Age‐Specific Effectiveness of Antiviral Agents on the Secondary Household Transmission of Influenza

ABSTRACT

Objectives

We investigate the effects of age, vaccination history, treatment timing, and type of antiviral agent in index cases and household members on the risk of influenza transmission.

Methods

We conducted a retrospective household survey in Japan between October 2018 and February 2019, enrolling 915 households (3248 members) with influenza cases. Secondary attack rates (SARs) and odds ratios (ORs) were calculated for subgroups stratified by treatment timing, antiviral agent, and age group.

Results

When treatment was initiated within 48 hours of symptom onset, both index cases and household contacts aged 0–14 and 15–50 years exhibited significantly higher odds of household transmission compared with those aged 51 years and older. Early treatment was associated with lower odds of transmission, with Baloxavir (OR = 0.74, 95% CI: 0.57–0.96) and Laninamivir (OR = 0.57, 95% CI: 0.41–0.79) showing lower ORs than Oseltamivir.

Conclusions

Our findings highlight that both clinical and demographic factors substantially influence household influenza transmission. Early initiation of antiviral treatment, combined with the use of Baloxavir or Laninamivir, significantly reduces the risk of secondary transmission, particularly in younger populations who play a central role in household spread.

1. Introduction

Influenza remains a significant public health concern due to its high transmissibility, particularly within households where transmission dynamics are age‐specific, with younger individuals playing a critical role in viral spread [1, 2]. Previous studies have examined household influenza transmission in relation to age and antiviral use. Cauchemez et al. and France et al. studied household secondary attack rates (SARs) according to household characteristics, including age and antiviral use [3, 4]. Hirotsu et al. evaluated SARs within households among index cases treated with Oseltamivir or Zanamivir and their household contacts according to the age and timing of treatment initiation [5]. Umemura et al. statistically compared the household transmission risk between Baloxavir and Oseltamivir [6]. These previous studies did not sufficiently stratify antiviral agent type or treatment timing. To address these gaps, we evaluated the combined impact of antiviral treatment timing and agent type on secondary transmission using data from the Japanese household survey.

Currently, common antiviral treatments include neuraminidase inhibitors (NAIs) such as Oseltamivir, Zanamivir, and Laninamivir, and the newer cap‐dependent endonuclease inhibitor, Baloxavir marboxil, which is distinguished by its novel mechanism and single‐dose regimen [7, 8, 9, 10]. Baloxavir was first approved in Japan in 2018 and subsequently by the US FDA in the same year. These agents are widely used within Japan's National Epidemiological Surveillance for Infectious Diseases (NESID) framework. As previous studies suggest that the effectiveness of these agents may vary by age [11, 12], it is crucial to investigate how household transmission of influenza is influenced by age and the type of antiviral agent.

Therefore, this study aims to clarify the determinants of household influenza transmission by examining how transmission risk varies with the characteristics of index cases and household members, including age, vaccination history, treatment timing, and type of antiviral agent (Baloxavir, Oseltamivir, Laninamivir, and Zanamivir). By analyzing SAR across these subgroups, we will assess the effectiveness of different antiviral therapies in preventing secondary infections using data from the nationwide internet‐based survey in Japan. The ultimate goal is to identify key clinical and treatment‐related factors that influence transmission and propose evidence‐based antiviral strategies to minimize influenza spread within households.

2. Method

We analyzed the SAR among index cases and household contacts to evaluate the effects of antiviral agents and treatment timing on household influenza transmission. Households were classified according to the treatment status of index cases, and clinical factors, such as age and vaccination history, were taken into account. Statistical analyses were performed to identify key determinants of household transmission.

2.1. Case Definition

Influenza is a notifiable acute respiratory disease caused by a highly contagious virus. When the host is infected, viral load increases and an immune response occurs, which naturally destroys the virus. In this study, infection with influenza was classified as confirmed or suspected cases based on information provided through the internet‐based questionnaire. Confirmed cases were defined as individuals reported to have been diagnosed with influenza by either rapid diagnostic test (RDT) or reverse‐transcription polymerase chain reaction (RT‐PCR). Most confirmed cases were diagnosed using RDT, which is known to have lower sensitivity than RT‐PCR [13]. Suspected cases were defined as individuals who reported fever ($\ge {37.5}^{°}\mathrm{C}$) accompanied by cough or sore throat (see Figure 1 and Supplementary Methods).

FIGURE 1.

Flowchart of household enrollment and case classification of index cases and household contacts.

