Influenza is caused by infection with an influenza virus, which may result in disease of varying severity and death in a wide variety of animals and humans. Besides the annually recurring seasonal flu outbreaks in humans in temperate climate zones, influenza is probably best known for its ability to cause pandemics — that is, worldwide outbreaks of influenza in humans — with probably the best known and most terrifying example being the ‘Spanish flu’ that started in 1918 and killed more than 50 million people worldwide.
Although it was Shope  who first isolated an influenza virus from pigs in 1930, it was not until 1933 that an influenza virus was identified in humans, by Smith, Andrews and Laidlaw . This happened following (unintentional) inoculation of a laboratory staff member with a clinical specimen. Because it was the first influenza virus isolated from humans it was named influenza A virus.
The current classification of influenza viruses is based on biological and molecular characteristics of the viruses. They all belong to the Orthomyxoviridae family, which encompasses five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Thogotovirus (a tick-borne virus of mammals) and Isavirus (infectious salmon anemia virus) . Although influenza A and B viruses are phylogenetically closely related, only influenza A viruses are able to infect a wide array of birds and mammals, including humans. Evolutionary relatedness among various groups of influenza A viruses and the fact that all known subtypes, characterized by their surface glycoproteins hemagglutinin (HA, n=16) and neuraminidase (NA, n=9), can be found in avian species led to the hypothesis that all influenza A viruses are derived from an avian influenza A virus pool that acts as a permanent reservoir of these viruses . Influenza B and C virus infections are largely restricted to humans (see below).
In order to sustain themselves in their mammalian host populations, influenza A viruses undergo continuous as well as more abrupt antigenic variation, which allows them to escape from immunosurveillance by their hosts. Two distinct mechanisms of variation are known to play a key role in this process: antigenic drift and antigenic shift.
ANTIGENIC SHIFT AND DRIFT
Immunity to influenza is long-lived but incomplete as new virus strains emerge continuously and new virus subtypes emerge from time to time. These two phenomena are known as antigenic drift and shift, respectively. Antigenic drift is the process of positive selection of influenza virus strains through random point mutations accumulated in the HA and NA genes. Selection of such mutants occurs as a result of escape from neutralizing antibodies that are formed in the population at large as a result of ongoing infections. These new antigenically distinct strains are thus, to a large degree, resistant to the antibody-mediated immunity induced by infection from the ‘parental’ strain. After several years of antigenic drift, the strain may have mutated to such an extent that it will be able to infect individuals protected against previous ‘parental’ viruses. Antigenic drift variants typically circulate in the population for 2 to 5 years before being replaced by a strain that has changed sufficiently to allow the complete replacement of the ancestral virus of the same subtype. Still, through a certain degree of remaining antibody-mediated cross-protection and T cell-mediated heterosubtypic immunity, the disease following infection with a drift variant is usually less severe . In conclusion, antigenic drift is the process that allows the annual recurrence of seasonal influenza epidemics. In some years, however, the new virus strain is much more divergent, resulting in infection of considerably higher numbers of previously protected individuals, which then may contribute to a significantly higher burden of disease than in previous seasons .
A new influenza A subtype virus can emerge in the human population through a second mechanism called antigenic shift. This can be the result of either of two mechanisms that can also happen simultaneously. The first is the reshuffling or reassortment of the eight RNA genome segments of different influenza A viruses that may simultaneously infect a cell of an avian or mammalian host. This may result in the introduction of a reassortant virus with completely new surface glycoproteins to which the human population has not been previously exposed. In theory, all gene segments are interchangeable . However, so far only three HAs and two NAs in three combinations (H1N1, H2N2, H3N2) have been found in truly human-adapted viruses. In contrast, the majority of all possible combinations between the 16 HAs and 9 NAs have been identified in the avian world. This suggests that there may be limitations in the possible combinations that can adapt to certain mammalian hosts . A second mechanism by which a new influenza A virus subtype can be introduced into the human population is by gradual adaptation of an avian influenza virus upon zoonotic transmission, through sequential mutation. Zoonotic transmissions of avian influenza viruses to humans are sporadic events and such viruses usually are not transmitted from human to human. However, if such transmissions do occur more frequently, this may eventually lead to adaptation of the virus to humans, allowing it to spread efficiently in the human population.
