Background and Epidemiology

Biology of Influenza

Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A and B viruses are further separated into subtypes (for A viruses) and lineages (for B viruses) on the basis of antigenic differences. Influenza A viruses are categorized into subtypes on the basis of characterization of two surface antigens: hemagglutinin (HA) and neuraminidase (NA). Influenza A(H1N1) viruses, influenza A(H3N2) viruses, and influenza B viruses co-circulate globally. New influenza virus variants emerge as a result of point mutations and recombination events that occur during viral replication, resulting in frequent antigenic change (i.e., antigenic drift) (1). Antibodies to  HA and NA reduce likelihood of infection (2). Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype (3). Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and necessitates consideration for adjustment of vaccine viruses each season.

Larger genetic changes, or antigenic shifts, can occur among influenza A viruses. Antigenic shifts occur less frequently than antigenic drift events, and generally arise though genetic reassortment. New or substantially different influenza A virus subtypes resulting from antigenic shifts have the potential to cause pandemics when they cause human illness because they might be transmitted efficiently from human to human in a sustained manner and because there is little or no preexisting immunity among humans (1). In April 2009, human infections with a novel influenza A(H1N1) virus caused a worldwide pandemic. This virus was antigenically distinct from human influenza A(H1N1) viruses in circulation from 1977 through spring 2009. The HA gene from this virus is related most closely to that of contemporary influenza A viruses circulating among pigs during several preceding decades. This HA gene is believed to have evolved from the avian-origin 1918 pandemic influenza A(H1N1) virus, and is thought to have entered human and swine populations at about the same time (4, 5).

Influenza B viruses are separated into two distinct genetic lineages (Yamagata and Victoria) but are not categorized into subtypes. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses (6). Influenza B viruses from both lineages have co-circulated during most influenza seasons since the 1980s (7, 8). The trivalent influenza vaccines available in recent seasons have contained one influenza B virus, representing only one lineage. The proportion of circulating influenza B viruses that are of the lineage represented in the vaccine has varied. For the 11 seasons from 2004–05 through 2015–16 (excluding the 2009 pandemic period, during which there was minimal influenza B activity), the more prevalent circulating B lineage was represented in the vaccine in eight seasons (CDC, unpublished data, 2016).

Burden of Influenza Illness

The exact timing of the onset, peak, and end of influenza activity vary, and cannot be predicted precisely from one season to the next.  In general, however, annual epidemics of influenza typically occur in the United States between October and April. Studies that report rates of clinical outcomes without laboratory confirmation of influenza (e.g., respiratory illness requiring hospitalization during influenza season) can be difficult to interpret because of coincident circulation of other respiratory pathogens (e.g., respiratory syncytial virus) (9). More precise estimates of burden are provided by surveillance studies based on laboratory-confirmed influenza (LCI) (10). However, increases in health care provider visits for acute febrile respiratory illness occur annually, coinciding with periods of increased influenza activity, making influenza-like illness (ILI) surveillance systems valuable in understanding the seasonal and geographic occurrence of influenza each year (11).

Persons of all age groups are susceptible to influenza. Incidence of influenza illness varies in different age groups, and is difficult to characterize precisely as not all cases are diagnosed. An estimated incidence of approximately 8% (varying from 3% to 11%) was derived through statistical extrapolation of U.S. hospitalization data and a meta-analysis of published literature (12). Data from the Influenza Incidence Surveillance Project (IISP) covering the 2009–10 through 2012–13 seasons revealed the highest rates of outpatient visits for influenza-positive ILI occurred among children aged 2 through 17 years (13). However, hospitalizations and deaths related to seasonal influenza are typically greatest among children aged <5 years (particularly those aged <2 years)(10, 14-18), persons aged ≥65 years (11, 19, 20), and persons of any age who have medical conditions that confer increased risk for complications from influenza (20-22).