We classified both confirmed and suspected cases as infected cases. Given the lower sensitivity of RDTs compared with RT‐PCR and the fact that most confirmed cases were diagnosed using RDTs, an analysis restricted to confirmed cases could miss some true influenza infections. To minimize this potential under‐ascertainment, we used the infected case definition for both index cases and household contacts in all primary analyses of household transmission. A secondary case was defined as a household contact who met the infected case definition after the identification of an infected index case. As an additional analysis, we repeated the analyses with index cases restricted to confirmed cases. In this analysis, a secondary case was defined as an household contact who developed infection after the identification of a confirmed index case. This definition was consistent with Pebody et al., who defined index cases by laboratory confirmation and secondary cases by laboratory confirmation or symptom‐based clinical criteria among household contacts [14].

The serial interval was defined as the number of days between symptom onset in the index case and symptom onset in the household contact. A previous study of household influenza transmission showed that serial intervals of 6 days or longer were uncommon but still possible [15]. In our data, only approximately 15% of secondary cases had a serial interval of 6 days or longer. Given that such longer serial intervals are possible based on the previously estimated distribution, we did not exclude these cases from the analysis. Therefore, all household contacts who satisfied the secondary case definition were assumed to have acquired influenza from the index case.

2.2. Data Collection

To assess the risk of influenza household transmission by different antiviral agents, a retrospective household survey was conducted using internet‐based questionnaire in Japan between October 2018 and February 2019. Participants were recruited from a nationwide online survey panel maintained by Melinks Ltd. (Nerima‐ku, Tokyo, Japan), a survey company with approximately three million registered members [16]. They received points as compensation for completing the questionnaire. A total of 936 households in which at least one household member met the study definition of an influenza case participated in the survey and were recruited using respondent‐driven sampling. Of the 936 households, 21 individuals with missing values for some variables and no infections were excluded from the study, and 915 households were used for analysis; this is explained in detail in the Supplementary Methods.

Data on influenza infections for each household member, use of antiviral agents, and the time from symptom onset to initiation of antiviral treatment (i.e., treatment timing) were collected. Additionally, information on age, sex, and vaccination for seasonal influenza was also collected. Each variable is composed of two or more categories, and detailed descriptions of these categories are provided in the Supplementary Methods.

2.3. Statistical Analysis for SAR by Characteristics of Index Cases and Household Contacts

2.3.1. SAR of Influenza by Antiviral Treatments

The SAR was defined as the number of secondary cases divided by the total number of household contacts. Higher SAR indicates greater transmissibility within households and has been widely used in previous studies as a key measure to assess the transmission potential of respiratory infections such as influenza [17, 18, 19, 20]. The differences in SAR within households were examined according to age group, sex and vaccination status of index cases and household contacts, as well as treatment timing and type of antiviral agent of the index cases.

SARs for index cases were further examined to explore how the characteristics of index cases influence household transmission of influenza. We stratified index cases into subgroups consisting of a combination of covariate in Table 1 defined by time from symptom onset to treatment ($T$), antiviral agent ($D$) and age ($A_i$). Each covariate is divided into two or more categories, for example, $T=1$ represent a group of index cases treated within 48 h from symptom onset. For each subgroup, SAR was calculated as the proportion of secondary cases among household contacts exposed to index cases in that subgroup, thereby representing the transmission probability associated with specific index case characteristics. The SAR for index cases in subgroup ($T,D,A_i$) was defined as $SA{R}_{\left(T,D,A_i\right)}^{\mathit{\text{index}}}$, which is the number of secondary cases observed in that subgroup divided by the total number of household contacts in the subgroup. The calculation is as follows:

$$\mathit{SA}{R}_{\left(T,D,A_i\right)}^{\mathit{\text{index}}}=\frac{{\sum }_{I\in \mathcal{I}\left(T,D,A_i\right)}S{C}_I}{{\sum }_{I\in \mathcal{I}\left(T,D,A_i\right)}\left(N_I-1\right)},$$

where $\mathcal{I}\left(T,D,A_i\right)$ denotes the set of IDs for index cases in subgroup $\left(T,D,A_i\right)$. For each index case $I\in \mathcal{I}\left(T,D,A_i\right)$, ${\mathit{SC}}_I$ and $N_I$ represent the number of secondary cases in the household and the total number of household members associated with the index case $I$.

TABLE 1.

Description of covariates used to estimate odds ratio (OR) and secondary attack rate (SAR). “Covariate” indicates the variable assessed for influence on transmission risk. “Subgroup type” specifies whether the variable applies to index cases or household contacts. “Subscript” denotes the symbol for each covariate by subgroup type. “Category” shows the classification of each covariate.

