Influenza

The Pathogen

Influenza viruses belong to the family Orthomyxoviridae and are divided into four types (A, B, C, and D) based on their protein composition and other properties ( E-Table 332-2 ). The virion ( E-Fig. 332-1 ) is a medium-sized enveloped pleomorphic particle covered with two types of surface glycoprotein spikes: the trimeric hemagglutinin (H or HA) and the tetrameric mushroom-shaped neuraminidase (N or NA). The envelope is composed of a lipid bilayer overlying the matrix (M1) protein that surrounds the viral genome, which consists of eight segments of single-stranded negative-sense RNA in influenza A and B viruses. Influenza C viruses have seven segments and only a single surface glycoprotein. Genomic replication occurs in the nucleus of infected cells, and multiple cellular proteins and pathways are involved during the infection of host cells.

Whereas influenza B and C viruses are principally human pathogens, influenza A viruses primarily infect aquatic birds and sometimes establish lineages that circulate in other animal hosts, including other avians, swine, horses, marine mammals, and dogs. Influenza D appears to be pathogenic in cattle and perhaps other domestic animals. Influenza A viruses are further classified into subtypes on the basis of their HA and NA glycoproteins. Sixteen HA and nine NA subtypes are currently recognized in avians, and two others are recognized in bats. Only three HAs (H1, H2, and H3) and two NAs (N1 and N2) have been documented thus far in epidemic and pandemic human influenza A viruses, although other HAs (e.g., H5, H6, H7, H9, H10) and NAs (e.g., N4, N7, N8, N9) have been found in zoonotic infections. Each strain is identified by type, subtype if influenza A, location of isolate, sample number, and year of isolation (e.g., A/California/04/2009 (H1N1)).

Antigenic and Genetic Variation

Influenza viruses are unique among the respiratory viruses with regard to their extent of genetic and antigenic variation, epidemic behavior, and frequent association with excess mortality during community outbreaks—characteristics and pathogenicity that exemplify human influenza virus’s efficient host-to-host transmissibility. The changing antigenicity of the surface glycoproteins largely accounts for repeated influenza epidemics. Antibody to HA can neutralize viral infectivity and is thus the major determinant of immunity. Current vaccines are based largely on inducing hemagglutination-inhibition (HAI) or neutralizing antibodies to HA. Anti-NA antibody limits viral replication and probably reduces the severity of infection. Variation involves either relatively minor (antigenic drift) or major (antigenic shift) changes in antigenicity. Significant antigenic variation is much less frequent with influenza B or C than with influenza A.

Antigenic drift results from point mutations in the HA gene segment that cause amino acid substitutions in at least one of five key antigenic sites on HA. Drift can also occur in NA and in T-cell epitopes on internal proteins. Antigenic variants emerge frequently (every year or every few years) within an influenza A or B virus. For example, the original H3N2 variant, A/Aichi/68, has undergone successive drifts resulting in epidemic strains that include the recent circulation of A/Kansas/14/2017 (H3N2)-like virus. Immunologic selection favors transmission of the new variant over the old because of the less frequent presence of antibody to the new virus in the population.

Antigenic shift results from the appearance of a novel influenza A virus with HA, NA, or both HA and NA glycoproteins that are new to humans or that reappear after decades of absence. Because of the lack of population immunity, a new strain that is efficiently transmitted from person to person can cause pandemic disease. The origins of new pandemic strains and the basis for their subsequent seasonal circulation remain incompletely understood. Avian influenza viruses have most frequently served as the reservoir of new genes for pandemic viruses. Reassortment of gene segments may occur when two influenza viruses simultaneously infect a single cell and in reassortment events in which human viruses acquired avian genes led to both the 1957 and 1968 pandemic viruses. Because swine can support replication of both human and avian viruses, they have been postulated to serve as a mixing vessel for the generation of new strains or as the host in which avian viruses can adapt to mammals. The 2009 H1N1 pandemic virus arose as a quadruple reassortant that derived gene segments from Asian and North American swine lineage viruses that harbored genes derived from swine, avian, and human viruses.

Multiple reassortment events may occur over a period of years before a pandemic virus emerges. For example, the 1918 pandemic virus appears to have been composed primarily of avian genes that underwent adaptation in a mammalian host before causing the pandemic. Frequent intra-subtypic reassortment also occurs among seasonal human influenza A viruses and sometimes leads to new antigenic variants and sometimes to altered virulence.