In typical influenza seasons, increases in deaths and hospitalizations are observed during periods when influenza viruses are circulating. Although not all excess events occurring during these periods can be attributed to influenza, these estimates are useful for following season-to-season trends in influenza-associated outcomes. Estimates that include only outcomes attributed to pneumonia and influenza (P&I) likely underestimate the burden of severe illnesses that are at least partly attributable to influenza, because this category excludes deaths caused by exacerbations of underlying cardiac and pulmonary conditions that are associated with influenza infection (23-25). Thus, some authors use the broader category of respiratory and circulatory excess events for influenza burden estimates. During the 1979–80 through 2000–01 seasons, the estimated annual overall number of influenza-associated hospitalizations in the United States ranged from approximately 55,000 to 431,000 per annual epidemic, with a mean of 226,000 (24). Between the 1976–77 and the 2006–07 influenza season, estimated annual deaths in the United States attributable to influenza ranged from 3,349 to 48,614 each season (19). A subsequent modeling analysis of population-based surveillance data for seasons following the 2009 pandemic (2010–11 through 2012–13) estimated that influenza was associated with 114,018—633,001 hospitalizations, 18,476–96,667 intensive care unit (ICU) admissions, and 4,866–27,810 deaths per year (26).  An estimated 54%–70% of hospitalizations and 71%–85% of deaths occurred among adults aged ≥65 years.  This model used a multiplier method to correct for under-detection in hospitalizations attributable to cases for which influenza testing was not performed and for insufficient test sensitivity.Using similar methodology, estimates for the 2016-17 season were 30.9 million influenza illnesses, 14.5 million influenza-related medical visits, and 600,000 influenza-related hospitalizations (27).

Influenza is an important cause of outpatient medical visits and hospitalizations among young children. In a long-term population-based retrospective cohort study conducted in three metropolitan areas (Nashville, Rochester, and Cincinnati), hospitalization rates for children aged <5 years with acute respiratory illness (ARI) or LCI-associated fever averaged 0.9 per 1000 (range 0.4-1.5) for seasons 2000-01 through 2003-04 and 0.58 per 1000 (range 0.36 to 0.97) for the seasons 2004-05 through 2008-09 (10, 16). In a retrospective cohort study of children aged <15 years over 19 seasons (1974–75 through 1992–93), an estimated average of 6–15 additional outpatient visits and 3–9 additional antibiotic courses per 100 children per season were attributed to influenza (28). During 1993–2004 in the Boston area, the rate of ED visits for respiratory illness attributed to influenza based on viral surveillance data among children aged 6 months–7 years during the winter respiratory illness season ranged from 22.1 per 1,000 children aged 6–23 months to 5.4 per 1,000 children aged 5–7 year (29). In a study conducted in a single county in Tennessee during the 2000–01 through 2010–11 seasons, estimated rates of influenza-related hospitalizations among children aged 6 through 59 months varied from 1.9 to 16 per 10,000 children per year; estimated rates of emergency department visits ranged from 89 to 620 per 10,000 children per year (30).

Estimated rates of influenza-associated hospitalization generally are substantially higher among infants and children <5 years than among older children (10, 14, 16-18, 31-34). During 1993–2008, estimated annual rates of influenza-associated hospitalizations were 151.0 per 100,000 among children aged <1 years and 38.8 per 100,000 among children aged 1–4 years, compared with 16.8 per 100,000 among persons aged 5 through 49 years (32). Estimates of influenza-related hospitalization rates for children with high-risk medical conditions are higher than for those without (14, 18, 32, 35, 36). In a study of children in 3 U.S. cities of children hospitalized with confirmed influenza infection, length of stay was longer for those with high-risk conditions than for healthy children of the same age (4.7 vs. 3.0 days for those aged 6 through 23 months; 5.8 vs. 3.6 days for those aged 2 through 17 years) (18). Thirty-seven percent had an ACIP-defined high-risk condition; the most common high-risk conditions were asthma (45%), followed by neurological (23%), cardiovascular (21%), metabolic and immunosuppressive disorders (7% each). In another study, asthma was associated with 23% of the influenza hospitalizations and 15% of the outpatient visits (35).

Estimates of influenza mortality rates for children based on pneumonia and influenza diagnoses, respiratory and circulatory diagnoses, or confirmed influenza have generally been low, <1 per 100,000 person-years (18, 23, 37, 38). However, the absolute number of pediatric deaths varies from season to season (39). Moreover, it is important to note that these deaths often occur in children with no other risk factors for severe influenza illness. In one study of the 2003-04 season, nearly half occurred in previously healthy children (37). In the United States, death associated with laboratory-confirmed influenza (LCI) among children aged <18 years has been a nationally reportable condition since October 2004 (38). Since reporting began, the annual number of reported influenza-associated pediatric deaths during regular influenza seasons has ranged from 37 deaths in the 2011-12 season to a high of 171 in 2012-13 (39). A larger number of deaths were reported during the 2009 pandemic, for which 358 pediatric deaths were reported to CDC from April 15, 2009 through October 2, 2010 (40).