It is now generally accepted that reassortment between human and avian influenza A viruses led to the emergence of the ‘Asian flu’ and the ‘Hong Kong flu’ in 1957 and 1968, respectively, whereas the Spanish flu of 1918 may have been the result of the gradual adaptation of an avian influenza virus to humans (Figure 1).
||Figure 1. The influenza A virus reservoir is found in migratory birds (center circle), from which the viruses may be transmitted to numerous other avian and mammalian species. Reassortment between human and avian influenza A viruses led to the emergence of
the ‘Asian flu' and the ‘Hong Kong flu' pandemics (H2N2 and H3N2, respectively), whereas the ‘Spanish flu' virus (H1N1) may have been the result of gradual adaptation of an avian influenza virus to humans, possibly with domestic pigs as an intermediate host. The exact processes and animal reservoirs associated with these adaptations remain a matter of debate. Occasional transmissions of influenza A viruses from swine to humans do occur. Pigs are hypothesized to be an important ‘mixing vessel' involved in reassortment and adaptation of influenza A viruses to humans. Sporadic zoonotic transmission of avian influenza viruses (e.g., H7N7 or H5N1) to humans does occur (dotted lines), but these events usually do not produce a virus that is efficiently transmitted between humans, thus limiting its pandemic potential.
(Adapted with permission from the World Organisation of Animal Health (OIE), paper by Reperant LA, Rimmelzwaan GF, Kuiken T. Avian influenza viruses in mammals, published in Rev. sci. tech. Off. int. Epiz. 2009;28:137-159)
MANIFESTATIONS OF INFLUENZA A IN HUMANS
Influenza A viruses are basically avian viruses that were probably introduced into the human population relatively recently. Three major manifestations of influenza A can be found in humans: 1) annually recurring seasonal flu, which in the moderate climate zones is seen in the fall or winter months; 2) avian flu, caused by sporadic zoonotic infections with avian influenza viruses; and 3) pandemic flu or worldwide outbreaks of influenza.
Interpandemic or seasonal influenza A
In the temperate climate zones, influenza epidemics occur virtually every year in the fall and winter months. Both influenza A and B viruses may cause these epidemics. Normally, influenza A epidemics are more serious, although in some years influenza B virus may cause greater health problems. The burden of disease caused by interpandemic influenza epidemics varies considerably, at least in part depending on the virus’ ability to escape the host’s immunosurveillance. Seasonal or interpandemic influenza activity can range from almost absent to more than 10 reported influenza cases per 10,000 individuals and may also differ between geographical regions. It is estimated that annually on average 2-10% of the world’s population is infected with an influenza virus, causing 250,000 to 500,000 deaths .
Classically, an outbreak of seasonal influenza begins with an increase in school absenteeism, later followed by an increase in work absenteeism. This indicates that school-age children play an important role in propagating and spreading influenza in the population. Indeed, influenza A virus infection in children is very common: a serological study in Germany showed that over 70% of children aged 3-6 years had influenza-A-specific antibodies, increasing up to 100% by the age of 12 years .
Since 1977, two influenza A virus subtypes (H1N1 and H3N2) have been circulating in the human population globally. Although they generally cause less severe disease than seen during most pandemic influenza episodes, the disease burden during seasonal influenza outbreaks is still considerable. In particular, H3N2 accounts for excess morbidity and mortality, the latter mainly being observed in high-risk groups (e.g., young children and the elderly) due to the development of complications . At this time, while the so-called new pandemic variant influenza A (H1N1) virus is still circulating, it is unclear what to expect in the near future. After the last three pandemics, one of the previously circulating seasonal influenza A virus subtypes was replaced by the newly introduced pandemic virus that subsequently became an annually recurring seasonal influenza A virus in all cases. The currently circulating pandemic new variant influenza A (H1N1) virus seems to have eliminated its seasonal influenza A (H1N1) virus counterpart, whereas, at least in the moderate climate zones, only low numbers of influenza A (H3N2) virus infections have been reported . However, the current situation appears to be different in several tropical areas, where influenza A (H3N2) virus infections do occur more abundantly in the presence or absence of the pandemic virus. Therefore, it seems realistic to expect that the pandemic new variant H1N1 virus will eventually become one of the future seasonal influenza viruses.
Hospitalization due to seasonal influenza occurs frequently. In the United States alone, it was estimated that annually an average of 90,000 primary and 130,000 of any listed pneumonia and influenza hospitalizations were associated with influenza virus. For any listed respiratory and circulatory disease these numbers were staggeringly high, an average of about 300,000 influenza-associated hospitalizations. Influenza-associated hospitalizations occur predominantly among the elderly, and the numbers of these hospitalizations have increased over the last 2 decades, at least in part due to aging of the population . Children are also at risk for hospitalization upon influenza virus infection [10-13]. Poeling et al  reported that the average influenza-associated hospitalization rate in the United States is an estimated 0.9 per 1000 children. Children below the age of 5 years and especially those younger than six months are particularly at risk for hospitalization [10-13]. It may well be that the actual burden of disease in children is even higher, because several studies showed that laboratory-confirmed viral diagnosis is often not obtained [11,12].
