Additionally, febrile seizures and Reye syndrome can occur, most commonly in children. Influenza-associated encephalopathy can occur directly from central nervous system infection from the presence of the virus in blood and presents as suddent onset of fever with convulsions, followed by rapid progression to coma. An atypical form of 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. Current or past tobacco use also places a person at risk.
The fundamental differences between viruses and bacteria, however, were not yet fully understood. 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 USA before spreading worldwide by 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 influenzas 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 first characterized during the second wave of the 1918 pandemic.