Over 3 influenza seasons, 290 (64%) of 454 eligible cases and 1089 (49%) of 2204 eligible controls were enrolled from 9 states after parental consent was obtained (Table 1). Among all children enrolled, 191 (14%) were enrolled in 2005–2006, 439 (32%) in 2006–2007 and 749 (54%) in 2007–2008. The median age was 20 months (range 6.01–59.6); 60% were 6–23 months of age and 40% were 24–59 months of age. The number of cases enrolled in each season by week of hospital admission is shown in Figure 2. The most common influenza diagnostic tests used to confirm influenza infection included rapid diagnostic test (57%), immunofluorescence antibody staining (29%), viral culture (7%) and reverse transcription polymerase chain reaction (4%). The mean time between each case’s hospital admission date and the positive influenza test result was 1.4 hours (standard deviation ± 26.2). The median number of days from case admission to case and control interviews was 53.5 (range 7–148) and 113.5 (range 15–278), respectively. Enrolled cases were slightly older than eligible cases who were not enrolled (mean age: 24 vs. 20 months; P = 0.003) and more likely to be white than non-white (56% vs. 28%; P < 0.001), but no significant differences by sex, black race or Hispanic ethnicity, length of hospitalization or number of medical conditions were found.

Children who were male, of Hispanic ethnicity, black race or low birth weight were at increased risk of hospitalization with laboratory-confirmed influenza (Table 2). Children who were never breast-fed were also at increased risk, but whether the child was breast-fed during the reference period or not was not significant (data not shown). Breast-feeding for ≥6 months was protective among infants, reducing risk of hospitalization by ≥50%, compared with never being breast-fed. Not having private insurance and not being fully vaccinated for influenza were also identified as risk factors for hospital admission with influenza.

Daycare attendance was not a risk factor for hospital admission with influenza. The number of hours per week in daycare, daycare attendance during the reference period, duration of time spent in daycare before the reference period and the number of children in the same room with the child in daycare were not associated with admission (data not shown). Data on sibling daycare attendance were not collected.

Detailed information on the prevalence of chronic underlying medical conditions among study participants is presented in Table 3. Having 1 or more chronic illnesses was a risk factor for hospitalization (Table 2) and pulmonary, hematologic/oncologic and neurologic conditions were identified as statistically significant risk factors. Although most children with any chronic illness had only 1 condition, the risk of hospitalization increased 17-fold if the child had >1 underlying medical conditions compared with none.

Caregiver and household characteristics associated with an increased risk of hospitalization are listed in Table 4. Having a mother or caregiver <26 years of age was a risk factor compared with a reference group 26–35 years of age, and having a caregiver ≥36 years of age old was protective. Having a caregiver with less than some college attendance and living in a non-single family home were identified as risk factors. A household crowding index greater than the median (0.75), having >1 person/bedroom in the household or ≥2 children sleeping in the same bedroom with the study child were risk factors. Although the absolute number of smokers in the household was not an identified risk factor, having a high proportion of persons living in the household who reported smoking (>50%) was. Very few household members reported smoking inside the home (data not shown). Influenza vaccination of any household member decreased the risk of hospitalization. Household income <2 times the poverty threshold increased the risk of hospitalization, and this risk increased substantially as household income decreased to below the poverty threshold.

In multivariable analyses, factors associated with influenza hospitalization were identified in a main effects model (Table 5). A final multivariable model including an interaction term between child age and child influenza immunization status was constructed (Table 6). Independent factors associated with influenza hospitalization included: maternal age <26 years, household income below the poverty threshold, the presence of specific chronic illnesses (including hematologic or oncologic, pulmonary and neurologic conditions), lack of a household member being vaccinated for influenza and >50% household members who reported smoking (Table 6). A significant interaction (P = 0.01) was identified between child age and child influenza immunization status (Table 6). Full immunization of the child for influenza decreased the risk of hospitalization among children 6–23 months of age [OR: 0.5, 95% confidence interval (CI): 0.3–0.9; P = 0.01], but not among children 24–59 months of age (OR: 1.5, 95% CI: 0.8–3.0; P = 0.24).

We identified a number of factors that increased the risk of hospitalization for influenza among children 6–59 months of age in the EIP population during 3 consecutive US influenza seasons. Maternal age <26 years, household income below the poverty threshold, lack of household member influenza vaccination and smoking by >50% of household members were identified as independent risk factors for hospitalization with laboratory-confirmed influenza. Consistent with prior studies,^7–9 specific chronic illnesses logically increased the risk for hospitalization with influenza. Among younger children, full immunization for influenza decreased the risk of hospitalization.

Our findings that several caregiver- and household-level factors increased the risk of an influenza-associated hospitalization were not unexpected. For example, an inverse relationship was demonstrated between maternal age and the risk of acute lower respiratory tract infection among children <59 months of age in a study conducted in Western Australia,¹⁶ and a US study found that maternal age <25 years was associated with increased risk of lower respiratory tract infection deaths among children <1 year of age.¹⁷ Young maternal age may increase the risk of hospitalization with influenza because younger mothers and their peers may have less experiential knowledge and/or less social support. Younger women also may be more susceptible to respiratory infections than older women¹⁸ and thus may be more likely to transmit influenza infections to their young children.

