Influenza

"Flu" redirects here. For other uses, see Flu (disambiguation).

Influenza Classification & external resources
TEM of negatively stained influenza virons, magnified approximately 100,000 times
ICD-10	J10., J11.
ICD-9	487
DiseasesDB	6791
MedlinePlus	000080
eMedicine	med/1170  ped/3006
MeSH	D007251

Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae (the influenza viruses). The name influenza comes from the Italian: influenza, meaning "influence", (Latin: influentia). In humans, common symptoms of the disease are fever, sore throat, muscle pains, severe headache, coughing, weakness and general discomfort.Merck Manual Home Edition. Influenza: Viral Infections. In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Although it is sometimes confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus.Eccles, R (2005). "Understanding the symptoms of the common cold and influenza". Lancet Infect Dis 5 (11): 718–25.  Influenza can produce nausea and vomiting, especially in children, but these symptoms are more characteristic of the unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu." Seasonal Flu vs. Stomach Flu by Kristina Duda, R.N.; accessed March 12, 2007 (Website: "About, Inc., A part of The New York Times Company")

Typically influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, faeces and blood. Infections also occur through contact with these body fluids or with contaminated surfaces. Flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C (32 °F), and indefinitely at very low temperatures (such as lakes in northeast Siberia). Most influenza strains can be inactivated easily by disinfectants and detergents.Suarez, D; Spackman E, Senne D, Bulaga L, Welsch A, Froberg K (2003). "The effect of various disinfectants on detection of avian influenza virus by real time RT-PCR". Avian Dis 47 (3 Suppl): 1091–5. Avian Influenza (Bird Flu): Implications for Human Disease. Physical characteristics of influenza A viruses. UMN CIDRAP.Flu viruses \'can live for decades\' on ice, NZ Herald, November 30, 2006.

Flu spreads around the world in seasonal epidemics, killing millions of people in pandemic years and hundreds of thousands in non-pandemic years. Three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing flu virus to humans from other animal species. A deadly avian strain named H5N1 has posed the greatest risk for a new influenza pandemic since it first killed humans in Asia in the 1990s. Fortunately, this virus has not mutated to a form that spreads easily between people.Avian influenza ("bird flu") fact sheet. WHO (February 2006). Retrieved on 2006-10-20.

Vaccinations against influenza are usually given to people in developed countries with a high risk of contracting the disease,WHO position paper: influenza vaccines WHO weekly Epidemiological Record 19 August 2005, vol. 80, 33, pp. 277–288. and to farmed poultry.Villegas, P (1998). "Viral diseases of the respiratory system". Poult Sci 77 (8): 1143–5. PMID 9706079.  The most common human vaccine is the trivalent influenza vaccine that contains purified and inactivated material from three viral strains. Typically this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain.Horwood, F; Macfarlane J. "Pneumococcal and influenza vaccination: current situation and future prospects.". Thorax 57 Suppl 2: II24–II30. PMID 12364707.  A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time and different strains become dominant. Antiviral drugs can be used to treat influenza, with neuraminidase inhibitors being particularly effective.

Flu

Influenza Virus Avian influenza Flu season Research Vaccine Treatment Genome project H5N1 strain

Contents 1 Etymology 2 History 3 Microbiology 3.1 Types of influenza virus 3.2 Structure and properties 3.3 Infection and replication 4 Symptoms and diagnosis 4.1 Symptoms 4.2 Laboratory tests 5 Epidemiology 5.1 Seasonal variations 5.2 Epidemic and pandemic spread 6 Prevention 6.1 Vaccination and infection control 7 Treatment 7.1 Neuraminidase inhibitors 7.2 M2 inhibitors (adamantanes) 8 Research 9 Infection in other animals 10 Economic impact 11 See also 12 References and notes 13 Further reading 14 External links

Etymology

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 del freddo, meaning "influence of the cold." The word "influenza" was first used in English in 1743 when it was borrowed during an outbreak of the disease in Europe.Harper, D. Influenza. Etymonlin. Archaic terms for influenza include epidemic catarrh, grippe (from the French.), sweating sickness, and Spanish fever (particularly for the 1918 pandemic strain).Smith, P. Archaic Medical Terms. Retrieved on 2006-10-23.

