Article: Influenza

Influenza, commonly known as the 'flu, is an infectious disease that infects birds and mammals (primarily of the upper airways and lungs in mammals) and is caused by an RNA virus of the Orthomyxoviridae family (the influenza viruses). The most common and characteristic symptoms of influenza in humans are fever, pharyngitis (sore throat), myalgia (muscle pains), severe headache, coughing, and malaise (weakness and fatigue).^[1]

A cold and a 'stomach flu' are very different from a flu. Influenza can be far more severe than the common cold and can even lead to death. Influenza and the common cold are caused by very different viruses. Gastroenteritis is commonly called "stomach flu" or "24 hour flu"; but that is a misnomer as it is not connected with actual flu.

Flu rapidly spreads around the world in seasonal epidemics, killing millions of people in pandemic years and hundreds of thousands in nonpandemic years. It creates health care costs and lost productivity. Three influenza pandemics in the 20^th century, each following a major genetic change in the virus, killed millions of people all over the world. The world's current major influenza pandemic threat is H5N1; but it is at present mostly a flu in birds, not in people.

The term influenza has its origins in 15th century Italy, where the cause of the disease was ascribed to unfavourable astrological influences. Evolution in medical thought led to its modification to "influenza di freddo", meaning "influence of the cold", which by the 18th century became the prevalent terminology in the English-speaking world as well.

Etymology

The Modern English word "influenza" was first attested in English in 1743 when it was borrowed during an outbreak of the disease in Europe and is derived from Italian "influenza". Which originally meant "influence" as it was believed influenza was caused by the stars.¹

History

It has been suggested that Influenza epicentre be merged into this article or section. (Discuss)

Hippocrates first described the symptoms of influenza in 412 B.C.. Since then, the virus has undergone mutations and shifts and has caused numerous pandemics. The first influenza pandemic was recorded in 1580, since this time, various methods have been employed to eradicate its cause.^[2] The etiological cause of influenza, the orthomyxoviridae was finally discovered by the Medical Research Council (MRC) of the United Kingdom in 1933.^[3]

The most known outbreaks are caused by antigenic shift, when two strains of influenza recombine forming a lethal new strain. The most famous outbreak (and the most lethal) was the so-called Spanish Flu pandemic (type A influenza, H1N1 strain), which lasted from 1918 to 1919, and is believed to have killed more people in total than World War I. While the war casualties accumulated over several years, the pandemic took most of its toll over a period of weeks. Lesser flu epidemics included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain).

Known flu pandemics ^[4]

• 1889-90 - Asiatic (Russian) Flu, mortality rate said to be 0.75-1 death per 1000 possibly H2N2
• 1900 - possibly H3N8
• 1918–20 – Spanish Flu, 500 million ill, at least 40 million died of H1N1
• 1957–58 – Asian Flu, 1 to 1.5 million died of H2N2
• 1968–69 – Hong Kong Flu, 3/4 to 1 million died of H3N2

Negatively stained flu virions. These were the causative agent of the Hong Kong Flu pandemic.

Although there were scares in New Jersey in 1976 (the Swine Flu), worldwide in 1977 (the Russian Flu), and in Hong Kong (as well as in other Asian countries, namely continental China, as became known later) in 1997 (Avian influenza), there have been no major pandemics subsequent to the 1968 infection. Increased immunity from antibodies, and the development of flu vaccines have limited the spread of the virus, and so far prevented any further pandemics.

Microbiology

All influenza viruses are either Influenzavirus A, Influenzavirus B or Influenzavirus C. They have two antigenic glycosylated enzymes on its surface: neuraminidase and hemagglutinin. Neuraminidase facilitates the release of progeny virus from infected cells, hemagglutinin facilitates binding of the virus to the target cell.^[5] The hemagglutinin (H) and neuraminidase (N) RNA strands also specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. They are also used as the basis for the naming of the different subtypes of influenza A viruses. This is where the H and N come from in H5N1.

Influenza A viruses are significant for their potential for disease and death in humans and other animals. The Influenza A virus subtypes that have been confirmed in humans, ordered by the number of known human deaths, are:

• H1N1 caused "Spanish Flu"
• H2N2 caused "Asian Flu"
• H3N2 caused "Hong Kong Flu"
• H5N1 is the current pandemic threat
• H7N7 has unusual zoonotic potential
• H1N2 is currently endemic in humans and pigs
• H9N2, H7N2, H7N3, H10N7.

Influenza A

The following applies for Influenza A viruses:

The type A virus is the most severe among the three influenza strains. It has eight pieces of segmented negative-sense RNA. It enters the body, and uses neuraminadase to attatch to cells and hemagglutin to enter them.