Covariate	Subgroup type	Subscript	Category	n a	Household contacts b	Secondary cases c
Time from symptom onset to treatment	Index	$T$		915	2312	591
			Within 48 h ($T=1$)	685	1751	430
			Over 48 h ($T=2$)	107	249	83
			Other antiviral agents ($T=3$) d	58	165	36
			Without treatment ($T=4$)	65	147	42
Antiviral agent	Index	$D$		915	2312	591
			Baloxavir ($D=1$)	229	549	124
			Laninamivir ($D=2$)	140	342	68
			Oseltamivir ($D=3$)	313	825	242
			Zanamivir ($D=4$)	110	284	79
			Other antiviral agents ($D=5$) d	58	165	36
			Without treatment ($D=6$)	65	147	42
Age	Index	$A_i$		915	2312	591
			0–14 ($A_i=1$)	260	822	238
			15–50 ($A_i=2$)	465	1122	278
			51+ ($A_i=3$)	190	368	75
	Household	$A_h$		2312	—	591
			0–14 ($A_h=1$)	493	—	156
			15–50 ($A_h=2$)	1223	—	321
			51 + ($A_h=3$)	596	—	114
Sex	Index	$S_i$		915	2312	591
			Male ($S_i=1$)	497	1304	338
			Female ($S_i=2$)	418	1008	253
	Household	$S_h$		2312	—	591
			Male ($S_h=1$)	1132	—	270
			Female ($S_h=2$)	1180	—	321
Vaccination status	Index	$V_i$		915	2312	591
			Vaccinated ($V_i=1$)	380	967	268
			Unvaccinated ($V_i=2$)	535	1345	323
	Household	$V_h$		2312	—	591
			Vaccinated ($V_h=1$)	817	—	231
			Unvaccinated ($V_h=2$)	1495	—	360

^a Number of individuals in each group.

^b Number of household contacts in each group.

^c Number of infected household contacts.

^d Other antiviral agents' refers to cases where the index cases took an antiviral agent that is not Baloxavir, Laninamivir, Oseltamivir, or Zanamivir. This category was not included in the analysis.

To assess the risk of infection among household contacts, SAR for household contacts, $\mathit{SA}{R}_{\left(T,D,A_h\right)}^{\mathit{\text{household}}}$, was calculated according to their subgroup characteristics. For each subgroup of household contacts, SAR was defined as the proportion of infected individuals within that subgroup. Specifically, for subgroup $\left(T,D,A_h\right),$ $T$ and $D$ denote the treatment timing and antiviral agent of the index case, respectively, while $A_h$ indicates the age group of their household contacts. $\mathit{SA}{R}_{\left(T,D,A_h\right)}^{\mathit{\text{household}}}$ was calculated as follows:

$$\mathit{SA}{R}_{\left(T,D,A_h\right)}^{\mathit{\text{household}}}=\frac{{\mathit{SC}}_{\left(T,D,A_h\right)}}{C_{\left(T,D,A_h\right)}}.$$

${\mathit{SC}}_{\left(T,D,A_h\right)}$ and $C_{\left(T,D,A_h\right)}$ represent the number of secondary cases and the total number of household contacts in age group $A_h$ within households where the index case belongs to subgroup $\left(T,D\right)$.

To quantify the uncertainty associated with the point estimate of the SAR, 95% confidence intervals (CIs) were estimated using the Wilson score method [17, 21]. This method adjusts for small sample sizes and extreme proportions by incorporating a correction term into the standard binomial interval. Detailed formulas and explanations are provided in Supplementary Methods.

2.3.2. Comparison of Secondary Infection Risk Using the Odds Ratio (OR)

The OR is a statistical measure that represents the ratio of the odds of infection probability between two groups, indicating the relative risk of a specific group compared with a reference group. In a logistic regression model, it is expressed as

$$\log \left(\mathit{\text{Odds}}\right)=\log \left(\frac{p}{1-p}\right)={\beta }_0+{\beta }_1{X}_1+{\beta }_2{X}_2+\dots +{\beta }_k{X}_k,$$

where $k$ is the number of covariates, the log‐odds change by the regression coefficient ${\beta }_i$ when $X_i$ increased by one unit. This represents the change in odds when $X_i$ changing from the reference group (group0, $X_i=0$) to group1 ($X_i=1$). The probability $p=P\left(Y=1|X_i=x\right)$ denotes the probability of infection in the group corresponding to $X_i=x$. $Y=1$ means infection and $Y=0$ indicates no infection. The OR shows how many times the odds change, and it can be expressed as $\mathit{\text{OR}}=\frac{\mathit{Odd}{s}_{\mathit{\text{group}}1}}{\mathit{Odd}{s}_{\mathit{\text{group}}0}}=\exp \left({\beta }_i\right)$. We can interpret that, compared with the group0, group1 has OR times odds of transmission when the OR is greater than 1, indicating greater household transmission in the study. We performed univariable and multivariable analyses and provided OR and 95% Wald CI (See Supplementary Methods). All statistical analyses were conducted with a significance level of 0.05 using R version 4.2.2 (R Development Core Team).

