Background and Epidemiology

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 or fever caused by laboratory-confirmed influenza 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 (12, 29). 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 (19). 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 years (30). 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 (31).

Estimated rates of influenza-associated hospitalization generally are substantially higher among infants and children <5 years than among older children (12, 20, 29, 32-38). 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 (36). Estimates of influenza-related hospitalization rates for children with high-risk medical conditions are higher than for those without (20, 39, 40). 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) (34). 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 (39).

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 (24, 34, 41, 42). However, the absolute number of pediatric deaths varies from season to season (43). 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 (42) . 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 (41). 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 (43). 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 (44).

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 (45). Studies of worker vaccination have reported lower rates of ILI (46, 47), lost work time (46-49), and health care visits (47, 49) in association with vaccination as compared with no vaccine or placebo.

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 (50) as compared with typical influenza seasons. During the 2009 influenza A (H1N1) pandemic period (for the period April 2009 through May 1, 2010), the cumulative crude rates of LCI-related hospitalization for the Emerging Infections Program (EIP; www.cdc.gov/ncezid/dpei/eip/index.html) 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 (51). 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 (52).

Hospitalization rates during typical influenza seasons are 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) (22). 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 non-invasive 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) (53).

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 (17). 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 (27).

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). Case reports and some observational studies suggest that pregnancy increases the risk for hospitalization and serious maternal medical complications (56-58). Most of these studies have measured changes in excess hospitalizations or outpatient visits for respiratory illness during influenza season rather than LCI. 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% confidence interval [CI] = 5.0–12.5) among women with comorbidities and 5.1 (95% CI = 3.6–7.3) among those without comorbidities (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 (66).

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). 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 (71-73).

Influenza symptoms often include fever, which during pregnancy might be associated with neural tube defects and other adverse outcomes (74). 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) (75). A 2005 meta-analysis of fifteen observational studies noted an association between maternal fever and neural tube defects (76). Associations between maternal fever and congenital heart defects (77) and orofacial cleft (78) 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 (79).

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 (80). 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 (81). 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. 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 in for whom HIV is well-controlled (82-90).

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 (91-93). 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) (94). 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) (95). Conversely, a two-season study (2007–09) in the United States found no association between obesity and medically attended LCI, including both seasonal and pandemic virus circulation (96).

The 2009 pandemic also emphasized racial and ethnic disparities in the risk for influenza-related complications among adults, including higher rates of severe influenza illness among blacks and among American Indians/Alaska Natives and indigenous populations in other countries (97-102). 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 (101, 103). 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 (104).