Among healthy younger adults, illness caused by seasonal influenza is typically less severe and results less frequently in hospitalization, as compared with children aged <5 years, adults aged ≥65 years, pregnant women, or persons with chronic medical conditions. However, influenza is an important cause of outpatient medical visits and worker absenteeism among healthy adults. In one economic modeling analysis, the average annual burden of seasonal influenza among adults aged 18–49 years without medical conditions that confer a higher risk for influenza complications was estimated to include approximately 5.2 million illnesses, 2.4 million outpatient visits, 31,800 hospitalizations, and 684 deaths (41). Studies of worker vaccination have reported lower rates of ILI (42, 43), lost work time (42-45), and health care visits (43, 45) in association with vaccination as compared with no vaccine or placebo.  Influenza may be associated with greater workplace productivity losses among working adults than acute respiratory infections caused by other pathogens (46).

During the 2009 influenza A(H1N1)pdm09 pandemic (2009[H1N1] pandemic), adults aged <65 years appeared to be at higher risk for influenza-related hospitalizations and deaths (47) as compared with typical influenza seasons. During the 2009 influenza A (H1N1) pandemic period (April 2009 through May 1, 2010), the cumulative crude rates of LCI-related hospitalization for the Emerging Infections Program (EIP; sites were 3.0 per 10,000 persons aged 18–49 years, 3.8 per 10,000 persons aged 50–64 years, and 3.2 per 10,000 persons aged ≥65 years. During the previous three seasons, rates had ranged from 0.3–0.7 per 10.000 persons aged 18–49 years to 0.4–1.5 per 10.000 persons aged 50–64 years and 1.4–7.5 per 10.000 persons aged ≥65 years (48). Adults aged 50–64 years had the highest mortality rate during the 2009 pandemic. This group was again severely affected during the 2013–14 season when H1N1pdm09 was the predominant virus, sustaining higher hospitalization rates than in previous seasons since the pandemic (49).

Hospitalization rates during typical influenza seasons are generally highest for adults aged ≥65 years. One retrospective analysis of data from three managed-care organizations collected during 1996–97 through 1999–2000 estimated that the risk during influenza season among persons aged ≥65 years with high-risk underlying medical conditions was 55.6 pneumonia and influenza-associated hospitalizations per 10,000 persons, compared with 18.7 per 10,000 among lower risk persons in this age group. Persons aged 50–64 years who had underlying medical conditions also were at substantially increased risk for hospitalization during influenza season compared with healthy adults aged 50–64 years (12.3 versus 1.8 per 10,000 person-periods) (20). In a retrospective study of adults hospitalized with laboratory-confirmed influenza during the 2014-15 season, when compared with patients under 80 years of age, patients aged 80 years or older had a lower glomerular filtration rate (mean: 49.7 mL/min vs. 62.2 mL/min; p=0.006), a greater need for noninvasive mechanical ventilation (22% vs 9%; p=0.02), greater co-morbidity due to cardiac insufficiency (40% vs. 16%; p<0.001) and/or chronic renal disease (32.9 vs. 20%, p=0.03), and elevated mortality (19% vs. 3%; p<0.001) (50).

Deaths associated with influenza are most frequent among older adults. From the 1976-77 through 2006-07 seasons, an estimated yearly average of 21,098 influenza-related deaths occurred among adults aged ≥65 years, corresponding to 90% of estimated annual average deaths across all age groups (19). In comparison, the average annual mortality was estimated to be 124 deaths among persons aged <19 years and 2,385 deaths among persons aged 19–64 years. In a later modeling analysis of population-based surveillance data covering the 2010–11 through the 2012–13 seasons, an estimated 71%–85% of deaths occurred among adults aged ≥65 years (26).