Influenza-associated mortality disproportionately affects elderly persons. In a study in the United States, the annual mean influenza-associated mortality rate for underlying pneumonia and influenza in persons 65 years and older was 22 per 100,000 person-years. This accounts for 90% of influenza-related deaths [6,13]. For children these figures are quite different. Although at high risk for hospitalization, mortality rates in children are relatively low [6,13,14]. This is all the more puzzling because a substantial proportion of young children are truly immunologically naïve to influenza and thus should suffer from a disease burden similar to that observed during pandemics. Therefore, in theory, the number of children admitted to intensive care units (ICUs) or dying because of an influenza virus infection should be substantial. Why this is not the case remains largely unclear. We speculate that children may be relatively protected from serious disease through one or several different mechanisms: 1) maternal antibodies, which may protect children during at least the first half year of life ; 2) development of a specific immune response while still protected from serious disease by maternally derived antibodies [8,15]; 3) age-related differences in the host immune response . This will be further discussed in the section on pandemics; 4) the lower pathogenicity of seasonal as compared to pandemic influenza viruses . Still, seasonal influenza-related critical disease and mortality do occur in children. Because a substantial proportion of influenza-related mortality is due to secondary bacterial infection, data on pediatric mortality in the United States that show an increase in the rates of bacterial co-infections are of concern, not the least because the majority of these were caused by methicillin-resistant Staphylococcus aureus .
Zoonotic infections with avian influenza viruses
Until 1997, sporadic infections of humans with avian influenza viruses were thought to be of minimal public-health risk. Up to that year only a limited number of avian influenza virus infections in humans were reported. However, in 1997 that view totally changed when highly pathogenic avian influenza A (H5N1) virus was transmitted to humans in Hong Kong and killed 6 of the 18 infected identified patients . After this unexpected event, multiple infections of humans with avian influenza A viruses were reported (Table 1). Here we will discuss only infections with avian H5N1 and H7N7 viruses, because these were associated with significant numbers of infections in humans.
||TABLE 1. Laboratory-confirmed influenza pandemics to the present
Highly pathogenic avian influenza A (H5N1) virus infections in humans
Highly pathogenic H5N1 evolved through a series of genetic changes from a 1996 progenitor strain. Currently it comprises at least 10 groups of antigenically and genetically distinct virus clades that have infected wild birds and domestic poultry in many countries. To date, four of these clades (0,1,2, and 7) are known to have infected humans .
The first human case of infection with highly pathogenic avian influenza A (H5N1) virus in Hong Kong occurred in May 1997 in a 3-year-old boy who died of influenza pneumonia with subsequent acute respiratory distress syndrome, multiorgan failure, and disseminated intravascular coagulation . Thereafter, late in 1997, 17 additional cases were described . Six of these infected individuals died, leading to a mortality rate of more than 30%. This high mortality rate was at that time atypical, but as we know now not uncharacteristic for human infections with highly pathogenic avian influenza A (H5N1) virus [19,20]. The human infections coincided with an epizootic caused by the same virus infection in domestic poultry in the same geographical area. Viral analyses showed that the human virus was genetically closely related, if not identical, to the avian virus [18,21] The Hong Kong authorities responded by having 1.6 million birds at live bird markets culled in order to eradicate the epizootic from the birds and prevent further zoonotic infections. In 2003, however, a highly pathogenic avian influenza A (H5N1) virus reappeared, as two cases were again recognized . From then onward the number of zoonotic H5N1 cases increased. Between 2003 and September 2009, 442 cases were reported in 15 countries. An alarming 262 (~60%) of these cases were fatal . One should, however, be cautious in interpreting these mortality figures. This virus is clearly highly pathogenic in humans, but it cannot be excluded that mild or even subclinical cases also occurred and went unreported [24,25]. Serological studies in possibly exposed persons do not, however, support this notion .
Highly pathogenic avian influenza A (H5N1) virus is most commonly transmitted to humans through contact with infected birds . Human-to-human infections have not occurred or they happen only very rarely and apparently inefficiently and in a nonsustained way [28,29]. The increasing number of avian-to-human infections does give rise to the fear that this virus may mutate or reassort with mammalian influenza viruses and thus become the basis of a future devastating pandemic.