The cell then takes in the virus by endocytosis by a vacuole. Proton pumps in the vesicle increase the internal pH of the vesicle. The cell envelope and capsid disintegrate, and the RNA molecules and RNA-dependent RNA transcriptase are released. The RNA-dependent RNA transcriptase begins actively transcribing complimentary positive-sense viral RNA. Other viral proteins begin to modify host cell mRNA, degrading certain portions, using the individual nucleotides for resources for positive-sense viral RNA synthesis by RNA-dependent RNA transcriptase, and then inserting the viral RNA into the mRNA.

The cell then creates viral proteins and nonfunctional self proteins on its ribosomes with the virally-modified mRNA. However, the failure to produce correct self proteins kills the cell, making the infection cytolytic, meaning that the influenza kills its host cells directly by lysis.

Negative-sense RNA for future viruses, RNA-dependent RNA transcriptase, and other viral proteins are then created and put together. Hemagglutin and neuraminadase molecules are inserted onto the cell membrane. When the RNA and viral proteins leave the cell by budding, also wrapping a phospholipid bilayer membrane around them as they leave, the two viral enzymes are naturally on the envelope of the virus as it leaves. After the release of influenza viruses, the host cell dies.

It is interesting to note that because of the absence of RNA proofreading enzymes, like the DNA polymerase I found in eukaryotes' cells, that the RNA-dependent RNA transcriptase makes a single nucleotide insertion error per every 10 thousand nucleotides, which is the approximate length of the influenza virus's RNA. This makes nearly every newly manufactured influenza virus a mutant! Selective mixing and matching of the segmented RNA strands also may aid in RNA mutations.

Symptoms

According to the on-line version of the Merck Manual of Diagnosis and Therapy:

"Symptoms start 24 to 48 hours after infection and can begin suddenly. Chills or a chilly sensation are often the first indication of influenza. Fever is common during the first few days, and the temperature may rise to 102 to 103° F. Many people feel sufficiently ill to remain in bed for days; they have aches and pains throughout the body, most pronounced in the back and legs."^[1]

The virus attacks the respiratory tract, is transmitted from person to person by saliva droplets expelled by coughing, and can cause the following symptoms:

• Body aches
• Cough
• Extreme coldness
• Fatigue
• Fever
• Headache
• Irritated watering eyes
• Loss of smell
• Nasal congestion
• Nausea
• Reddened eyes, skin (especially face), mouth, throat
• Runny nose
• Sore joints
• Sore throat
• Sneezing
• Vomiting

Influenza's effects are much more severe than those of the "cold", and last longer. Recovery takes about one to two weeks. Influenza can be deadly, especially for the weak, old or chronically ill. Some flu pandemics have killed millions of people.

Most people who get influenza will recover in one to two weeks, but others will develop life-threatening complications (such as pneumonia). Millions of people in the United States (about 10% to 20% of U.S. residents) are infected with influenza each year. An average of about 36,000 people per year in the United States die from influenza, and 114,000 per year are admitted to a hospital as a result of influenza. According to estimates by the World Health Organization, between 250,000 and 500,000 die from influenza infection each year worldwide. Even healthy people can be affected, and serious problems from influenza can happen at any age. People age 65 years and older, people of any age with chronic medical conditions, and very young children are more likely to get complications from influenza. Pneumonia, bronchitis, sinus, and ear infections are four examples of such complications.

The flu can make chronic health problems worse. For example, people with asthma may experience asthma attacks while they have the flu, and people with chronic congestive heart failure may have a worsening of this condition, that is triggered by the flu.

Many symptoms of the flu (fever, muscle aches, headaches, and fatigue), are caused by the huge production of interferon from influenza-infected cells.

A CDC press release on January 7, 2003 said: "Using new and improved statistical models, CDC scientists estimate that an average of 36,000 people (up from 20,000 in previous estimates) die from influenza-related complications each year in the United States."^[6]

Flu season

Main article: Flu season

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemisphere have winter at different times of the year, there are actually two flu seasons each year. Therefore, the World Health Organization (assisted by the National Influenza Centers) makes two vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.

While most influenza outbreaks in the Northern Hemisphere tend to peak in January or February, not all do. For example, the influenza pandemic of 1918 and 1919 reached peak virulence during late spring and summer worldwide, and not until October in the US. It remains unclear why outbreaks of the flu occur seasonally rather than uniformly throughout the year.

One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also linger longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel and visitation due to the Northern Hemisphere winter holiday season may also play a role. ^[7]

Prevention

US navy personnel receiving influenza vaccination

Main articles: Flu vaccine, Influenza pandemic#Personal health and hygiene

It is possible and in many cases recommended to get vaccinated against influenza with a flu vaccine. Its effectiveness varies with many criteria.

Due to the high mutability of the virus, a particular flu vaccine formulation usually only works for about a year. The World Health Organization co-ordinates the contents of the vaccine each year to contain the most likely strains of the virus that probably will attack the next year.