Some studies have noted an association between influenza infection and acute vascular events, particularly for older adults.  A self-controlled case series analysis of 364 hospitalizations for myocardial infarction found an increased risk for myocardial infarction within 7 days of detection of influenza (IRR=6.05, 95%CI 3.86—9.50 for all influenza; IRR=10.11, 95%CI 4.37—23.38 for influenza B, and IRR=5.17, 95%CI 3.02—8.84 for influenza A) (51).  A self-controlled case series analysis of the United Kingdom Myocardial Ischaemia National Audit Project and the General Practice Research Database found that the risk of acute myocardial infarction was significantly higher 1-3 days after the onset of an acute respiratory infection (incidence ratio=4.19, 95%CI 3.18—5.53). This effect was greatest among those aged ≥80 years (52). In an analysis of hospitalization data, admissions for myocardial infarction and stroke among persons aged ≥75 years were correlated with circulation of influenza (53).

Pregnant women are vulnerable to severe symptoms and illness attributable to influenza. Physiologic changes associated with pregnancy, such as altered cardiopulmonary mechanics and changes in cell-mediated immunity, might contribute to enhanced susceptibility (54). In a case-cohort study of 1,873 pregnant women conducted over the 2010–11 and 2011–12 seasons, among 292 women with acute respiratory illnesses, those with influenza reported greater symptom severity than those with non-influenza acute respiratory illness (55). Two observational studies which measured changes in excess hospitalizations or outpatient visits for respiratory illness during influenza season rather than LCI noted that pregnancy increased the risk for hospitalization and serious maternal medical complications (56, 57). A retrospective cohort study of pregnant women conducted in Nova Scotia during 1990–2002 compared medical record data for 134,188 pregnant women to data from the same women during the year before pregnancy. During the influenza seasons, the rate ratio of hospital admissions during the third trimester compared with admissions in the year before pregnancy was 7.9 (95%CI 5.0–12.5) among women with comorbidities and 5.1 (95%CI 3.6–7.3) among those without comorbidities (57).  A systematic review and meta-analysis of observational studies concluded that influenza infection during pregnancy was associated with an increased risk for hospitalization relative to infection in non-pregnant individuals (OR=2.44, 95%CI 1.22—4.87), but not for death (58).

Increased severity of influenza among pregnant women was reported during the pandemics of 1918–19, 1957–58, and 2009–10 (59-64). During the 2009(H1N1) pandemic, severe infections among postpartum (delivered within previous 2 weeks) women also were observed (60, 63, 65). In a case series conducted during the 2009(H1N1) pandemic, 56 deaths were reported among 280 pregnant women admitted to intensive care units. Among U.S. deaths due to pandemic influenza reported to CDC, five percent of all US deaths from pandemic influenza involved pregnant women, even though they represented <1% of the population (66, 67). Among the deaths, 36 (64%) occurred in the third trimester. Pregnant women who were treated with neuraminidase inhibitor antivirals >4 days after symptom onset were more likely to be admitted to an intensive care unit (57% versus 9%; relative risk [RR]=6.0, 95%CI 3.5–10.6) than those treated within 2 days after symptom onset (67).

Some studies of pregnancy outcomes have suggested increased risk for pregnancy complications attributable to maternal influenza illness; others have not. A review of data from the National Inpatient Sample (a publically available hospital discharge database; covering the 1998–99 through the 2001–02 seasons and including over 6.2 million hospitalizations of pregnant women, reported increased risk for fetal distress, preterm labor, and cesarean delivery among those women with respiratory illness during influenza seasons, compared with women without respiratory illness (68). A study of 117,347 pregnancies in Norway during the 2009–10 pandemic noted an increased risk for fetal death among pregnant women with a clinical diagnosis of influenza (adjusted hazard ratio [aHR]=1.91; 95%CI 1.07–3.41) (69). A cohort study conducted among 221 hospitals in the United Kingdom observed an increased risk for perinatal death, stillbirth, and preterm birth among women admitted with confirmed 2009(H1N1) infection (70). In a retrospective cohort study of 86,779 pregnancies in which 192 cases of LCI were identified during the 2012-14 and 2013-14 seasons, women infected during the first trimester had a significantly lower mean gestation than uninfected women (38 vs. 39 weeks).  The infants of those infected with influenza B had a 4% lower mean percent of optimal weight (71). However, other studies of infants born to women with LCI during pregnancy have not shown higher rates of prematurity, preterm labor, low birth weight, or lower Apgar scores compared with infants born to uninfected women (72-74).