History

Further information: Influenza pandemic, Spanish flu

The influenza viruses that caused Hong Kong Flu. (magnified approximately 100,000 times)

The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).Taubenberger, J; Morens D (2006). "1918 Influenza: the mother of all pandemics.". Emerg Infect Dis 12 (1): 15–22. PMID 16494711. 

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.Martin, P; Martin-Granel E (Jun 2006). "2,500-year evolution of the term epidemic". Emerg Infect Dis 12 (6). PMID 16707055. Hippocrates; Adams, Francis (transl.) (400 BCE). Of the Epidemics. Retrieved on 2006-10-18. Since then, the virus has caused numerous pandemics. Historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other diseases, such as diphtheria, pneumonic plague, typhoid fever, dengue, or typhus. The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Asia and spread to Europe via Africa. In Rome over 8,000 people were killed, and several Spanish cities were almost wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.Potter, CW (Oct 2006). "A History of Influenza". J Appl Microbiol. 91 (4): 572–579. PMID 11576290. 

The most famous and lethal outbreak was the so-called Spanish flu pandemic (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. Older estimates say it killed 40–50 million peoplePatterson, KD; Pyle GF (Spring 1991). "The geography and mortality of the 1918 influenza pandemic.". Bull Hist Med. 65 (1): 4–21. PMID 2021692.  while current estimates say 50 million to 100 million people worldwide were killed. "1: The Story of Influenza", in Knobler S, Mack A, Mahmoud A, Lemon S: The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005). Washington, D.C.: The National Academies Press, 60–61.  This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.Taubenberger, J; Reid A, Janczewski T, Fanning T (Dec 29 2001). "Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus.". Philos Trans R Soc Lond B Biol Sci 356 (1416): 1829–39. PMID 11779381. 

The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%. Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.Simonsen, L; Clarke M, Schonberger L, Arden N, Cox N, Fukuda K (Jul 1998). "Pandemic versus epidemic influenza mortality: a pattern of changing age distribution.". J Infect Dis 178 (1): 53–60. PMID 9652423.  This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world\'s population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.

Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.

Known flu pandemicsHilleman, M (Aug 19 2002). "Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control.". Vaccine 20 (25–26): 3068–87. PMID 12163258. 

Name of pandemic	Date	Deaths	Subtype involved	Pandemic Severity Index
Asiatic (Russian) Flu	1889–1890	1 million	possibly H2N2	?
Spanish Flu	1918–1920	40 to 100 million	H1N1	5
Asian Flu	1957–1958	1 to 1.5 million	H2N2	2
Hong Kong Flu	1968–1969	0.75 to 1 million	H3N2	2

The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Schope in 1931.Shimizu, K (Oct 1997). "History of influenza epidemics and discovery of influenza virus". Nippon Rinsho 55 (10): 2505–201. PMID 9360364.  This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933.Smith, W; Andrewes CH, Laidlaw PP (1933). "A virus obtained from influenza patients". Lancet 2: 66–68.  However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.

The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr.. This built on work by Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen\'s eggs.Sir Frank Macfarlane Burnet: Biography The Nobel Foundation. Accessed 22 Oct 06 Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first influenza vaccine, with support from the U.S. Army.Kendall, H (2006). "Vaccine Innovation: Lessons from World War II". Journal of Public Health Policy 27 (1): 38–57.  The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.

Although there were scares in New Jersey in 1976 (with the Swine Flu), world wide in 1977 (with the Russian Flu), and in Hong Kong and other Asian countries in 1997 (with H5N1 avian influenza), there have been no major pandemics since the 1968 Hong Kong Flu. Immunity to previous pandemic influenza strains and vaccination may have limited the spread of the virus and may have helped prevent further pandemics.

Microbiology

Types of influenza virus

Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).