3. Result

3.1. Comparison of Household Transmission by Timing of Antiviral Administration

Figure 2 and Table S1 describe the household transmission by the time from symptom onset to treatment and antiviral agent for index cases. The transmission risk varies depending on the treatment timing of the index cases and the type of antiviral agent taken. The OR analysis by time from symptom onset to treatment indicated that index cases treated after 48 h had 54% higher odds of household transmission than those treated within 48 h (OR = 1.54, 95% CI: 1.16–2.04, p = 0.003). Consistently, the SAR was lower among cases treated within 48 h (0.25) than among those treated after 48 h (0.33). These findings indicate that initiating antiviral treatment within 48 h of symptom onset was associated with lower household transmission. Also, although the difference was not statistically significant (p = 0.280), the OR indicated a higher household transmission among index cases without treatment compared with those treated within 48 h.

FIGURE 2.

Odds ratios (ORs) for household transmission according to treatment timing and antiviral agent in index cases. Circles indicate ORs, and horizontal lines indicate 95% confidence intervals (CIs). Antiviral agents were stratified by treatment initiated within 48 h or over 48 h after symptom onset.

Since SAR and OR decreased when antiviral agents were administered within 48 h of symptom onset, we compared SAR and OR between groups stratified by antiviral agent and treatment timing. We compared groups that received treatment within or over 48 h, with Oseltamivir serving as the reference antiviral agent. Index cases treated within 48 h with Baloxavir (OR = 0.74, 95% CI: 0.57–0.96, p = 0.026) or Laninamivir (OR = 0.57, 95% CI: 0.41–0.79, p < 0.001) showed significantly lower odds of household transmission compared with those treated with Oseltamivir. SAR was also lower among index cases treated with Baloxavir (0.22) or Laninamivir (0.18) compared with those treated with Oseltamivir (0.28). These findings suggest that Baloxavir and Laninamivir were associated with lower household transmission than Oseltamivir when treatment was initiated within 48 h of symptom onset. When treated over 48 h from symptom onset, no significant differences in the odds of household transmission were observed among the antiviral agents, although Baloxavir and Zanamivir showed numerically lower household transmission than Oseltamivir.

To further investigate whether treatment delays were associated with higher household transmission, we conducted an additional analysis with more detailed stratifications of time from symptom onset to treatment, as shown in Figure S1 and Table S2. In this analysis, index cases who were treated at 24–48, 48–72, 96–120, or over 120 h after symptom onset had a significantly higher odds of household transmission than those treated within 24 h after symptom onset. These results suggest that initiating antiviral treatment promptly, particularly within 24 h of symptom onset, was associated with lower household transmission of influenza.

3.2. Comparison of Antiviral Effectiveness by Age Groups With Treatment Within 48 h

We aimed to assess how household transmission is affected by the age group of the index cases and household contacts and the type of antiviral agent the index case took. As shown in Figure S2A, the proportion of index cases who initiated treatment within 48 h differed across antiviral agents, ranging from 74.5% to 90.7%. Because treatment initiation within 48 h was also associated with lower household transmission, comparisons based on all treated index cases could reflect differences in treatment timing as well as differences among antiviral agents. As shown in Figure S2B and S2C, the distribution of antiviral agents differed across age groups among index cases and household contacts. For example, the proportion associated with Baloxavir treatment increased with age, from 23.4% to 33.8% among index cases and from 25.9% to 29.8% among household contacts. Comparison of antiviral agents without accounting for age could partly reflect differences in age composition as well as differences among the antiviral agents. Therefore, the association between antiviral agent and household transmission was evaluated within each age group using SAR and OR analyses restricted to index cases treated within 48 h of symptom onset, with Oseltamivir serving as the reference antiviral agent.

