We estimated the household serial interval of influenza to be between 3 and 4 days, which is longer than previous estimates based on similar study designs.5,6
A strength of our study is that secondary cases were confirmed by laboratory testing. We adjusted for potential bias from truncation by study design (eAppendix
). This was necessary because index cases were not recruited if secondary cases had already appeared. Our resulting estimate for the serial interval is longer than the generation time used in some transmission models.3–6
The serial interval is the sum of 2 distinct phases of the natural history of influenza infection, namely, the infectious period (from exposure to infection) and the incubation period (from infection to symptoms). An often-used estimate of the incubation distribution is based on 36 laboratory-confirmed secondary cases from a single infector on an airplane where symptom onset mostly appeared within 1–2 days of infection (median 1.5 days).19
Even less is known about the duration of infectiousness and its variability over time. Experimental infections suggest that viral shedding peaks around the time of symptom onset and declines with time; viral shedding can persist for up to 1 week after infection20
(perhaps longer in children). Our finding of a mean serial interval of 3.6 days suggests that the average time from symptom onset in the index case to secondary infection in the household setting may be around 2 days, assuming that time from secondary infection to secondary onset is 1.5 days (based on the airplane data19
Studies currently in progress are using case-ascertainment recruitment designs to evaluate the efficacy of interventions to reduce influenza transmission in households.10
Given that index cases in these studies are often not recruited until at least 1 day after symptom onset, our findings suggest that these designs may underestimate the true effectiveness of the interventions because some infections may have occurred prior to recruitment and intervention. Nevertheless, provided that interventions can be applied soon after symptom onset, it is likely that such studies would be able to observe attenuated efficacies, and this should be taken into consideration when interpreting the results.
Our study had some limitations. First, our results are based on a small number of transmission events. Second, our data correspond only to transmission of interpandemic influenza within the household; the serial interval of transmission in other settings or in a pandemic may be different. Third, we may have misinterpreted some coprimary cases as secondary cases, leading us to underestimate the serial interval. With a small sample size and no obvious bimodality in the distribution of onset times, it is difficult to separate possible coprimary cases from the left-hand tail of the distribution. However, most coprimary cases would be excluded by our study design.
Some secondary cases may be wrongly attributed to the household index where infection of the household contact actually occurred outside the home from another infected person. Our main analysis does not explicitly allow for community transmission. However, the external force of infection is thought to be orders of magnitude lower than the force of infection within the household.21
Incorporating this in sensitivity analyses did not change our estimates of the serial interval (eTable 3
It is unlikely that we have confused secondary and tertiary cases in our analysis, because in households with multiple apparent secondary infections, symptoms appeared at the same time (in 1 household 2 asymptomatic secondary cases appeared at different times) (eTable 1
). In datasets in which there is the possibility of coprimary or tertiary cases, the methods presented here would need to be modified.
We may have missed some secondary cases due to errors in the laboratory data, or for example if the period of viral shedding fell entirely within the home visits, which on average took place at 3-day intervals. It is known from experimental infections that viral shedding typically begins around the same time as symptom onset,20
Therefore we felt justified in incorporating laboratory data when determining the true date of symptom onset (eTable 1
). Finally, our case-ascertainment study design naturally excluded household index cases with asymptomatic or subclinical infections. It would be challenging to collect longitudinal data on a cohort large enough to detect asymptomatic index cases and subsequent secondary cases.
There is a well-known relationship between the basic reproductive number, R0
, and the serial interval, and modeling results can be sensitive to the choice of serial interval.22,23
If and when larger datasets become available, it would be interesting to compare estimates of the serial interval for transmission in different settings and to investigate heterogeneities in the serial interval due to infector characteristics (eg, viral shedding), infectee characteristics (eg, antibody titers) or virus type or subtype.