Influenza symptoms often include fever, which during pregnancy might be associated with neural tube defects and other adverse outcomes (75). A meta-analysis of 22 observational studies of congenital anomalies following influenza exposure during the first trimester of pregnancy noted associations with several types of congenital anomalies, including neural tube defects, hydrocephaly, heart and aortic valve defects, digestive system defects, cleft lip, and limb reduction defects. However, many of the included studies were conducted during the 1950s through 1970s, and a nonspecific definition of influenza exposure was used (any reported influenza, ILI, or fever with influenza, with or without serological or clinical confirmation) (76). A 2005 meta-analysis of fifteen observational studies noted an association between maternal fever and neural tube defects (77). Associations between maternal fever and congenital heart defects (78) and orofacial cleft (79) have been reported in some studies; in one study of congenital anomalies such as orofacial clefts, congenital heart defects, and omphalocele, the association with maternal fever was ameliorated among those mothers who had taken multivitamins (80).

In the first U.S. recommendations for annual influenza vaccination of the civilian population, published by the Surgeon General in 1960, persons with “chronic debilitating diseases” (particularly cardiovascular disease, pulmonary disease, and diabetes) were cited as being among the groups contributing most to the excess deaths observed during the 1957 influenza pandemic (81). In a study of 4,756 adults hospitalized with influenza from October 2005 through April 2008, characteristics significantly associated with pneumonia included underlying chronic lung disease and immunosuppression. Among patients with pneumonia, patients with a poor outcome (defined as ICU admission, need for mechanical ventilation, or death) were more likely to be affected by chronic lung disease, cardiovascular disease, renal disease, or immunosuppression (82). While some observational studies (mostly conducted prior to the widespread use of highly effective antiretroviral therapy) noted increased likelihood of severe influenza illness among persons with HIV infection, more recent studies indicate that there may be no increased risk of severe disease among persons whose HIV is well-controlled (83-88).

Prior to the 2009 pandemic, obesity had not been recognized as a risk factor for severe influenza illness. However, several studies during the 2009 pandemic noted a high prevalence of obesity among persons with severe illness attributable to A(H1N1)pdm09 (89-91). In a case-cohort study, among persons aged ≥20 years, hospitalization with illness attributable to laboratory-confirmed influenza A(H1N1)pdm09 was associated with extreme obesity (body mass index [BMI] ≥40) even in the absence of other risk factors for severe illness (odds ratio [OR]=4.7; 95%CI 1.3–17.2) (92). Death was associated with both obesity, defined as BMI ≥30 (OR=3.1; 95%CI 1.5–6.6) and extreme obesity (OR=7.6; 95%CI 2.1–27.9). A Canadian cohort study covering 12 seasons (1996–97 through 2007–08) found that persons with a BMI of 30.0–34.9 and those with a BMI ≥35 were more likely than normal-weight persons to have a respiratory hospitalization during influenza seasons (OR=1.45; 95%CI 1.03–2.05 for BMI 30–34.9 and OR=2.12; 95%CI 1.45– 3.10 for BMI ≥35) (93). A retrospective cohort study of Australian national health insurance data between 2006 and 2015 found that compared to adults with a healthy BMI, those with a BMI of 30 to <40 had a higher risk of hospital admission (aHR=1.57, 95%CI 1.22–2.01); those with a BMI of ≥40 had an even higher risk (aHR=4.81, 95%CI 3.23—7.17).  Conversely, a two-season prospective cohort study (2007–09) in the United States found no association between obesity and medically attended LCI, including both seasonal and pandemic virus circulation (94).

During the 2009 pandemic, racial and ethnic disparities in the risk for influenza-related complications among adults were noted, including higher rates of severe influenza illness among blacks and among American Indians/Alaska Natives and indigenous populations in other countries (95-100). These disparities might be attributable in part to the higher prevalence of underlying medical conditions or disparities in medical care among these racial/ethnic groups (99, 101). A more recent case-control study of risk factors for death from 2009 pandemic influenza that adjusted for factors such as pre-existing medical conditions, barriers to health care access, and delayed receipt of antivirals found that American Indian/Alaska Native status was not independently associated with death (102).