We collected data for several factors related to socioeconomic status, including household income, household crowding and receipt of Medicaid insurance. In other studies, a number of such indicators of low socioeconomic status have been identified as risk factors for hospitalization with common acute infectious diseases among young children. For example, receiving Medicaid insurance has been identified as risk factors among young children for hospitalization with rotavirus gastroenteritis.^19,20 In our analysis, only household income was identified as an independent risk factor for an influenza hospitalization, suggesting it may be a more encompassing predictor of risk than type of insurance. Low family income has been shown to increase the risk of lower respiratory tract infections, asthma attacks and respiratory-related hospitalizations among children²¹ and has been associated with worse outcomes in infants with respiratory syncytial virus infection.²² A recent study examining risks of hospitalization with 2009 H1N1 influenza found an inverse association between odds of hospitalization and neighborhood poverty among adults and children.²³ Of course, lower socioeconomic status is associated with other factors, including poor access to medical care because of lack of transportation and fewer general available resources, which might mediate this increased risk.²⁴

Smoking by the mother and other household members is known to increase the risk of infectious and noninfectious respiratory illness in children. In a recent meta-analysis,²⁵ exposure to smoking by any household member was associated with an OR of 1.5 for lower respiratory infections among children <2 years of age. Our findings are consistent with those of other studies and provide evidence that exposure to passive smoking specifically increases the risk of serious outcomes related to influenza infection.

Our finding that full immunization for influenza decreased the risk of hospitalization among younger children (6–23 months of age) but not among older children (24–59 months of age) was unexpected, but may be because of an unmeasured case ascertainment bias related to differences in health-seeking behavior. Advisory Committee on Immunization Practices recommendations for influenza vaccination were expanded during our study enrollment to include children in the older age group. It is possible that older children who received the vaccination in line with the new recommendations were more likely to have seen a physician in general and therefore more likely to seek medical attention for a respiratory illness and be identified as a case.

Neither child race nor ethnicity was associated with an increased risk for influenza hospitalization in our case-control study. Although racial disparities for hospitalization associated with acute respiratory illness including influenza have been reported,^26,27 it is likely that other data we collected in our study, including household income and the presence of specific chronic medical conditions, accounted for any greater risk of influenza hospitalization among select racial/ethnic groups. For example, other studies have found that black children have higher asthma prevalence,²⁸ black and Hispanic women have lower maternal age at first parity²⁹ and blacks and Hispanics have highest US poverty rates.³⁰ It also should be noted that our sample size of non-Caucasian children was small, and therefore it is unlikely that this study was powered to detect small differences in risk, especially after controlling for the factors mentioned above.

This study has several limitations. First, cases were identified by influenza laboratory tests ordered by clinicians and not through use of a standardized protocol. Therefore, our results may not be representative of all children hospitalized (but not necessarily diagnosed) with influenza. Second, the diagnostic tests used to diagnose influenza infection were of variable sensitivity and specificity. In particular, there is concern with the use of commercially available influenza antigen detection assays, as the sensitivity and specificity of these tests can be quite variable.^31,32 In the context of a case-control study, the specificity of the test used to provide laboratory confirmation of influenza infection in the cases is of great importance, as false positives can lead to substantial bias in the results.³² Third, because household member vaccination status was collected by self-report and not verified by physician records and because the date of household member vaccination was not collected, some household members may have reported incorrect information about their vaccination status and/or may have been vaccinated after the case was hospitalized. Fourth, recall bias may have affected parental responses to some questions; differential recall bias by case or control status is possible, as the controls as a group were interviewed later than cases were compared with the reference period. Fifth, selection bias is always a possibility in observational studies and may be of particular concern in case-control studies. Children eligible to be controls of higher socioeconomic status may have been easier to reach and enroll than other eligible controls, which would likely bias the strength of associations, especially for sociodemographic indicators, away from the null. However, it is also possible that case children of lower socioeconomic status were less likely to be enrolled if their caregivers were more difficult to reach because of lack of contact information or difficulty traveling to the hospital. As a lower proportion of controls were enrolled compared with cases, the potential for selection bias may be a greater concern among controls.

However, a strength of our study is that the eligible controls represented the true population from which the cases arose and included all children exposed to influenza viruses. Recently, a variation of traditional case-control study design known as the test negative design has become widely used in studies of influenza vaccine effectiveness. In such studies, all subjects are tested for influenza infection; cases are those testing positive and “controls” are those testing negative.^33,34 These studies are popular because they permit investigators to enroll cases and non-cases from only those persons tested for influenza. For example, in a study of risk factors for influenza-related hospitalizations, one would only enroll children tested in the hospital for influenza infection. Such studies do have limitations, however, and by not limiting control selection to children tested for influenza, we were able to evaluate factors that might lead children to have more intense exposure to influenza viruses (such as daycare attendance or household crowding) as well as factors potentially associated with more severe influenza infections (including chronic illnesses and having household members who smoke).

We found child, caregiver and household factors associated with hospitalization with influenza infection among young children eligible for influenza vaccination (ie, 6 months of age and older). Our findings that chronic illnesses, young maternal age, poverty, household smoking and lack of household member influenza vaccination increase the risk of an influenza hospitalization may help providers to identify young children at greatest risk for poor outcomes from influenza illness, including those for whom early interventions such as treatment with influenza antivirals is of paramount importance.

The authors acknowledge the following persons: Deborah Aragon and Becky Rosenblatt, Colorado Department of Public Health and Environment, Denver, CO; Meredith Vandermeer, MPH, Oregon Public Health Division, Portland, OR; Darcy Fazio, Kimberly Yousey-Hindes, MPH, CPH, and John Palumbo, MT (ASCP) MS, MBA, Connecticut Emerging Infections Program, New Haven, CT; Kyle Openo, Norisse Tellman, Olivia Almendares and Suzanne Segler, Georgia Emerging Infections Program, Atlanta, GA; Brenda Barnes, RN, Sandra Gray, RN, Terri McMinn and Katie Dyer, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN and Emily Hancock, New Mexico Department of Health, Santa Fe, NM.