It is possible to get vaccinated for the season and still catch the flu. The vaccine is reformulated each season for a few specific flu strains, but cannot possibly include all the different strains actively infecting people in the world for that season. This means that you could catch a virus not covered by the vaccine. Also, it takes about six months for the manufacturers to formulate and make the millions of doses required to deal with the seasonal epidemics; occasionally a new or overlooked strain becomes prominent during that six months and infects people even though they've been vaccinated (as in the 2003-2004 season). The vaccine may have partial coverage for these unexpected strains. It is also possible to get infected and then get vaccinated the next day, before flu symptoms appear, and still get sick with the very strain that the vaccine is supposed to prevent. The vaccine can take a few days to become effective.

Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or as long lasting as the flu.

The viruses in the flu shot are killed (inactivated), so you cannot get the flu from a flu shot. The risk of a flu shot causing serious harm, or death, is extremely small. However, a vaccine, like any medicine, may rarely cause serious problems, such as severe allergic reactions. Almost all people who get influenza vaccine have no serious problems from it.^[8]

Personal health and hygiene are important in avoiding and minimizing influenza.

Treatment

Main article Flu treatment contains curative treatments, symptom treatments and unconventional treatments such as antivirals, decongestants, and echinacea, respectively.

If you get the flu, get plenty of rest, drink a lot of liquids, and avoid using alcohol and tobacco. You can take medications such as acetaminophen to relieve the fever and muscle aches associated with the flu. Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin as taking aspirin in the presence of influenza infection (especially influenza type B) can lead to Reye syndrome, a rare but potentially fatal disease of the liver. ^[9]

Research

Main article: Flu research

Influenza research includes molecular virology, pathogenesis, host immune responses, and epidemiology. These help in developing influenza countermeasures such as vaccines, therapies and diagnostic tools.

Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response.

The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time.

Solutions to limitations in current vaccine methods are being researched. The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be used in case of an influenza pandemic from H5N1 and is conducting clinical trials on them. ^[10] ABC News reported on April 1, 2006 that "Beginning in late 1997, the human trials have tested 30 different vaccines, all pegged to the H5N1 virus." ^[11]

Flu in nonhumans

Main articles: Influenzavirus A, H5N1, Transmission and infection of H5N1

While all flu is caused by the family of virus species called Orthomyxoviridae, most flu is caused by the species Influenza A virus which is hosted by birds, but may infect several species of mammals.

Variants of flu virus are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are:

• Bird flu
• Human Flu
• Swine Flu
• Horse Flu
• Dog Flu

Influenza A virus subtype H5N1, also known as H5N1, is a subtype of the Influenza A virus that is capable of causing illness in many species, including humans.^[12] An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian influenza virus of type A of subtype H5N1") is the causative agent of H5N1 flu, commonly known as "avian influenza" or simply "bird flu", and is endemic in many bird populations, especially in Southeast Asia.

An Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in nonhumans) and panzootic (a disease affecting animals of many species, especially over a wide area) killing tens of millions of birds and spurring the culling of hundreds of millions of other birds in an attempt to control its spread. Most references in the media to "bird flu" and most references to H5N1 are about this specific strain.^[13]

HPAI A(H5N1) is an avian disease and there is no evidence suggesting either efficient human-to-human transmission of HPAI A(H5N1) or of airborne transmission of HPAI A(H5N1) to humans. Those infected with H5N1 have had, in almost all cases, extensive physical contact with infected birds. However, H5N1 has the potential to mutate or reassort into a strain capable of efficient human-to-human transmission. Due to the high lethality and virulence of human HPAI A(H5N1) infection to date, its endemic presence, its large and increasing biological host reservoir, and its significant ongoing mutations, the H5N1 virus is today the world's major current pandemic threat, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential influenza pandemic.^[14]

According to Avian Influenza by Timm C. Harder and Ortrud Werner:

Following an incubation period of usually a few days (but rarely up to 21 days), depending upon the characteristics of the isolate, the dose of inoculum, the species, and age of the bird, the clinical presentation of avian influenza in birds is variable and symptoms are fairly unspecific (Elbers 2005). Therefore, a diagnosis solely based on the clinical presentation is impossible. The symptoms following infection with low pathogenic AIV may be as discrete as ruffled feathers, transient reductions in egg production or weight loss combined with a slight respiratory disease (Capua and Mutinelli 2001). Some LP strains such as certain Asian H9N2 lineages, adapted to efficient replication in poultry, may cause more prominent signs and also significant mortality (Bano 2003, Li 2005). In its highly pathogenic form, the illness in chickens and turkeys is characterised by a sudden onset of severe symptoms and a mortality that can approach 100 % within 48 hours (Swayne and Suarez 2000).^[15]