Diagram of influenza virus nomenclature (for a Fujian flu virus)

The influenza virus is an RNA virus of the family Orthomyxoviridae, which comprises the influenzaviruses Isavirus and Thogotovirus.Kawaoka Y (editor). (2006). Influenza Virology: Current Topics. Caister Academic Press. ISBN 978-1-904455-06-6.  There are three types of influenza virus: Influenzavirus A, Influenzavirus B, and Influenzavirus C. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans.Hay, A; Gregory V, Douglas A, Lin Y (Dec 29 2001). "The evolution of human influenza viruses". Philos Trans R Soc Lond B Biol Sci 356 (1416): 1861–70. PMID 11779385.  Wild aquatic birds are the natural hosts for a large variety of influenza A viruses. Occasionally viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.Klenk et al (2008). "Avian Influenza: Molecular Mechanisms of Pathogenesis and Host Range", Animal Viruses: Molecular Biology. Caister Academic Press. ISBN 978-1-904455-22-6.  The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The Influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

• H1N1 caused "Spanish Flu."
• H2N2 caused "Asian Flu."
• H3N2 caused "Hong Kong Flu."
• H5N1 is a pandemic threat in 2007–8 flu season.
• H7N7 has unusual zoonotic potential.Fouchier, R; Schneeberger P, Rozendaal F, Broekman J, Kemink S, Munster V, Kuiken T, Rimmelzwaan G, Schutten M, Van Doornum G, Koch G, Bosman A, Koopmans M, Osterhaus A (2004). "Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome.". Proc Natl Acad Sci U S A 101 (5): 1356–61. PMID 14745020. 
• H1N2 is endemic in humans and pigs.
• H9N2, H7N2, H7N3, H10N7.

Influenza B virus is almost exclusively a human pathogen and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal.Osterhaus, A; Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R (2000). "Influenza B virus in seals.". Science 288 (5468): 1051–3. PMID 10807575.  This type of influenza mutates at a rate 2–3 times lower than type ANobusawa, E; Sato K (Apr 2006). "Comparison of the mutation rates of human influenza A and B viruses". J Virol 80 (7): 3675–8. PMID 16537638.  and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.R, Webster; Bean W, Gorman O, Chambers T, Kawaoka Y (1992). "Evolution and ecology of influenza A viruses.". Microbiol Rev 56 (1): 152–79. PMID 1579108.  This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.Zambon, M (Nov 1999). "Epidemiology and pathogenesis of influenza.". J Antimicrob Chemother 44 Suppl B: 3–9. PMID 10877456. 

The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.Matsuzaki, Y; Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K (2002). "Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998". J Clin Microbiol 40 (2): 422–9. PMID 11825952.  However, influenza C is less common than the other types and usually seems to cause mild disease in children.Matsuzaki, Y; Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H (May 1 2006). "Clinical features of influenza C virus infection in children.". J Infect Dis 193 (9): 1229–35. PMID 16586359. Katagiri, S; Ohizumi A, Homma M (Jul 1983). "An outbreak of type C influenza in a children\'s home.". J Infect Dis 148 (1): 51–6. PMID 6309999. 

Structure and properties

The following applies for Influenza A viruses, although other strains are very similar in structure:International Committee on Taxonomy of Viruses descriptions of: Orthomyxoviridae, Influenzavirus B and Influenzavirus C

The influenza A virus particle or virion is 80–120 nm in diameter and usually roughly spherical, although filamentous forms can occur.International Committee on Taxonomy of Viruses. The Universal Virus Database, version 4: Influenza A. Unusually for a virus, the influenza A genome is not a single piece of nucleic acid; instead, it contains eight pieces of segmented negative-sense RNA (13.5 kilobases total), which encode 11 proteins (HA (hemagglutinin), NA (neuraminidase), NP (nucleoprotein), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2, PB2).Ghedin, E; Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro D, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman D, Fraser C, Taubenberger J, Salzberg S (Oct 20 2005). "Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution.". Nature 437 (7062): 1162–6. PMID 16208317.  The best-characterised of these viral proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. By contrast, hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.Suzuki, Y (2005). "Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses.". Biol Pharm Bull 28 (3): 399–408. PMID 15744059.  The hemagglutinin (HA or H) and neuraminidase (NA or N) proteins are targets for antiviral drugs.Wilson, J; von Itzstein M (Jul 2003). "Recent strategies in the search for new anti-influenza therapies". Curr Drug Targets 4 (5): 389–408. PMID 12816348.  These proteins are also recognised by antibodies, i.e. they are antigens. The responses of antibodies to these proteins are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.

