encephalitis called encephalitis lethargica, characterized by headache, drowsiness, and coma, may rarely occur sometime after infection. in survivors of influenza-associated encephalopathy, neurological defects may occur. primarily in children, in severe cases the immune system may rarely dramatically overproduce white blood cells that release cytokines, causing severe inflammation. people who are at least 65 years of age, due to a weakened immune system from aging or a chronic illness, are a high-risk group for developing complications, as are children less than one year of age and children who have not been previously exposed to influenza viruses multiple times. pregnant women are at an elevated risk, which increases by trimester and lasts up to two weeks after childbirth. obesity, in particular a body mass index greater than 35–40, is associated with greater amounts of viral replication, increased severity of secondary bacterial infection, and reduced vaccination efficacy. people who have underlying health conditions are also considered at-risk, including those who have congenital or chronic heart problems or lung (e.g. asthma), kidney, liver, blood, neurological, or metabolic (e.g. diabetes) disorders, as are people who are immunocompromised from chemotherapy, asplenia, prolonged steroid treatment, splenic dysfunction, or hiv infection. tobacco use, including past use, places a person at risk. the role of genetics in influenza is not well researched, but it may be a factor in influenza mortality. epidemiology further information: flu season and flu pandemics influenza mortality in symptomatic cases in the us for the 2018/2019 season. influenza is typically characterized by seasonal epidemics and sporadic pandemics. most of the burden of influenza is a result of flu seasons caused by iav and ibv. among iav subtypes, h1n1 and h3n2 circulate in humans and are responsible for seasonal influenza. cases disproportionately occur in children, but most severe causes are among the elderly, the very young, and the immunocompromised. in a typical year, influenza viruses infect 5–15% of the global population, causing 3–5 million cases of severe illness annually and accounting for 290,000–650,000 deaths each year due to respiratory illness. 5–10% of adults and 20–30% of children contract influenza each year. the reported number of influenza cases is usually much lower than the actual number of cases. during seasonal epidemics, it is estimated that about 80% of otherwise healthy people who have a cough or sore throat have the flu. approximately 30–40% of people hospitalized for influenza develop pneumonia, and about 5% of all severe pneumonia cases in hospitals are due to influenza, which is also the most common cause of ards in adults. in children, influenza is one of the two most common causes of ards, the other being the respiratory syncytial virus. about 3–5% of children each year develop otitis media due to influenza. adults who develop organ failure from influenza and children who have pim scores and acute renal failure have higher rates of mortality. during seasonal influenza, mortality is concentrated in the very young and the elderly, whereas during flu pandemics, young adults are often affected at a high rate. seasonal risk areas for influenza: november–april (blue), april–november (red), and year-round (yellow) in temperate regions, the number of influenza cases varies from season to season. lower vitamin d levels, presumably due to less sunlight, lower humidity, lower temperature, and minor changes in virus proteins caused by antigenic drift contribute to annual epidemics that peak during the winter season. in the northern hemisphere, this is from october to may (more narrowly december to april), and in the southern hemisphere, this is from may to october (more narrowly june to september). there are therefore two distinct influenza seasons every year in temperate regions, one in the northern hemisphere and one in the southern hemisphere. in tropical and subtropical regions, seasonality is more complex and appears to be affected by various climatic factors such as minimum temperature, hours of sunshine, maximum rainfall, and high humidity. influenza may therefore occur year-round in these regions. influenza epidemics in modern times have the tendency to start in the eastern or southern hemisphere, with asia being a key reservoir of influenza viruses. iav and ibv co-circulate, so the two have the same patterns of transmission. the seasonality of icv, however, is poorly understood. icv infection is most common in children under the age of 2, and by adulthood most people have been exposed to it. icv-associated hospitalization most commonly occurs in children under the age of 3 and is frequently accompanied by co-infection with another virus or a bacterium, which may increase the severity of disease. when considering all hospitalizations for respiratory illness among young children, icv appears to account for only a small percentage of such cases. large outbreaks of icv infection can occur, so incidence varies significantly. outbreaks of influenza caused by novel influenza viruses are common. depending on the level of pre-existing immunity in the population, novel influenza viruses can spread rapidly and cause pandemics with millions of deaths. these pandemics, in contrast to seasonal influenza, are caused by antigenic shifts involving animal influenza viruses. to date, all known flu pandemics have been caused by iavs, and they follow the same pattern of spreading from an origin point to the rest of the world over the course of multiple waves in a year. pandemic strains tend to be associated with higher rates of pneumonia in otherwise healthy individuals. generally after each influenza pandemic, the pandemic strain continues to circulate as the cause of seasonal influenza, replacing prior strains. from 1700 to 1889, influenza pandemics occurred about once every 50–60 years. since then, pandemics have occurred about once every 10–50 years, so they may be getting more frequent over time. history the main types of influenza viruses in humans. solid squares show the appearance of a new strain, causing recurring influenza pandemics. broken lines indicate uncertain strain identifications. it is impossible to know when an influenza virus first infected humans or when the first influenza pandemic occurred. the first influenza epidemic