An outbreak of highly pathogenic avian influenza A (H7N7) virus infection in domestic poultry associated with human infections
In 2003, an outbreak of highly pathogenic avian influenza A (H7N7) virus infection occurred in domestic poultry in The Netherlands. The same virus was eventually also detected in 86 humans who were involved in the mass culling of about 30 million poultry in The Netherlands. Three additional cases were found in family members of infected poultry workers, indicating that indeed human-to-human transmission had taken place, albeit at a moderate level. Poultry workers and others in contact with the infected chickens or their excrement were treated preventively with the NA inhibitor oseltamivir. Serological investigation indicated that about half of the 500 poultry workers involved had indeed been exposed to the virus . Most of the clinical cases were mild and self-limiting, with the predominant clinical presentation being conjunctivitis. However one infected veterinarian who had not been treated with oseltamivir developed acute respiratory distress syndrome associated with bilateral viral pneumonia with high viral loads in his lungs and died .
Pandemics are defined as outbreaks that impact large geographic areas and large portions of the population in time. The most infamous and deadly so far has been the Spanish flu of 1918-1920. This is also the first pandemic for which hard virological evidence for the involvement of an influenza virus exists . However, based on clinical and sero-archeological data influenza outbreaks can be traced back longer. Reports on possible (pandemic) influenza outbreaks have even been identified in early Greek writings. It was Molineux (1694) who published the first convincing report on an influenza epidemic . Although clearly speculative and only based on clinical data, influenza outbreaks are thought to have occurred in 1173, 1580, 1729 and 1781 . These may not all have been true pandemics, but the 1580 outbreak surely qualifies as one. This pandemic originated in Asia in the summer and then spread to Africa and through the Middle East to Europe. The whole of Europe was affected within a six-month period and mortality figures were high: Rome reported 8000 deaths and some Spanish cities were reported to have been decimated .
Influenza pandemics apparently occur with a 10- to 40-year interval, usually causing significant morbidity and mortality  (Table 2). Here we will discuss the four pandemics from the 20th century until now.
||TABLE 2. Transmission of avian influenza to humans since 1997
The pandemic of 1918-1920 - Spanish influenza - (H1N1)
The pandemic of 1918-1920 has become the most fearsome example of how devastating an influenza pandemic can be. Like all pandemic influenza A viruses, the virus originated in birds . Whether it had directly crossed the species barrier to humans, as seen with H5N1 and H7N7 viruses, or whether an intermediate host was involved before it started to circulate among humans, remains unclear . There are indications that domestic pigs in the United States were involved as an intermediate host [36,37]. This pandemic killed many more people worldwide than did World War I, and it reduced the life expectancy in the United States by approximately ten years [3,33]. No figures exist for many other parts of the world, but it is estimated that at least 50% of the total world population was affected during the Spanish flu. Of those, 25% suffered from a clinically manifest infection and an estimated minimum of 50 million people died. Although this is already a staggering number, it has been argued that this is an underestimate, failing to account for a much higher death toll in non-Western societies. When corrected for under-registration, the actual death toll may be around 100 million people [33,38].
The geographical origin of the Spanish flu virus is not known . The first pandemic influenza wave appeared in the spring of 1918 in the United States. Outbreaks occurred almost at the same time in Detroit, Michigan, South Carolina, and San Quentin Prison in California. With the transportation of military personal the infection spread probably across the United States and to Europe. From Europe, it spread with great rapidity to Africa and Asia . Although devastating, at that time events like this were not considered exceptional. Pandemics had occurred before and the number of deaths was comparable with those seen during earlier pandemics [17,33,38]. However, what happened subsequently was exceptional. In the fall (Northern Hemisphere) of 1918 a second wave of influenza spread over the world. The virus that caused this wave was extremely virulent. It probably originated in Western France and then spread all over Europe. It has been speculated that through shipping of troops, influenza again reappeared in the United States. Only this time it was much more lethal. Death tolls reached over 10,000 persons per week, with deaths in hospitals exceeding 25% per night [2,40] After two months the epidemic finally subsided. However, in the winter period of 1918-1919, a third wave, that has generally been considered to be less virulent than its predecessors, again caused disease and death [17,33,38]. This three-wave pattern of disease was not universal, as some countries had suffered only one or two (e.g., Australia) usually longer outbreaks. Overall, in the Western world the mortality rate exceeded 1%. In isolated subpopulations (e.g., Alaska) the death rates were much higher and sometimes reached levels as high as 70% .