Infection and replication

Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.

Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells; typically in the nose, throat and lungs of mammals and intestines of birds (Stage 1 in infection figure).Wagner, R; Matrosovich M, Klenk H (May–Jun 2002). "Functional balance between haemagglutinin and neuraminidase in influenza virus infections.". Rev Med Virol 12 (3): 159–66. PMID 11987141.  The cell imports the virus by endocytosis. In the acidic endosome, part of the haemagglutinin protein fuses the viral envelope with the vacuole\'s membrane, releasing the viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA transcriptase into the cytoplasm (Stage 2).Lakadamyali, M; Rust M, Babcock H, Zhuang X (Aug 5 2003). "Visualizing infection of individual influenza viruses.". Proc Natl Acad Sci U S A 100 (16): 9280–5. PMID 12883000.  These proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA transcriptase begins transcribing complementary positive-sense vRNA (Steps 3a and b).Cros, J; Palese P (Sep 2003). "Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses.". Virus Res 95 (1–2): 3–12. PMID 12921991.  The vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly-synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.Kash, J; Goodman A, Korth M, Katze M (Jul 2006). "Hijacking of the host-cell response and translational control during influenza virus infection.". Virus Res 119 (1): 111–20. PMID 16630668. 

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA transcriptase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).Nayak, D; Hui E, Barman S (Dec 2004). "Assembly and budding of influenza virus.". Virus Res 106 (2): 147–65. PMID 15567494.  As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell. After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA transcriptase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutantDrake, J (May 1 1993). "Rates of spontaneous mutation among RNA viruses.". Proc Natl Acad Sci USA 90 (9): 4171–5. PMID 8387212.  - antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allow the virus to infect new host species and quickly overcome protective immunity. This is important in the emergence of pandemics, as discussed below in the section on Epidemiology.

Symptoms and diagnosis

Influenza spreads by aerosols created by coughs or sneezes.

In humans, influenza\'s effects are much more severe than those of the common cold, and last longer. Recovery takes about one to two weeks. Influenza, however, can be deadly, especially for the weak, old or chronically ill. The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure.Angelo SJ, Marshall PS, Chrissoheris MP, Chaves AM. "Clinical characteristics associated with poor outcome in patients acutely infected with Influenza A." Conn Med. 2004 Apr;68(4):199–205. PMID 15095826 Smoking is another risk factor associated with more serious disease and increased mortality from influenza.Murin S, Bilello K (2005). "Respiratory tract infections: another reason not to smoke.". Cleve Clin J Med 72 (10): 916-20. PMID 16231688. 

Symptoms

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation but fever is also common early in the infection, with body temperatures as high as 39 °C (approximately 103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worst in their backs and legs. Symptoms of influenza may include:

• Body aches, especially joints and throat
• Coughing and sneezing
• Extreme coldness and fever
• Fatigue
• Headache
• Irritated watering eyes
• Nasal congestion
• Reddened eyes, skin (especially face), mouth, throat and nose
• Abdominal pain (in children with Influenza B)Kerr AA, McQuillin J, Downham MA, Gardner PS (1975). "Gastric \'flu influenza B causing abdominal symptons in children". Lancet 1 (7902): 291–5. PMID 46444. 

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections, but usually the symptoms of the flu are more severe than their common-cold equivalents. Research on signs and symptoms of influenza found that the best findings for excluding the diagnosis of influenza were:Call S, Vollenweider M, Hornung C, Simel D, McKinney W (2005). "Does this patient have influenza?". JAMA 293 (8): 987-97. doi:10.1001/jama.293.8.987. PMID 15728170. 