Figure 3 and Table S3 summarize the transmission odds and SAR by antiviral agents across age groups among index cases and household contacts, among households in which the index case was treated within 48 h of symptom onset. Index cases aged 0–14 years treated with Baloxavir had 38% lower odds of household transmission than those treated with Oseltamivir (OR = 0.62, 95% CI: 0.40–0.97, p = 0.036), and index cases aged 15–50 years treated with Laninamivir showed 52% lower odds (OR = 0.48, 95% CI: 0.30–0.78, p = 0.003). A similar trend was also observed in SAR. Among household contacts aged 0–14 years, Baloxavir was associated with 47% lower odds of infection (OR = 0.53, 95% CI: 0.30–0.93, p = 0.026) compared with Oseltamivir, while Laninamivir was associated with 63% lower odds (OR = 0.37, 95% CI: 0.19–0.73, p = 0.004). Moreover, household contacts aged 15–50 years whose index case was treated with Laninamivir had 41% lower odds of infection (OR = 0.59, 95% CI: 0.38–0.92, p = 0.019) than Oseltamivir. SAR showed a similar trend with OR. Integrating results from index cases and household contacts, we found that initiating Baloxavir or Laninamivir within 48 h of symptom onset was associated with lower household transmission than Oseltamivir, particularly among those aged 0–50 years.

FIGURE 3.

Odds ratios (ORs) for household transmission according to age group and antiviral agent in index cases who initiated treatment within 48 h of symptom onset and household contacts. (A) Index cases. (B) Household contacts. Circles indicate ORs, and horizontal lines indicate 95% confidence intervals (CIs).

In contrast, additional SAR and OR analyses considering both age group and antiviral agents were performed among cases treated over 48 h after symptom onset, again with Oseltamivir serving as the reference. Although no significant differences in transmission odds were observed across antivirals for either index cases or household contacts (Table S4), the SAR and OR analyses showed a trend toward lower odds of transmission with Baloxavir and Zanamivir than with Oseltamivir when treatment was initiated over 48 h after symptom onset.

3.3. Comparison of Household Transmission by Vaccination Status and Age Group

We conducted multivariable logistic regression to determine the independent effect of each covariate, such as age, sex, and vaccination status, on the household transmission while controlling for the influence of the other covariates. The dependent variable was the infection status of household contacts. As a result, household contacts aged 0–14 years exhibited 82% higher odds of household transmission than those aged 51 years and older (adjusted OR = 1.82, 95% CI: 1.36–2.44, p < 0.001), and those aged 15–50 years had 39% higher odds (adjusted OR = 1.39, 95% CI: 1.08–1.79, p = 0.010). In contrast, the age of index cases, the sex of the index case and household contact, and the vaccination status of the index case and household contact were not significantly associated with household transmission. It concluded that multivariable analysis showed that younger household contacts exhibited significantly higher odds of infection than those aged 51 years and older.

To explore the crude association between a single variable (e.g., age group) and the dependent variable (i.e., infection status of household contacts), univariable logistic regression analysis was performed. Table 2 and Figure 4 summarize the results of SAR and OR analyses, in which those aged 51 years or older were defined as the reference group. The results were stratified by the time from symptom onset to treatment and age group for both index cases and household contacts.

TABLE 2.

Transmission risk within households by age group and time from symptom onset to treatment in index cases and household contacts.

Time from symptom onset to treatment	Group type	Age group	n a	Secondary cases b	SAR	OR	95% CI of OR c	p d
All	Index	0–14	822	238	0.29	1.59	(1.19, 2.14)	0.002**
		15–50	1122	278	0.25	1.29	(0.97, 1.72)	0.086
		51+	368	75	0.20	Ref	Ref	Ref
	Household	0–14	493	156	0.32	1.96	(1.48, 2.59)	< 0.001***
		15–50	1223	321	0.26	1.50	(1.18, 1.91)	0.001**
		51+	596	114	0.19	Ref	Ref	Ref
Within 48 h	Index	0–14	644	189	0.29	2.30	(1.59, 3.34)	< 0.001***
		15–50	832	199	0.24	1.74	(1.21, 2.51)	0.003**
		51+	275	42	0.15	Ref	Ref	Ref
	Household	0–14	371	114	0.31	2.26	(1.62, 3.16)	< 0.001***
		15–50	941	244	0.26	1.78	(1.33, 2.39)	< 0.001***
		51+	439	72	0.16	Ref	Ref	Ref
Over 48 h	Index	0–14	60	21	0.35	0.75	(0.35, 1.65)	0.479
		15–50	141	42	0.30	0.59	(0.30, 1.17)	0.132
		51+	48	20	0.42	Ref	Ref	Ref
	Household	0–14	41	16	0.39	1.28	(0.58, 2.80)	0.537
		15–50	130	41	0.32	0.92	(0.51, 1.68)	0.789
		51+	78	26	0.33	Ref	Ref	Ref
Without treatment	Index	0–14	8	4	0.50	2.50	(0.50, 12.51)	0.265
		15–50	111	30	0.27	0.93	(0.37, 2.33)	0.870
		51+	28	8	0.29	Ref	Ref	Ref
	Household	0–14	33	13	0.39	2.67	(0.97, 7.33)	0.056
		15–50	68	20	0.29	1.71	(0.70, 4.20)	0.239
		51+	46	9	0.20	Ref	Ref	Ref
Over 48 h or Without treatment	Index	0–14	68	25	0.37	1	(0.51, 1.96)	0.992
		15–50	252	72	0.29	0.69	(0.40, 1.18)	0.171
		51+	76	28	0.37	Ref	Ref	Ref
	Household	0–14	74	29	0.39	1.64	(0.89, 3.01)	0.112
		15–50	198	61	0.31	1.13	(0.69, 1.86)	0.622
		51+	124	35	0.28	Ref	Ref	Ref

