Influenza Viruses

Antigenic Variation

Influenza A and B viruses contain a genome consisting of 8 single-stranded RNA segments. Minor changes within a subtype continually occur through point mutations during viral replication, particularly in the HA gene, and result in new influenza strains of the same HA type. This phenomenon, termed antigenic drift , occurs in both influenza A and B viruses. Variation in antigenic composition of influenza virus surface proteins occurs almost yearly, which confers a selective advantage to a new strain and contributes to annual epidemics. For this reason, the formulation of the influenza vaccine is reviewed each year and updated as needed.

Less frequent but more dramatic, major changes in virus subtype can occur, resulting in a new influenza A subtype to which most people have little to no immunity. This process is called antigenic shift and can occur through reassortment of viral gene segments when there is simultaneous infection by more than one strain of influenza in a single host, or by direct adaptation of an animal virus to a human host. Antigenic shift occurs in influenza A viruses, which have multiple avian and mammalian hosts acting as reservoirs for diverse strains.

Through the process of reassortment , potentially any of 18 HA and 11 NA proteins currently known to reside in influenza A viruses of nonhuman hosts could be introduced into humans, who may have little existing immunologic cross protection to emerging viruses. A global pandemic can result if an influenza A virus with a novel HA or NA enters a nonimmune human population and acquires the capacity for sustained and efficient transmission between people. Four major global pandemics have occurred since 1900: in 1918 caused by an influenza A(H1N1) virus, 1957 caused by an influenza A(H2N2) virus, 1968 caused by an influenza A(H3N2) virus, and 2009 caused by an influenza A virus designated A(H1N1)pdm09. The most severe pandemic in recorded history occurred in 1918, when the virus was estimated to have killed at least 50 million people. The 1918 pandemic virus was likely the result of direct adaptation of an avian influenza virus to the human host, rather than from reassortment. The 2009 pandemic virus stemmed from reassortment of genes from swine, avian, and human viruses ( Fig. 285.2 ). This resulted in the emergence of a novel influenza A(H1N1)pdm09 virus that spread quickly from North America across the globe and replaced the previously circulating seasonal H1N1 viruses.

Several novel influenza viruses, all originating in animals, have also caused outbreaks of human infections. Avian influenza A(H5N1), a virulent avian influenza virus that was first identified in 1997, has caused more than 800 documented cases in 16 countries, with a mortality rate over 50%. Another novel avian influenza, A(H7N9) virus, has caused more than 1,300 documented cases and also appears highly virulent. This virus first caused an outbreak of human infections in China during the spring of 2013, with annual epidemics in China occurring in subsequent years. During the first 4 yearly epidemics, infection was fatal in approximately 40% of documented cases.

In addition, novel influenza A variant viruses have caused human infections ( Table 285.1 ). These include H3N2v viruses, which caused 372 confirmed human infections in the United States from 2011 to 2016 and were primarily transmitted through swine contact at agricultural fairs. Influenza viruses that normally circulate in swine are designated variant (“v”) viruses when detected in humans, and H3N2v and other variant viruses, including H1N1v and H1N2v, have sporadically infected humans. In contrast to avian influenza A(H5N1) and A(H7N9) viruses, variant viruses generally cause mild illness and have been primarily detected in children. However, none of these viruses has exhibited sustained, efficient human-to-human transmission.

Seasonal Influenza

An estimated 11,000-45,000 children younger than 18 yr of age are hospitalized annually in the United States as a result of seasonal influenza-associated complications, with approximately 6,000-26,000 hospitalizations in children younger than 5 yr of age. Since 2004, the annual number of reported influenza-associated pediatric deaths in the United States has ranged from 37 to 171 during regular influenza seasons (358 were reported to have occurred during the 2009 H1N1 pandemic). Influenza disproportionately affects children with specific chronic conditions, such as underlying pulmonary, cardiac, or neurologic and neuromuscular disorders. Very young children, especially those younger than 2 yr of age, and children with chronic medical conditions are more likely to develop severe influenza-related complications, including viral and bacterial pneumonia, hospitalization, respiratory failure, and death. However, while children with underlying medical conditions are at higher risk of complications, many healthy children are hospitalized with influenza, and nearly half of pediatric influenza-associated deaths are in children that have no known underlying medical condition.

Influenza also causes a substantial burden of disease in outpatient settings. It contributes to an estimated 600,000 to 2,500,000 outpatient medical visits annually in children younger than 5 yr of age, and has been identified in 10–25% of outpatient visits among all children with respiratory symptoms during influenza season. Influenza may also be underdiagnosed. Many who seek medical care for influenza do not have laboratory testing performed and do not receive a diagnosis of influenza. Every year, 3-4 influenza virus types or subtypes typically co-circulate, including influenza A(H3N2), influenza A(H1N1), and B viruses. Although 1 subtype usually predominates in any given season, it is difficult to predict which will be predominant. Thus, the influenza vaccine varies annually and contains 3 or 4 antigens representing the expected circulating types.