Highest sensitive individual findings for diagnosing influenza

Finding:	sensitivity	specificity
Fever	86%	25%
Cough	98%	23%
Nasal congestion	70–90%	20–40%

Notes to table:

• Sensitivity is the proportion of people who tested positive of all the positive people tested. In this case, being positive or negative is having influenza or not, and being tested positive or negative is having the symptom or not. For instance, 86% of those with influenza had fever.
• Specificity is the proportion of people who tested negative of all the negative people tested. In this case, the ones without fever only constitute 25% of those without influenza. In other words, the majority of people with fever do not have influenza.
• All three findings, especially fever, were less sensitive in patients over 60 years of age.

Since anti-viral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of findings below can improve diagnostic accuracy.Monto A, Gravenstein S, Elliott M, Colopy M, Schweinle J (2000). "Clinical signs and symptoms predicting influenza infection.". Arch Intern Med 160 (21): 3243–7. PMID 11088084.  Unfortunately, even combinations of findings are imperfect. However, Bayes Theorem can combine pretest probability with clinical findings to adequately diagnose or exclude influenza in some patients. The pretest probability has a strong seasonal variation; the current prevalence of influenza among patients in the United States receiving sentinel testing is available at the CDC.Centers for Disease Control and Prevention. Weekly Report: Influenza Summary Update. Accessed January 1, 2007. Using the CDC data, the following table shows how the likelihood of influenza varies with prevalence:

Combinations of findings for diagnosing influenza

Combinations of findings	Sensitivity	Specificity	As reported in study. and projected during local outbreaks (prevalence= 66%)		Projected during influenza season (prevalence=25%)		Projected in off-season (prevalence=2%)
			PPV	NPV	PPV	NPV	PPV	NPV
Fever and cough	64%	67%	79%	49%	39%	15%	4%	1%
Fever and cough and sore throat	56	71	79	45	39	17	4	2
Fever and cough and nasal congestion	59	74	81	48	43	16	4	1

Two decision analysis studiesSmith K, Roberts M (2002). "Cost-effectiveness of newer treatment strategies for influenza.". Am J Med 113 (4): 300-7. doi:10.1016/S0002-9343(02)01222-6. PMID 12361816. Rothberg M, Bellantonio S, Rose D (2003). "Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy.". Ann Intern Med 139 (5 Pt 1): 321-9. PMID 12965940.  suggest that during local outbreaks of influenza, the prevalence will be over 70% and thus patients with any of the above combinations of symptoms may be treated with neuramidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.

Most people who get influenza will recover in one to two weeks, but others will develop life-threatening complications (such as pneumonia). According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the world-wide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don\'t usually verify who actually died of influenza and who died of a flu-like illness."Peter M. Sandman and Jody Lanard "Bird Flu: Communicating the Risk" 2005 Perspectives in Health Magazine Vol. 10 issue 2. Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions, are more likely to get complications from influenza: such as pneumonia, bronchitis, sinus, and ear infections. Key Facts about Influenza (Flu) Vaccine CDC publication. Published October 17, 2006. Accessed 18 Oct 2006.

Common symptoms of the flu such as fever, headaches, and fatigue come from the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells.Schmitz N, Kurrer M, Bachmann M, Kopf M (2005). "Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection.". J Virol 79 (10): 6441–8. PMID 15858027.  In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.Winther B, Gwaltney J, Mygind N, Hendley J. "Viral-induced rhinitis.". Am J Rhinol 12 (1): 17–20. PMID 9513654. 

Laboratory tests

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.Centers for Disease Control and Prevention. Lab Diagnosis of Influenza. Accessed on January 1, 2007 According to the CDC, rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% when compared with viral culture. These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season (prevalence=10%).

Epidemiology

Seasonal variations

Further information: Flu season

Cumulative Confirmed Human Cases of H5N1.WHO Confirmed Human Cases of H5N1 Data published by WHO Epidemic and Pandemic Alert and Response (EPR). Accessed 24 Oct. 2006 The regression curve for deaths is shown extended through the end of April 2007.

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 different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.Recommended composition of influenza virus vaccines for use in the 2006–2007 influenza season WHO report 2006-02-14. Accessed 19 October 2006.

