The cohort of households was derived from persons who had selected a primary health care provider from within the University of Michigan (UM) health system based in Ann Arbor Michigan; households were targeted for enrollment by direct mail [14]. Eligible households had at least four members, at least two of whom were children less than age 18 years. Adult household members provided written informed consent for participation for themselves and their children, and children age 7 to 17 years provided their oral assent. Enrollment and all follow-up activities took place at the research study site at the UM School of Public Health (UM-SPH). Health system medical records were reviewed to document the presence of health conditions considered high risk for complications of influenza [15]; electronic medical records and a statewide immunization registry were reviewed to document influenza vaccine receipt for the 2010-2011 season. Households were surveyed to collect information on household environmental factors, including crowding, humidification and exposure to tobacco smoke.

The study was reviewed and approved by the institutional review board at the University of Michigan Medical School.

Surveillance activities were carried out from October 2010 through April 2011. Households were sent weekly email or telephone reminders to report all acute respiratory illnesses defined by two or more of the following symptoms: cough, fever or feverishness, nasal congestion, chills, headache, body aches or sore throat. Subjects with symptomatic illness attended an illness visit at the research study site within 7 days of onset and had a throat swab (or nasal swab in children <7 years) collected for influenza virus identification. Subjects were contacted by telephone 4 to 6 days after the illness visit for collection of follow-up data.

Collected specimens were tested for influenza by means of RT-PCR using the SuperScript III Platinum One-Step Quantitative RT-PCR system® and an ABI 7500 RT-PCR system platform (Life Technologies). The primers and probes used were developed by the CDC Influenza Division, and designed for universal detection of influenza A and B, and subtype identification of influenza A viruses. Laboratory tests were performed in the investigators’ respiratory virus laboratory at the UM-SPH.

Households were characterized by size, composition and environment, and subjects by demographics, health history and vaccination status. Influenza illnesses were characterized by type/subtype, reported symptoms, whether medically-attended or treated with antiviral medications, and by quantification of viral shedding. Illness duration was calculated as time from illness onset to reported resolution of illness symptoms; duration of symptomatic illness was used as a proxy for duration of infectiousness [8], [16].

Influenza cases were classified as household index cases (community-acquired influenza) if they were not linked by transmission from another household member. A secondary household-acquired illness was defined by transmission link to a household index case (or co-index cases) if both cases were the same influenza type/subtype and influenza onset in the secondary case occurred from 1 to 7 days after illness onset in the index case. Secondary infection risks - the proportion of those exposed to index cases that are subsequently infected - were estimated overall and for each influenza type/subtype, and examined by household environment, characteristics of index and secondary cases including age and vaccination status, and with consideration of the specimen viral loads of index cases.

Households were considered to have influenza introduced if at least one household member had community-acquired influenza (index case). Household transmission of influenza was documented if at least one household member developed influenza following exposure to a household index case, as defined above. Influenza illnesses in a household differentiated by type/subtype or separated by more than 7 days were considered separate introductions to the household from the community.

The serial interval, the time (days) from onset of illness symptoms in index cases to onset of symptoms in transmission linked secondary cases, was calculated with all transmission considered secondary to the index case [13]. Mean serial intervals were estimated overall and for each influenza type/subtype; confidence intervals around estimates were calculated using bootstrap techniques with 1000 resamples [17].

Categorical data were analyzed by Chi-square test or when necessary, Fisher exact test; continuous values were analyzed using Wilcoxon rank sum tests or ANOVA tests when comparing values across more than two categories. Survival functions were estimated and compared by log-rank test in analyses examining time to illness resolution. Statistical analyses were conducted using SAS version 9.2 (SAS Institute, Cary, NC). A P-value <.05 was considered to indicate statistical significance. No correction for multiple testing was considered.

By enrollment closure in October 2010, 328 households with 1,441 participants were enrolled. Among enrolled subjects, 58% were children less than 18 years, 11% had high risk health conditions and 60% had documentation of influenza vaccine receipt for the 2010-11 season [14]. Participant characteristics and distributions of influenza outcomes are presented in Table 1.

Household size ranged from 4 to 9 members (mean 4.4, SD = 0.7); mean household age was 22 years (SD = 5.9, range 10 to 38 years). In 55% of households more than half of subjects had documented evidence of influenza vaccine receipt. Most (78%) households reported home humidification; less than 2% reported household exposure to tobacco smoke. Household crowding was estimated based on number of persons per room with values less than the household median (0.6) indicating less crowded conditions. Household characteristics and distributions of households with influenza introduced and transmission documented are presented in Table 2.

Influenza circulated locally between early January and early April 2011; the epidemic curve based on study surveillance is presented in Figure 1. During this period, 465 (32%) individuals from 193 (59%) households reported 605 acute respiratory illnesses and 580 (96%) specimens were collected. All specimens were tested for influenza viruses by RT-PCR and 130 (22%) were determined to be positive for influenza, including 59 (45%) type A (H3N2), 44 (34%) type B, 26 (20%) type A (H1N1)pdm09 and 1 (1%) type B/ type A (H1N1)pdm09 co-infection [14]. Antigenic testing was not performed on study specimens; however, all viral isolates assessed in another study conducted in the same community were considered antigenically similar to the vaccine strains [18].

