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 (HA) and mushroomshaped tetrameric projections of neuraminidases (NA). Frequent changes in HA and NA produce waves of influenza known as flu or grippe in people who have no immunity from prior exposure.

Infection and epidemics

Influenza infection results from the transfer of virus-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. This effect is exacerbated in enclosed environments with poor ventilation systems. 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 infected cell are released to infect nearby cells and propagate the infection. Viral shedding in respiratory secretions begins about twentyfour hours before the onset of symptoms and continues for five to ten days.

Influenza infection elicits a potent innate immune response, which initially limits viral replication and spread, followed by both local (mucosal) and systemic antibody as well as T-cell lymphocyte responses. Mucosal antibodies of both the IgA and the IgG isotype 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 can neutralize 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. CD4+ T-helper cells and CD8+ effector T cells have been shown to play a role in controlling (CD4+ and CD8+) and even preventing (CD8+) infection with influenza.

Following infection and an incubation period of one to two days, the illness has an abrupt onset, signaled through 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 coughing, and a 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 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, or sputum. Influenza viruses are grown in chicken eggs or cultured mammalian cells, and viral cultures usually grow within three days. Molecular techniques such as reverse-transcriptase polymerase chain reaction (TR-PCR) or hemagglutination assays are then used to identify the specific viral strains that were isolated. Susceptibility testing of virus to antivirals is performed in only a few research laboratories. 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.

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. Epidemics and any subsequent pandemics can be attributed, in part, to the ability of influenza to mutate several residues or acquire novel residues to which the human population has not been exposed, sometimes through the reassortment of several influenza viruses within a singular host. 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 Amaintains 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 ones that have 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.

During epidemics, the attack rate in unvaccinated populations is usually 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 can cause 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.

Treatment and Therapy

Viral infections are notoriously difficult to treat, and as such prevention is preferable to therapeutic intervention. As an old proverb puts it, “An ounce of prevention is worth a pound of cure.” Primary prevention is preventing a disease before it occurs. In the case of influenza, vaccination has become commonplace to provide both individual and herd immunity.

Vaccine development begins up to 6 months in advance of the flu season, and large scale vaccine production is determined from periodic sampling of viral subtypes across many sites around the world to predict which viral strains are likely to emerge later in the year. Vaccination at the start of flu season (around September) for all persons older than 6 months reduces both the risk and severity of the illness. This is particularly important for persons at increased risk for severe infections, including children under 4 years old, persons 50 and over, persons with chronic illnesses (e.g., asthma, diabetes), immunocompromised patients, pregnant women, persons in long-term facilities (e.g., nursing homes), American Indians/Alaska Natives, persons with BMI 40, healthcare workers, and persons in contact with those in the previously listed groups. Contraindication to vaccination is a previous allergic reaction to influenza vaccine. Vaccine efficacy varies by age and type of circulating virus. As the vaccine is made months in advance to have enough vaccine material available, sometimes the predicted viral candidates are not the ones that emerge throughout the season and thus this may reduce the efficacy of the vaccines.

The traditional vaccination route of administration is via an intramuscular injection, though there are alternative routes which include intradermal methods and a nasal spray (this is a live-attenuated vaccine). Alternative formulations include high dose inactivated vaccines, thimerosalfree vaccines, and non-egg-based vaccines (cell culture/recombinant hemagglutinin).

Other methods of prevention include hand hygiene, covering one’s cough, proper disposal of used tissues and facemasks, gloves and gowns, droplet precautions, negative pressure room, N95 masks for healthcare workers conducting aerosol-generating procedures, and avoiding public spaces for at least 24 hours or until afebrile (extend time if caring for immunocompromised patients). Of these additional preventative methods studies show that good hand hygiene is perhaps the most effective in controlling spread of viral infection.

The mainstay treatment for influenza is supportive care and symptomatic treatment. This includes adequate hydration via oral or IV fluids, antipyretics for fever and/or myalgia, and bed rest. Avoid use of aspirin in children as the combination of viral infection and aspirin use in children is associated with Reye’s syndrome, a potentially fatal illness that causes damage to the blood, liver and brain. Antibiotics may be indicated if concomitant bacterial pneumonia is suspected or present.

Antiviral agents for influenza include viral M2 channel inhibitors (Amantadine, Rimantadine) and neuraminidase inhibitors (Zanamivir, Oseltamivir). These agents can be used for prevention in households as well as for treatment of influenza within 1-2 days of onset of symptoms. These agents reduce the duration of illness by about 1 day. H1N1 and H3N2 are resistant to M2 channel inhibitors; however, neuraminidase inhibitors have activity against most strains of influenza A and B, and are thus the recommended antivirals in the US. Oseltamivir and Zanamivir are excreted by the kidneys, and their concentrations increase in patients with decreased renal function. Experts recommend adjusting the dose of Oseltamivir for patients with creatinine clearance of less than 30mL/min.

M2 channel inhibitors and Oseltamivir have GI side effects. Zanamivir may cause bronchospasm and is thus contraindicated in asthmatics. Zanamivir is approved for treatment of adults and children 7 years and older, and prophylaxis of adults and children 5 years and older. Oseltamivir is approved for adults and children 1 year and older, and prophylaxis of adults and children 13 years and older. Widespread usage of these antivirals has resulted in mutations conferring resistance in some influenza A subtypes. Specific antiviral treatment must be targeted to the current strain of influenza A or B producing disease to be effective.

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 filterable 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 a virus caused human influenza, 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 meant the virus could be grown in quantities to facilitate further study and enabled 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 1930s. 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 no longer agglutinable. Hirst believed that the virus had altered the red cell surface to make the cells unable 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 Agenetic 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 rates is still unexplained. This data has 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 allow prevention of the appearance of a new pandemic strain by the altering of 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 and 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 into 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 (WHO).

As of August 2017, the strain with the greatest likelihood of a pandemic potential is still the Influenza AH7N9 virus. Both the Centers for Disease Control (CDC) and WHO report that there is a 5th wave of a H7N9 epidemic in China, with reports suggesting a mortality rate of up to around 30%. Person to person and animal to person transmission rates are currently low, though the consensus is that those engaged in the poultry production process are at greater risk of becoming infected.

See also

Avian influenza; Bacterial infections; Centers for Disease Control and Prevention (CDC); Emerging infectious diseases; Epidemics and pandemics; Epidemiology; Fever; H1N1 influenza; Lungs; Microbiology; Nausea and vomiting; Noroviruses; Pneumonia; Pulmonary diseases; Pulmonary medicine; Pulmonary medicine, pediatric; Respiration; Reye’s syndrome; Sever acute respiratory syndrome (SARS); Viral infections; World Health Organization; Zoonoses.

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