One of the more striking aspects of the 1918-1920 pandemic was the relatively heavy toll among individuals aged 15 to 35 years. Normally, the influenza-related mortality curve by age at death is U-shaped, reflecting excess mortality in the very young and elderly. During the 1918-1920 pandemic the mortality curve by age was W-shaped. Overall mortality rates for young adults were 20-fold higher than in previous years . Nearly half of the deaths were in young adults, and individuals below the age of 65 years were more at risk for influenza death than those above that age . The reason why the curve exhibited this W-shape remains one of the great riddles of influenza. A hypothesis is that individuals older than 65 had cross-protective immunity induced by exposure to a related influenza virus earlier in their lifetime . This does not answer the question why children from 4 to 15 years old had the lowest death rate, despite the high influenza incidence in this age group [16,17]. An explanation for this phenomenon may be related to age-specific differences in the immune response. Age-related differences in the antiviral immune response may lead to better protection of children from severe illness. Several examples exist of infectious diseases from which children suffer less severe disease than adults. Classic examples are mumps, measles, mononucleosis, varicella and severe acute respiratory syndrome (SARS) [42-44].
The 1918 pandemic has a persistent legacy. All subsequent influenza outbreaks are usually related to the Spanish flu. Both of the viruses that caused the 1957 and 1968 pandemics share parts of their genetic makeup with the Spanish flu virus . After having been replaced by the Asian flu virus in 1957, the H1N1 virus, which had initially continued to circulate as a seasonal influenza virus, reappeared in 1977 and continued to circulate globally, albeit as a less virulent virus until April 2009. In April 2009 a new influenza virus emerged: the pandemic new variant influenza A (H1N1) virus . It caused the first influenza pandemic, which at least so far has been relatively mild even though the subtype of the causative virus was identical to that of the Spanish flu that happened almost a century earlier. Perhaps one may conclude with Taubenberger et al  that the 1918 Spanish flu was the mother of all subsequent influenza pandemics to the present .
The pandemic of 1957-1958 - Asian influenza - (H2N2)
The cause of this pandemic was an influenza A (H2N2) virus of avian origin in China . The virus caused extensive infections in mainland China in March 1957 and reached Hong Kong in April 1957. From Hong Kong it quickly spread to Singapore and Japan, and from there to the Southern Hemisphere. Within 6 months the pandemic spanned the globe . A second wave of infections was observed early in 1958. In total the global infection rate of the pandemic was 30-40% of the population. An estimated 25% of infected individuals showed clinical disease. The infection rate was highest in 5- to 19-year-olds, in whom it exceeded 50% . The mortality rate was estimated at 1 in 40,000. Death occurred predominantly in the very young and the very old, not unlike what is usually seen in seasonal influenza. The total worldwide death toll of this pandemic probably ranged between 2 million and 4 million people.
The pandemic of 1968 - Hong Kong influenza - (H3N2)
As in 1957, the H3N2 pandemic also arose from an avian virus in China. This pandemic was not as explosive as the previous ones. The virus spread across the world during the winters of 1968-69 and 1969-70 . Its mortality and death rates differed significantly between regions . Whereas in Western Europe only an increase in disease but not mortality was seen, disease and death rates were relatively high on the West Coast of the United States. It has been speculated that a possible reason for the relatively mild clinical course was the widespread presence of N2 antibodies, which had been induced by the H2N2 epidemic 11 years before. The overall worldwide death toll of this pandemic probably did not exceed 1-2 million people.
The pandemic of 2009 - Mexican or swine influenza - (H1N1)
At the end of March 2009, two children who were treated for airway infections in San Diego County, California for their respiratory symptoms had an uneventful recovery. Although these clinical cases were not unusual, the viral laboratory test results were surprising: both children had been infected with influenza A virus that could not be typed with standard reagents . The causative virus turned out to be genetically related to a swine influenza A virus and differed substantially from circulating human influenza viruses [48,49]. Its potential to cause a pandemic was immediately appreciated, thus containment strategies were implemented globally. Still, the apparently emerging pandemic spread fast. Off-season influenza epidemics occurred both in the United States and Mexico . By the end of April it was estimated that, in Mexico alone, 23,000 individuals had already been infected . Through travelling, mainly by airplane, the virus quickly spread globally, facilitated by its efficient human-to-human transmission. Initially, in countries other than the United States and Mexico, introduction of the virus occurred sporadically via travelers. As early as June 11, 2009, only seven weeks after the first cases were identified, a pandemic was declared by the World Health Organization. After the initial sporadic outbreaks or isolated epidemics, which due to air travel contacts were most prominent in the United Kingdom and Spain, influenza activity in the Northern Hemisphere subsided in the summer while in the Southern Hemisphere a full-blown epidemic phase of this pandemic occurred during the winter months. At that time the new variant influenza A (H1N1) virus had become the dominant influenza virus in the Southern Hemisphere . In the fall of 2009 the virus reappeared in the Northern Hemisphere and again caused a significant epidemic. As of November 22, 2009, more than 207 countries and overseas territories or communities had reported laboratory-confirmed cases of pandemic new variant influenza A (H1N1) virus infection, including over 7820 deaths .