Quantification of viral shedding was estimated based on cycle threshold (Ct) values from RT-PCR testing using previously established cut points [19]; 36 (28%) influenza positive specimens had high (Ct <25), 41 (32%) had medium (Ct 25–30) and 53 (41%) had low (Ct 31–39) viral loads. Ct values were correlated with time from illness onset to specimen collection with fewer (mean) days for those with higher viral loads (1.9 high, 2.2 medium, 2.5 low [P = .09]). The mean time from illness onset to specimen collection was 2.6 days for specimens testing negative for influenza, and 2.3 days for specimens testing positive for influenza (P = 0.12). Ct values did not significantly differ by virus type.

Subjects with laboratory-confirmed influenza were significantly more likely to report symptoms of fever, cough, chills, body aches (all P<.001) and fatigue (P = .043) than subjects with non-influenza acute respiratory illnesses, however, median illness duration was similar (8 vs. 9 days, P = 0.93). Forty-two (32%) influenza cases were medically-attended based on medical record review and three cases (2%) were treated with antiviral medications; two of the three treated cases were children, both had high risk health conditions. Median illness duration significantly varied by age category with shorter duration of symptoms among children compared with adults (7 days vs. >10 days, P = .01) (Figure 2); illnesses were not yet resolved for 52% of influenza cases at time of final illness follow-up. Illness duration did not significantly vary by influenza type/subtype, or based on presence of high risk health condition or the influenza vaccination status (9 days vaccinated cases vs. 7 days unvaccinated cases, P = .53) (Figure 2) of case subjects.

Influenza was identified in 78 (24%) households and 125 (9%) individuals, including 5 individuals with two separate influenza infections (all >14 days apart; 3 of 5 had both influenza type A and type B infections). Younger households (those with mean age <22 years) and households with young children (age <9 years) were more likely to have influenza introduced (Table 2). None of household size or crowding, household vaccination coverage, humidification or exposure to tobacco smoke was significantly associated with likelihood of influenza introduction.

Overall influenza infection risks significantly varied by subject age category (P<.001) and were highest among children age <9 years (15.0%) and lowest among adults (5.3%) (Table 1). There were no significant differences in influenza infection risk by sex, presence of high risk health condition or documented influenza vaccine receipt.

There were 91 total introductions of influenza to 78 households by 100 index or co-index community-acquired cases. Thirteen households had two introductions each (differentiated by influenza type/subtype or time); co-index cases (identical illness onset dates) were identified in eight introduction events – seven with two index cases and one with three index cases.

Household transmission of influenza was demonstrated in 23 (29%) households as a result of first (n = 20) or second (n = 3) influenza introductions, with 30 cases of secondary household acquired influenza identified. Seventeen introductions each produced one secondary case, five each produced two secondary cases, and one produced three secondary cases. The likelihood of household transmission was not associated with household size, vaccination coverage, crowding or exposure to tobacco smoke, but was more likely in households with younger mean household age (<22 years)(P<.05) and households reporting no home humidification (P = 0.10) (Table 2).

Multiple introductions of influenza to some households complicated examination of the characteristics of index cases and those exposed, and estimation of secondary infection risks, as some subjects were both index cases and exposed household members. As a result only the first household introductions of influenza were considered here. First introductions to 78 households, committed by 85 index or co-index cases, exposed 267 household members and resulted in 26 secondary household-acquired cases in 20 households for a secondary infection risk of 9.7% [26/267].

Characteristics of household index cases, exposed household members and household secondary cases are presented in Table 1. Household index cases were most likely to be young (<9 years) children (59%) and equally likely to be older children (20%) or adults (21%); 17% of index cases had a high risk health condition and 57% had documented influenza vaccine receipt. The secondary infection risk among exposed household members significantly varied (P = .02) by age category of exposed subjects; risk was highest among young children (16.7%), lowest among older children (3.6%) and intermediate for adults (7.8%). Secondary infection risks were higher among exposed household members with high risk conditions and those with documented influenza vaccine receipt, but not significantly.

Secondary infection risks by characteristics of household index cases are presented in Table 3. Secondary risks did not significantly vary based on the age, health or vaccination status of household index cases. Household members exposed to index cases with high or medium specimen viral loads had a significantly higher secondary infection risk than those exposed to index cases with low specimen viral loads. Secondary infection risks varied significantly by influenza type/subtype with the highest secondary risk for influenza A (H3N2) [15.3%] and the lowest for influenza A (H1N1)pdm09 [2.9%]; influenza B was intermediate [7.7%].

The serial interval was calculated overall and by influenza type/subtype, with secondary cases resulting from both first and second influenza introductions to households considered. The mean serial interval was 3.2 days overall (Table 4). Serial intervals were similar for influenza A (H3N2) and A (H1N1)pdm09 (2.5 vs. 2.8 days), but significantly longer for influenza B (4.9 days, P = .02).