may have occurred around 6,000 bc in china, and possible descriptions of influenza exist in greek writings from the 5th century bc. in both 1173–1174 ad and 1387 ad, epidemics occurred across europe that were named "influenza". whether these epidemics or others were caused by influenza is unclear since there was then no consistent naming pattern for epidemic respiratory diseases, and "influenza" didn't become clearly associated with respiratory disease until centuries later. influenza may have been brought to the americas as early as 1493, when an epidemic disease resembling influenza killed most of the population of the antilles. the first convincing record of an influenza pandemic was chronicled in 1510. it began in east asia before spreading to north africa and then europe. following the pandemic, seasonal influenza occurred, with subsequent pandemics in 1557 and 1580. the flu pandemic in 1557 was potentially the first time influenza was connected to miscarriage and death of pregnant women. the 1580 flu pandemic originated in asia during summer, spread to africa, then europe, and finally america. by the end of the 16th century, influenza was beginning to become understood as a specific, recognizable disease with epidemic and endemic forms. in 1648, it was discovered that horses also experience influenza. influenza data after 1700 is more accurate, so it is easier to identify flu pandemics after this point, each of which incrementally increased understanding of influenza. the first flu pandemic of the 18th century started in 1729 in russia in spring, spreading worldwide over the course of three years with distinct waves, the later ones being more lethal. the second flu pandemic of the 18th century was in 1781–1782, starting in china in autumn. from this pandemic, influenza became associated with sudden outbreaks of febrile illness. the next flu pandemic was from 1830 to 1833, beginning in china in winter. this pandemic had a high attack rate, but the mortality rate was low. a minor influenza pandemic occurred from 1847 to 1851 at the same time as the third cholera pandemic and was the first flu pandemic to occur with vital statistics being recorded, so influenza mortality was clearly recorded for the first time. highly pathogenic avian influenza was recognized in 1878 and was soon linked to transmission to humans. by the time of the 1889 pandemic, which may have been caused by an h2n2 strain, the flu had become an easily recognizable disease. the microbial agent responsible for influenza was incorrently identified in 1892 by r. f. j. pfeiffer as the bacteria species haemophilus influenzae, which retains "influenza" in its name. in succeeding years, the field of virology began to form as viruses were identified as the cause of many diseases. from 1901 to 1903, italian and austrian researchers were able to show that avian influenza, then called "fowl plague", was caused by a microscopic agent smaller than bacteria by using filters with pores too small for bacteria to pass through. the fundamental differences between viruses and bacteria, however, were not yet fully understood. 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). from 1918 to 1920, the spanish flu pandemic became the most devastating influenza pandemic and one of the deadliest pandemics in history. the pandemic, probably caused by h1n1, likely began in the united states before spreading worldwide via soldiers during and after the first world war. the initial wave in the first half of 1918 was relatively minor and resembled past flu pandemics, but the second wave later that year had a much higher mortality rate, accounting for most deaths. a third wave with lower mortality occurred in many places a few months after the second. by the end of 1920, it is estimated that about a third to half of all people in the world had been infected, with tens of millions of deaths, disproportionately young adults. during the 1918 pandemic, the respiratory route of transmission was clearly identified and influenza was shown to be caused by a "filter passer", not a bacterium, but there remained a lack of agreement about influenza's cause for another decade and research on influenza declined. after the pandemic, h1n1 circulated in humans in seasonal form up until the next pandemic. in 1931, richard shope published three papers identifying a virus as the cause of swine influenza, a then newly recognized disease among pigs that was characterized during the second wave of the 1918 pandemic. shope's research reinvigorated research on human influenza, and many advances in virology, serology, immunology, experimental animal models, vaccinology, and immunotherapy have since arisen from influenza research. just two years after influenza viruses were discovered, in 1933, iav was identified as the agent responsible for human influenza. subtypes of iav were discovered throughout the 1930s, and ibv was discovered in 1940. during the second world war, the us government worked on developing inactivated vaccines for influenza, resulting in the first influenza vaccine being licensed in 1945 in the united states. icv was discovered two years later in 1947. in 1955, avian influenza was confirmed to be caused by iav. four influenza pandemics have occurred since wwii, each less severe than the 1918 pandemic. the first of these was the asian flu from 1957 to 1958, caused by an h2n2 strain and beginning in china's yunnan province. the number of deaths probably exceeded one million, mostly among the very young and very old. the 1957 pandemic was the first flu pandemic to occur in the presence of a global surveillance system and laboratories able to study the novel influenza virus. after the pandemic, h2n2 was the iav subtype responsible for seasonal influenza. the first antiviral drug against influenza, amantadine, was approved for use in 1966, with additional antiviral drugs being used since the 1990s. in 1968, h3n2 was introduced into humans through a rearrangement between an avian h3n2 strain and an h2n2 strain that was circulating in humans. the novel h3n2 strain emerged in hong kong and spread worldwide, causing the hong kong flu pandemic, which resulted in 500,000–2,000,000 deaths. this was the first pandemic to spread significantly by air travel. h2n2 and h3n2 co-circulated after the pandemic until 1971 when h2n2 waned in prevalence and was completely replaced by h3n2. in 1977, h1n1 reemerged