Early in the Mexican or swine pandemic it became clear that older individuals were relatively protected from developing severe disease upon infection; especially those born before 1958 seemed to be ‘seroprotected’ [49,52,53]. This may at least partly explain why this pandemic has so far had a relatively mild course. Most seriously affected have been children, with reported attack rates of up to 60% [50,54]. Children also constitute the majority of hospital admissions, but are underrepresented in mortality figures [55,56]. Still, despite the relative mildness of this pandemic, severe illness and death did occur. Countries that had experienced the first influenza wave reported frequent ICU admissions, often in younger individuals. Although most of the admitted individuals had serious underlying medical conditions, about 30% did not [57-60]. A complication in a small minority of the affected individuals was acute respiratory distress syndrome, often associated with shock and diffuse intravascular coagulation (Figure 2) [57,59,60]. This condition requires intense treatment, ultimately even with Extra Corporal Membrane Oxygenation (ECMO). In Australia and New Zealand it was calculated that this influenza outbreak resulted in about 2.6 extra ECMO cases per million people , a figure that needs to be reckoned with when planning for future influenza pandemics.
||Figure 2. Chest X-ray of a 15-year-old girl with influenza-associated acute respiratory
distress syndrome (ARDS) requiring ECMO treatment. Hyperinflation and extensive
bilateral infiltrative lesions can clearly be seen.
How the still-ongoing pandemic will evolve remains to be seen. Major factors that will clearly influence its course are the ongoing mass-vaccination campaigns and the availability of antiviral therapy. Initial reports from Norway and France and more recently from many other countries highlighted research findings of a more virulent strain in fatal cases. Luckily, the virus with this mutation apparently does not spread more efficiently than the wild-type virus and it has remained sensitive to the antiviral drugs that are currently in use. Furthermore, the immune response induced by the currently used pandemic vaccines may also provide adequate protection from infection by this mutated virus. On the other hand, viruses from numerous fatal cases worldwide have not shown this mutation, which in the meantime has also been found in relatively mild cases. The public health significance of this finding is still unclear .
THE EPIDEMIOLOGY OF INFLUENZA B AND C VIRUSES
Type B and C influenza viruses evolve more slowly than influenza A viruses. They appear to be more adapted to the human host than influenza A viruses. Influenza B virus infections are generally considered to be restricted to the human host, although recently, infections in seals were also demonstrated . Influenza C viruses seem to have a somewhat broader host range, with isolation of the virus from pigs and dogs . One can speculate that the influenza epidemics described before the introduction of influenza A viruses into the human population in the 19th century may have been caused by infections with these viruses. Subsequent adaptation to the human host would then have resulted in the current situation: compared to influenza A, relatively little is known about the epidemiology of influenza B and especially influenza C. Influenza B viruses may cause influenza-like illness in humans during seasonal (winter) epidemics, with excess mortality in the elderly . They do circulate globally but less frequently than influenza A viruses and the disease they cause is generally milder than that caused by influenza A. In a sero-survey in Germany, only 1-2% of children up to 9 years had influenza B antibodies, increasing to 25% by the age of 18 years and to 70% among adults aged 30 years .
Relatively little data are available on influenza C virus infections in humans. They cause generally mild upper respiratory tract infections which usually present as a common cold. During a two-year survey in Japan, 20 strains of influenza C virus were isolated from 13,426 specimens. These isolates were recovered throughout the year. Most were obtained from children around the age of one year [63,64]. By early adulthood most people have acquired antibodies to influenza C. This implies that, although clinically not very relevant, influenza C infections are ubiquitous .
1. Shope RE. The etiology of swine influenza. Science 1931;73:214-215. [Medline]
2. Wright PF, Neumann G, Kawaoka Y. Orthomyxoviruses. In: Knipe DM, ed. Field’s Virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:1692-1727.