It is not completely clear 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 survive longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel due to the Northern Hemisphere winter holiday season may also play a role.Weather and the Flu Season NPR Day to Day, December 17 2003. Accessed, 19 October 2006 A contributing factor is that aerosol transmission of the virus is highest in cold environments (less than 5 degrees Celsius) with low humidity.Lowen AC, Mubareka S, Steel J, Palese P (2007). "Influenza virus transmission is dependent on relative humidity and temperature". PLoS Pathog. 3 (10): 1470–6. PMID 17953482.  However, seasonal changes in infection rates also occur in tropical regions, and these peaks of infection are seen mainly during the rainy season.Shek LP, Lee BW. "Epidemiology and seasonality of respiratory tract virus infections in the tropics." Paediatr Respir Rev. 2003 Jun;4(2):105–11. PMID 12758047 Seasonal changes in contact rates from school-terms, which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in flu. A combination of these small seasonal effects may be amplified by "dynamical resonance" with the endogenous disease cycles.Dushoff J, Plotkin JB, Levin SA, Earn DJ. "Dynamical resonance can account for seasonality of influenza epidemics." Proc Natl Acad Sci U S A. 30 November2004;101(48):16915–6. PMID 15557003 H5N1 exhibits seasonality in both humans and birds.

An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus.Cannell, J; Vieth R, Umhau J, Holick M, Grant W, Madronich S, Garland C, Giovannucci E (2006). "Epidemic influenza and vitamin D". Epidemiol Infect 134 (6): 1129–40. PMID 16959053.  This idea was first proposed by Robert Edgar Hope-Simpson in 1965.HOPE-SIMPSON, R. "The nature of herpes zoster: a long-term study and a new hypothesis". Proc R Soc Med 58: 9–20. PMID 14267505.  He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall. Furthermore, some studies have suggested that administering cod liver oil, which contains large amounts of vitamin D, can reduce the incidence of respiratory tract infections.Linday, L; Shindledecker R, Tapia-Mendoza J, Dolitsky J (2004). "Effect of daily cod liver oil and a multivitamin-mineral supplement with selenium on upper respiratory tract pediatric visits by young, inner-city, Latino children: randomized pediatric sites". Ann Otol Rhinol Laryngol 113 (11): 891–901. PMID 15562899. 

Epidemic and pandemic spread

Further information: Flu pandemic

Antigenic drift creates influenza viruses with slightly-modified antigens, while antigenic shift generates viruses with entirely novel antigens.

How antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out while others create epidemics while yet another strain can cause a pandemic. Typically, in a year\'s normal two flu seasons (one per hemisphere) there are between three and five million cases of severe illness and up to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic.Influenza WHO Fact sheet No. 211 revised March 2003. Accessed 22 October 2006 Although the incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every year in America.Thompson, W; Shay D, Weintraub E, Brammer L, Cox N, Anderson L, Fukuda K (2003). "Mortality associated with influenza and respiratory syncytial virus in the United States". JAMA 289 (2): 179–86. PMID 12517228. Thompson, W; Shay D, Weintraub E, Brammer L, Bridges C, Cox N, Fukuda K (2004). "Influenza-associated hospitalizations in the United States". JAMA 292 (11): 1333–40. PMID 15367555. Flu factsheet National Institute of Allergy and Infectious Diseases Accessed 22 Dec 2006 Every ten to twenty years a pandemic occurs, which infects a large proportion of the world\'s population, and can kill tens of millions of people (see history section).

New influenza viruses are constantly being produced by mutation or by reassortment. Mutations can cause small changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic drift, which creates an increasing variety of strains over time until one of the variants eventually achieves higher fitness, becomes dominant, and rapidly sweeps through the human population – often causing an epidemic. (2006) "Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus". Biol Direct 1 (1): 34. PMID 17067369.  In contrast, when influenza viruses re-assort, they may acquire new antigens — for example by reassortment between avian strains and human strains; this is called antigenic shift. If a human influenza virus is produced with entirely novel antigens, everybody will be susceptible and the novel influenza will spread uncontrollably, causing a pandemic.Parrish, C; Kawaoka Y. "The origins of new pandemic viruses: the acquisition of new host ranges by canine parvovirus and influenza A viruses". Annual Rev Microbiol 59: 553–86. PMID 16153179.  In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach has been proposed where the perio