, May 16, 2013.