3. Strauss JH, Strauss EG. Family Orthomyxoviridae. In: Strauss JH, Strauss EG, eds. Viruses and Human Disease. London: Elsevier Academic Press publications; 2008:162-175.
4. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992;56:152-179. [Medline]
5. Bodewes R, Kreijtz JH, Rimmelzwaan GF. Yearly influenza vaccinations: a double-edged sword? Lancet Infect Dis 2009;9:784-788. [Medline]
6. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-186. [Medline]
7. Morens DM, Taubenberger JK, Fauci AS. The persistent legacy of the 1918 influenza virus. N Engl J Med 2009;361:225-229. [Medline]
8. Sauerbrei A, Schmidt-Ott R, Hoyer H, Wutzler P. Seroprevalence of influenza A and B in German infants and adolescents. Med Microbiol Immunol 2009;198:93-101. [Medline]
9. Yang Y, Sugimoto JD, Halloran ME, et al. The transmissibility and control of pandemic influenza A (H1N1) virus. Science 2009;326:729-733. [Medline]
10. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333-1340. [Medline]
11. Poehling KA, Edwards KM, Weinberg GA, et al; New Vaccine Surveillance Network. The underrecognized burden of influenza in young children. N Engl J Med 2006;355:31-40. [Medline]
12. Glezen WP, Paredes A, Taber LH. Influenza in children. Relationship to other respiratory agents. JAMA 1980;243:1345-1349. [Medline]
13. Jansen AG, Sanders EA, Hoes AW, van Loon AM, Hak E. Influenza- and respiratory syncytial virus-associated mortality and hospitalisations. Eur Respir J 2007;30:1158-1166. [Medline]
14. Finelli L, Fiore A, Dhara R, et al. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection. Pediatrics 2008;122:805-811. [Medline]
15. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. Pediatr Infect Dis J 1997;16:1065-1068. [Medline]
16. Ahmed R, Oldstone MB, Palese P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat Immunol 2007;8:1188-1193. [Medline]
17. Taubenberger JK, Morens DM. 1918 Influenza: the mother of all pandemics. Emerg Infect Dis 2006;12:15-22. [Medline]
18. Claas EC, Osterhaus AD, van Beek R, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 1998;351:472-477. [Medline]
19. Uyeki TM. Human infection with highly pathogenic avian influenza A (H5N1) virus: review of clinical issues. Clin Infect Dis 2009;49:279-290. [Medline]
20. Gambotto A, Barratt-Boyes SM, de Jong MD, Neumann G, Kawaoka Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet 2008;371:1464-1475. [Medline]
21. Shortridge KF, Zhou NN, Guan Y, et al. Characterization of avian H5N1 influenza viruses from poultry in Hong Kong. Virology 1998;252:331-342. [Medline]
22. Peiris JS, Yu WC, Leung CW, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004;363:617-619. [Medline]
23. WHO. http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_09_24/en/index.html. 2009 (Accessed November 23, 2009)
24. Katz JM, Lim W, Bridges CB, et al. Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J Infect Dis 1999;180:1763-1770. [Medline]
25. Chan PK. Outbreak of avian influenza A (H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002;34 Suppl 2:S58-S64. [Medline]
26. Vong S, Ly S, Van Kerkhove MD, et al. Risk factors associated with subclinical human infection with avian influenza A (H5N1) virus-- Cambodia, 2006. J Infect Dis 2009;199:1744-1752. [Medline]
27. Arabi Y, Gomersall CD, Ahmed QA, Boynton BR, Memish ZA. The critically ill avian influenza A (H5N1) patient. Crit Care Med 2007;35:1397-1403. [Medline]
28. Ungchusak K, Auewarakul P, Dowell SF, et al. Probable personto- person transmission of avian influenza A (H5N1). N Engl J Med 2005;352:333-340. [Medline]
29. Buxton Bridges C, Katz JM, Seto WH, et al. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 2000;181:344-348. [Medline]
30. Meijer A, Bosman A, van de Kamp EE, Wilbrink B, Du Ry van Beest Holle M, Koopmans M. Measurement of antibodies to avian influenza virus A (H7N7) in humans by hemagglutination inhibition test. J Virol Methods 2006;132:113-120. [Medline]
31. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. 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 2004;101:1356-1361. [Medline]
32. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature 2005;437:889-893. [Medline]
33. Potter CW. A history of influenza. J Appl Microbiol 2001;91:572-579. [Medline]
34. Gatherer D. The 2009 H1N1 influenza outbreak in its historical context. J Clin Virol 2009;45:174-178. [Medline]
35. Beveridge WI. The chronicle of influenza epidemics. Hist Philos Life Sci 1991;13:223-234. [Medline]
36. Gibbs MJ, Gibbs AJ. Molecular virology: was the 1918 pandemic caused by a bird flu? Nature 2006;440:E8; discussion E9-10. [Medline]
37. Antonovics J, Hood ME, Baker CH. Molecular virology: was the 1918 flu avian in origin? Nature 2006;440:E9; discussion E9-10. [Medline]
38. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918-1920 “Spanish” influenza pandemic. Bull Hist Med 2002;76:105-115. [Medline]
39. Reid AH, Taubenberger JK, Fanning TG. Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus. Nat Rev Microbiol 2004;2:909-914. [Medline]
40. Starr I. Influenza in 1918: recollections of the epidemic in Philadelphia. Ann Intern Med 1976;85:516-518. [Medline]
41. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53-60. [Medline]
42. Langford C. The age pattern of mortality in the 1918-19 influenza pandemic: an attempted explanation based on data for England and Wales. Med Hist 2002;46:1-20. [Medline]
43. Feigin RD, Cherry J, Demmler-Harrison GJ, Kaplan SL. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia: W.B. Saunders; 2004.