Abbreviations: OR, odds ratio; Ref, reference category; SAR, secondary attack rate.

^a Number of household contacts of index cases.

^b Number of infected household contacts of infected index cases.

^c 95% confidence interval of the odds ratio.

^d p‐value for the odds ratio.

^* p < 0.05.

^** p < 0.01.

^*** p < 0.001.

FIGURE 4.

Secondary attack rates (SARs) within households with 95% confidence intervals by age group. (A) Index cases (red). (B) Household contacts (blue). Diamonds indicate SARs, and the numbers next to them represent their value. Whiskers show the 95% confidence intervals calculated using Wilson's method.

When stratified by time from symptom onset to treatment, significant differences by age group were observed only among those who received treatment within 48 h. Among index cases, those aged 0–14 years exhibited 130% higher odds of household transmission than those 51 years and older (OR = 2.30, 95% CI: 1.59–3.34, p < 0.001), and those aged 15–50 years showed 74% higher odds (OR = 1.74, 95% CI: 1.21–2.51, p = 0.003). Among household contacts, those aged 0–14 years had 126% higher odds of infection than those 51 years and older (OR = 2.26, 95% CI: 1.62–3.16, p < 0.001), and those aged 15–50 years had 78% higher odds (OR = 1.78, 95% CI: 1.33–2.39, p < 0.001). The SAR of index cases and household contacts also showed the same trend with odds, and it increased as age decreased. Without stratifying by treatment timing, a pattern similar to that observed in the subgroup treated within 48 h was observed, with younger age groups generally showing higher odds of household transmission than those aged 51 years and older.

Also, we want to find out whether there are differences in infection transmission depending on the treatment timing and the personal characteristics of index cases and household contacts. We conducted OR analyses for sex among both index cases and household contacts, whereas the analysis of vaccination status was limited to household contacts. Analyses were stratified by time from symptom onset to treatment (Table S5). We did not analyze vaccination status among index cases because all index cases were already infected, and the association between their vaccination status and household transmission may not fully reflect the overall effect of vaccination in the general population.

When not stratified by time from symptom onset to treatment, vaccinated household contacts had 24% higher odds of household transmission than unvaccinated household contacts in the univariable analysis. As shown in Figure S3, 68.8% of vaccinated household contacts had vaccinated index cases, compared with 27.1% of unvaccinated household contacts. The difference between the two groups was 41.7%. In contrast, the age and sex distributions were broadly similar between the two groups. Because the vaccination status of index cases was associated with that of household contacts in our data, it was retained as a potential confounding factor in the multivariable model. After adjustment for age group, sex, and the vaccination status of index cases, the vaccination status of household contacts was no longer significantly associated with household transmission.

3.4. Analysis of Household Transmission Among Confirmed Index Cases and Infected Household Contacts

An additional analysis restricted index cases to confirmed cases while retaining infected household contacts to assess whether the findings were sensitive to the definition of index cases. Table S6 showed the ORs and SARs for household transmission by age group, time from symptoms to treatment and antiviral agents. Results for age groups showed a similar pattern, with younger age groups having significantly higher odds of transmission. Table S7 presented the transmission odds and SAR by antiviral agent, stratified by age group, for both index cases and household contacts.

Table 3 shows a comparison of significant results by age groups and antiviral agents from the analyses of infected and confirmed index cases, presented in Tables S3 and S7, respectively. In both analyses, Laninamivir was associated with a significantly lower risk of household transmission than Oseltamivir among index cases aged 15–50 years and household contacts aged 0–50 years. However, the findings differed for index cases and household contacts aged 0–14 years. In the analysis of infected index cases and infected household contacts, Baloxavir was also associated with a significantly lower transmission risk than Oseltamivir. Although this association was not statistically significant in the analysis of confirmed index cases and infected household contacts, the OR for Baloxavir was less than 1, and SAR was lower than that for Oseltamivir.

TABLE 3.

The comparison of the significant differences in transmission risk by age group and antiviral agent for confirmed or infected index cases treated within 48 h of symptom onset and infected household contacts.