Epidemic or Interpandemic Influenza

An epidemic is an outbreak of influenza confined to one geographic location. In temperate climates, community epidemics of influenza A virus infection often have a characteristic pattern, typically reaching a sharp peak in 2 or 3 weeks after initial recognition and persisting for 6 to 10 weeks. Increased numbers of schoolchildren with febrile respiratory illness are often the first indication of influenza in a community, soon followed by illnesses in adults and, 1 to 2 weeks later, by increased hospital admission of patients with influenza-related complications. Hospitalization rates in high-risk persons increase two- to five-fold during major epidemics. School and employment absenteeism increases, as does mortality from pneumonia and underlying conditions, especially in older adults during A/H3N2 epidemics. Epidemics occur almost exclusively during the late autumn and winter months in temperate areas, but activity may extend into spring months. Because of the seasonal differences between northern and southern hemispheres, seasons cycle between the hemispheres. Influenza activity may occur year-round in the tropics or display other patterns. The reasons for the distinct seasonality of influenza in temperate climates are uncertain but may include the school calendar, increased close indoor contact, and low absolute humidity, which affects airborne transmissibility. Winter holidays delay the peaks of seasonal epidemics and shift the risk of infection toward adults. Outbreaks sometimes occur in tour groups (land or ship) and in chronic care facilities during summer months, particularly after the appearance of a drift variant. Regional differences in the timing, magnitude, and causative viruses of influenza outbreaks are common. During epidemics, overall attack rates typically range from 5 to 20% in adults. Attack rates of 40 to 50% may occur in semiclosed populations, such as on hospital floors and chronic care facilities, as well as in highly susceptible age groups such as children. Influenza A and B viruses, two different influenza A subtypes, two different influenza B lineages, or two different strains within a single subtype may co-circulate or occur sequentially during one season in a given location. In addition, simultaneous outbreaks of influenza A virus and RSV or other respiratory viruses occur. Strains circulating at the end of one season’s epidemic are sometimes responsible for the next season’s outbreak (the so-called herald wave phenomenon).

Pneumonia- and influenza-related deaths fluctuate annually, with peaks in the winter months in temperate climates. When such deaths exceed the expected threshold, the cause is typically influenza A, but influenza B virus or RSV can occasionally be responsible. Influenza A/H3N2-dominant seasons are associated with two to three times higher mortality rates than are nonpandemic H1N1- and B-dominant seasons. Although mortality is usually greatest during pandemics, substantial mortality occurs with epidemics. During seasonal influenza, more than 85% of pneumonia- and influenza-related deaths occur in persons aged 65 years and older. Mortality risk is especially high in those aged 85 years and older. Cardiovascular events (e.g., myocardial infarction) and worsening of other chronic diseases (e.g., asthma, chronic obstructive pulmonary disease) contribute substantially to the increased mortality during influenza epidemics.

Pandemic Influenza

Pandemics of influenza A result from the emergence of a new virus capable of sustained person-to-person transmission and to which the population contains no or limited immunity. The virus spreads worldwide, often circulating outside of the usual influenza season, and usually infects persons of all ages. Preexisting immunity due to prior infection with antigenically related viruses can provide partial protection, as occurred in older adults during the 2009 H1N1 pandemic. Pandemics are associated with high morbidity rates, especially in children, and sometimes notably increased mortality rates in pregnant women and young and middle-aged adults. For example, more than 90% of deaths in the 1918 and 2009 pandemics occurred in persons younger than 65 years. In the 2009 pandemic, adults hospitalized with H1N1 were more likely to have severe pneumonia, shock, sepsis, and organ failure and to require intensive care unit (ICU) care than were patients with seasonal influenza.

The interval between pandemics is variable (10 to 40 years) and unpredictable. The most severe pandemics have been associated with major antigenic alterations in both major surface glycoproteins. Depending on population susceptibility and perhaps changes in the virus, one or more waves, sometimes with increased severity, may follow the initial one. As the level of immunity in the population increases, antigenic drift within the subtype may cause repeated epidemics in subsequent years, and excess mortality in persons younger than age 65 may continue for some years. For example, the pandemic 2009 H1N1 virus has continued to cause fatal infections at least 10 years after its initial emergence.

Zoonotic Influenza

Zoonotic infections may be acquired from swine, poultry, or rarely other animals. Although most avian influenza viruses do not cause infections directly in humans, zoonotic infections due to avian H5, H7, H9, and rarely other subtypes continue to cause outbreaks in regions where human and poultry live in close proximity (e.g., chicken farming, wet markets), thereby representing potential pandemic threats. Initially recognized by a cluster of human cases in Hong Kong in 1997, an epizootic of avian H5N1 infections has affected poultry in many areas of Asia, the Middle East, Europe, and Africa and continues to cause sporadic human illnesses with high mortality and occasional instances of nonsustained human-to-human transmission. From 2013 to 2017, repeated waves of zoonotic avian H7N9 infections have occurred during winter and early spring in China, with case-fatality rates of approximately 35% among hospitalized patients. This virus continues to evolve genetically, thereby leading to variants with altered antigenicity and increased virulence for birds and possibly humans.

In the United States infrequent zoonotic infections have been recognized for decades in people exposed to swine. Since 2012, reassortant swine H3N2 viruses that acquired the M gene and sometimes other genes from the pandemic 2009 H1N1 virus (designated variant H3N2, or H3N2v) have caused hundreds of sporadic infections, particularly in the context of agricultural fairs, sometimes followed by limited human-to-human transmission and serious infections. Other variant swine-origin viruses (H1N1v, H1N2v) have also caused zoonotic infections.