44. Stadler K, Masignani V, Eickmann M, et al. SARS–beginning to understand a new virus. Nat Rev Microbiol 2003;1:209-218. [Medline]
45. Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009;325:197-201. [Medline]
46. Kilbourne ED. Influenza pandemics of the 20th century. Emerg Infect Dis 2006;12:9-14. [Medline]
47. Dawood FS, Jain S, Finelli L, et al; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swineorigin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-2615. [Medline]
48. Smith GJ, Vijaykrishna D, Bahl J, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009;459:1122-1125. [Medline]
49. Itoh Y, Shinya K, Kiso M, et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 2009;460:1021-1025. [Medline]
50. Fraser C, Donnelly CA, Cauchemez S, et al. Pandemic potential of a strain of influenza A (H1N1): early findings. Science 2009;324:1557-1561. [Medline]
51. WHO. Pandemic (H1N1) 2009 - update 76. http://www.who.int/csr/don/2009_11_27a/en/index.html. 2009 (Accessed November 28, 2009).
52. Hancock K, Veguilla V, Lu X, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med 2009;361:1945-1952. [Medline]
53. Vaillant L, La Ruche G, Tarantola A, Barboza P; Epidemic Intelligence Team at InVS. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill 2009;14:pii:19309. [Medline]
54. Chowell G, Bertozzi SM, Colchero MA, et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med 2009;361:674-679. [Medline]
55. La Ruche G, Tarantola A, Barboza P, Vaillant L, Gueguen J, Gastellu-Etchegorry M; Epidemic Intelligence Team at InVS. The 2009 pandemic H1N1 influenza and indigenous populations of the Americas and the Pacific. Euro Surveill 2009;14:pii:19366. [Medline]
56. ECDC. http://www.ecdc.europa.eu/en/healthtopics/Documents/091127_Influenza_AH1N1_Situation_Report_0900hrs.pdf. 2009 (Accessed November 27, 2009)
57. Davies A, Jones D, Bailey M, et al; Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal Membrane Oxygenation for 2009 Influenza A (H1N1) Acute Respiratory Distress Syndrome. JAMA 2009;302:1888-1895. [Medline]
58. Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A (H1N1) infection in Canada. JAMA 2009;302:1872-1879. [Medline]
59. Dominguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza A (H1N1) in Mexico. JAMA 2009;302:1880-1887. [Medline]
60. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009;361:1935-1944. [Medline]
61. WHO, Public health significance of virus mutation detected in Norway: Pandemic (H1N1) 2009 briefing note 17. http://www.who.int/csr/disease/swineflu/notes/briefing_20091120/en/index.html, 2009 (Accessed February 23, 2010)
62. Osterhaus AD. Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA. Influenza B virus in seals. Science 2000;288:1051-1053. [Medline]
63. Moriuchi H, Katsushima N, Nishimura H, Nakamura K, Numazaki Y. Community-acquired influenza C virus infection in children. J Pediatr 1991;118:235-238. [Medline]
64. O’Callaghan RJ, Gohd RS, Labat DD. Human antibody to influenza C virus: its age-related distribution and distinction from receptor analogs. Infect Immun 1980;30:500-505. [Medline]