Group type	Age group	Index: Infected cases a Household: Infected cases a		Index: confirmed cases b Household: Infected cases a
		Significant antiviral agent (ref: Oseltamivir) c	Transmission risk vs. ref. d	Significant antiviral agent (ref: Oseltamivir) c	Transmission risk vs. ref. d
Index	0–14	Baloxavir	Low	—	—
	15–50	Laninamivir	Low	Laninamivir	Low
	51+	—	—	—	—
Household	0–14	Baloxavir, Laninamivir	Low	Laninamivir	Low
	15–50	Laninamivir	Low	Laninamivir	Low
	51+	—	—	—	—

^a Cases involving both confirmed and suspected cases defined as individuals who self‐confirmed as having influenza when both fever (≥ 37.5°C) and either cough or sore throat were present.

^b Cases confirmed by rapid diagnostic testing and reverse‐transcription polymerase chain reaction.

^c Antiviral agent category with statistically significant differences compared with the reference Oseltamivir.

^d Difference in transmission risk compared to the reference Oseltamivir based on OR analysis results.

4. Discussion

This study aimed to identify key determinants of household influenza transmission by examining differences in transmission according to treatment timing, antiviral agent (Baloxavir, Oseltamivir, Laninamivir, and Zanamivir) and age group (0–14, 15–50, and 51+ years) in 915 Japanese households with 3248 members, using SARs and ORs. In the analysis combining all age groups, early treatment, when initiated within 48 h after onset, was associated with lower odds of transmission, particularly with Baloxavir and Laninamivir compared with Oseltamivir. This finding may partly reflect the more rapid suppression of infectious virus and viral shedding after treatment with Baloxavir and Laninamivir [22, 23]. Because influenza transmission frequently occurs through close contact within households, rapid suppression of viral shedding in index cases can reduce the exposure of household contacts to infectious virus [24]. This reduced exposure may contribute to lower household transmission observed with Baloxavir and Laninamivir. In addition, their effectiveness in reducing transmission was significantly higher among index cases and household contacts younger than 51 years. Regarding age groups, individuals aged 0–14 and 15–50 years exhibited significantly higher odds of transmission.

This study extends literature in three important ways. First, by jointly analyzing treatment timing, antiviral type, and age, we provide one of the most comprehensive assessments to date of their relative contributions to household transmission dynamics. While Cauchemez et al. demonstrated that children were the most likely to be infected and adults older than 50 were the least, they did not consider the effects of antiviral type or treatment timing [3]. In contrast, our analysis explicitly incorporates these factors and stratifies results by age to better capture their combined impact.

Second, we demonstrate that Baloxavir and Laninamivir, when administered within 48 h of symptom onset, significantly reduced the household transmission risk compared with Oseltamivir, especially among younger index cases. While Umemura et al. and Fry et al. compared the risk of household transmission by age group and antiviral agents, separately, they did not evaluate age‐specific antiviral efficacy [6, 25].

Third, we consistently show younger age groups carry a higher transmission risk, highlighting the central role of age structure in shaping household influenza dynamics. Consistent with our findings, France et al. (2010) reported a higher risk of household transmission among younger contacts and identified antiviral treatment as a protective factor [4]. However, their index cases were restricted to high school students. Our study benefits from the diverse age range of survey respondents, enabling a more detailed evaluation of age‐specific differences in the association between antiviral treatments and household transmission.

This study has several limitations. First, some subgroup analyses had limited statistical power due to small sample sizes. However, our overall sample of 915 index cases and 2312 household contacts is substantially larger than those in previous studies, which strengthens the reliability of our main findings. For instance, Hirotsu et al. examined only 591 index cases with 1629 household contacts [5]. Second, we did not account for antiviral resistance. Antiviral resistance in influenza viruses can affect the effectiveness of antiviral agents [26], and previous household transmission studies have evaluated the influence of antiviral resistance [27, 28]. However, according to antiviral resistance surveillance in Japan, resistance to Oseltamivir, Zanamivir, and Laninamivir was rare or not detected, and resistance to Baloxavir ranged from 0.0% to 8.0% across influenza subtypes [29]. Moreover, Baloxavir was approved in Japan shortly before the 2018–2019 influenza season and individual information on resistance was unavailable in our data. Therefore, we were unable to account for antiviral resistance in the analysis.

Third, surveillance data used in this study has several limitations. Individual‐level information on influenza virus type was not available. However, national surveillance data showed that influenza A viruses predominated in Japan during the survey period from October 2018 to February 2019, whereas influenza B activity increased mainly after this period [30]. Most influenza cases included in our study were likely caused by influenza A viruses. In addition, information on influenza infection was obtained from questionnaire responses and was not independently verified using medical records. The questionnaire also did not collect information on underlying medical conditions or concomitant medications. These factors may have affected both the selection of antiviral treatment and the risk of influenza transmission. Future studies with more detailed individual‐level information could further evaluate the potential influence of these factors on household infection.

Despite these limitations, this study demonstrates that both clinical and demographic factors significantly impact household influenza transmission. The most effective strategies for reducing secondary infections are early antiviral treatment, ideally within 48 h of symptom onset, and the use of Baloxavir or Laninamivir over Oseltamivir. These results provide new evidence to optimize household‐level intervention strategies and can inform public health policies aimed at curbing influenza transmission, particularly among the younger age groups who drive household spreads.

5. Conclusion

Our findings highlight the critical role of treatment timing and antiviral selection in reducing household influenza transmission. Early initiation of treatment within 48 h of symptom onset was associated with a lower secondary transmission risk, underscoring the importance of prompt clinical intervention. Baloxavir and Laninamivir demonstrated superior effectiveness compared to Oseltamivir when administered early, and their preventive effects were most evident in younger age groups (0–14 and 15–50 years). These results suggest that timely antiviral therapy, especially with Baloxavir or Laninamivir, should be prioritized as a key strategy to mitigate household influenza transmission.

Author Contributions

Jeonghwa Seo: methodology, formal analysis, data curation, writing – review and editing, writing – original draft, visualization. Jihyeon Kim: methodology, visualization, formal analysis, data curation, writing – original draft, writing – review and editing. Hiroshi Nishiura: writing – review and editing, methodology. Hyojung Lee: writing – review and editing, writing – original draft, methodology.

Funding

HL was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. RS‐2022‐NR070839, RS‐2022‐NR071821, RS‐2026‐25537933).HN received financial support from the Japan Science and Technology Agency CREST program (grant number JPMJCR24Q3).

Ethics Statement

Respondents are anonymous, do not target personal specimens or information, and they do not handle personal information. The individual's age information is collected for a retrospective household survey. This study (Approval No. 19–007) was approved by the Ethics Committee of Hokkaido University on June 6, 2019.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: Secondary attack rates (SARs) within households with 95% confidence intervals by time from symptom onset to treatment of index cases. Diamonds represent SARs, and the numbers next to them show their value. Whiskers show the 95% confidence intervals calculated using Wilson's method.

Figure S2: Distribution of treatment timing by antiviral agent and antiviral agents by age group. (A) Distribution of treatment timing within each antiviral agent. Bars represent the proportions of index cases treated within 48 h and more than 48 h after symptom onset, and the numbers within the bars indicate the corresponding percentages and number of index cases. (B–C) Distribution of antiviral agents among index cases treated within 48 h of symptom onset according to the age groups of index cases (B) and household contacts (C). Values in each cell indicate the percentage of each antiviral agent within the corresponding age group.

Figure S3: Age and sex distributions of index cases and household contacts, and vaccination status of index cases, by vaccination status of household contacts. Stacked bars show the distribution of characteristics among vaccinated and unvaccinated household contacts. (A–C) distributions of the age group (A), sex (B), and vaccination status (C) of index cases according to the vaccination status of household contacts. (D–E) Distributions of the age group (D) and sex (E) of household contacts according to their vaccination status. Numbers within the bars indicate the percentage in each category.

Table S1: Transmission risk within households by time from symptom onset to treatment and antiviral agents in index cases.

Table S2: Transmission risk by time from symptom onset to treatment in index cases.

Table S3: Transmission risk within households by age group and antiviral agents in index cases who initiated treatment within 48 h of symptom onset and household contacts.

Table S4: Transmission risk within households by age group and antiviral agents in index cases who initiated treatment after 48 h of symptom onset and household contacts.

Table S5: Household transmission risk by time from symptom onset to treatment in index cases, sex of index cases and household contacts, and vaccination status of household contacts.

Table S6: Transmission risk within households by age group, time from symptom onset to treatment, and antiviral agents in confirmed index cases and infected household contacts.

Table S7: Transmission risk within households by age group and antiviral agents among confirmed index cases who initiated treatment within 48 h of symptom onset and infected household contacts.

Seo J., Kim J., Nishiura H., and Lee H., “Age‐Specific Effectiveness of Antiviral Agents on the Secondary Household Transmission of Influenza,” Influenza and Other Respiratory Viruses 20, no. 11 (2026): e70337, 10.1111/irv.70337.

Data Availability Statement

The summary of the data is included in Table 1 and Figure 1. Further inquiries can be directed at the corresponding author.