Three studies reported that both SIRPCR and SIRFARI were higher among household contacts of younger index cases,22,25,33 2 studies reported that they were lower with younger index cases,19,29 and one study found no difference by index age.41 Four studies that stratified by sex found no difference in SIRs,27,34,40,41 whereas one study reported female contacts to be at greater risk of infection,24 and another reported that adult women were more likely to transmit pH1N1 to children.36
Eight studies reported SIRARI, with point estimates ranging from 13% to 51% [I 2 = 94.3%] (eFigure 2, http://links.lww.com/EDE/A584). Stratified analysis reported ranges of 15% to 55% [I 2 = 86.0%] in children and 10% to 49% [I 2 = 90.6%] in adults.
In addition to the effects of contact and index age on household transmission, some studies analyzed the effects of antiviral treatment and prophylaxis with oseltamivir or zanamivir, vaccination history, and household size. Eleven studies recorded infection rates among household contacts that received antiviral prophylaxis,19,23,24,27,28,32 – 34,36,44,46 but only one study reported the prophylaxis group to be more susceptible to pH1N1 (eFigure 3, http://links.lww.com/EDE/A584). One study reported seasonal influenza vaccination history to have no effect on the SIR,45 whereas 3 studies24,30,35 reported elevated SIRs among people who had been vaccinated for seasonal influenza. The SIR was variously observed to increase with household size25,30,35,39 or not to be associated with household size.19,24,27,29,33 In one study with a broader definition of household contacts (eTable 2, http://links.lww.com/EDE/A584), the SIR decreased in larger households.20
Among the 27 included studies, 18 (67%) reported either the mean or median household serial interval, and 8 reported both (Fig. 5). Mean serial intervals ranged from 2.6 to 3.9 days, whereas median serial intervals ranged from 2.0 to 4.0 days. Of the 26 point estimates of the serial interval, 20 (77%) fell within the range 2.8–3.5 days.
Illness in Household Contacts With Confirmed pH1N1 Infection
The clinical signs and symptoms associated with confirmed pH1N1 infection among household contacts are summarized in Table 3 from 3 studies that collected respiratory specimens from household contacts, regardless of reported illness. Cough was the most commonly reported symptom, and fever was reported in approximately 60% of the confirmed cases. Two studies reported asymptomatic fractions among virologically confirmed cases to be 11% and 7%,22,41 and when cases under antiviral prophylaxis were included, the asymptomatic fraction was 20%.41 One study reported a subclinical fraction (9%),22 and the other study similarly reported that 9% of household contacts with serologic evidence of infection remained asymptomatic.35 One study that reported only serological data found a crude asymptomatic fraction of 25%.26 Two studies reported the proportion of household contacts with various clinical signs, symptoms, and syndromes that were confirmed with pH1N1 (eTable 3, http://links.lww.com/EDE/A584).
Serologic data on household contacts were available from 5 studies.21,22,26,35,40 Two studies reported SIRs based solely on serology to be 20% and 27%.21,26 In addition to using of serology to identify asymptomatic infections,35 2 studies used serology and RT-PCR results in combination to estimate pH1N1 SIRs.35,40 One study reported no evidence of a protective effect for subjects with elevated baseline antibody titer levels against RT-PCR-confirmed infection.22
During the 2009 pandemic, household studies were conducted in many countries to improve understanding of the epidemiologic characteristics of the novel pH1N1 virus in a specific community setting. We described the design of household transmission studies conducted during the pandemic, and we compared the findings of the studies, including the household SIR, the household serial interval, and the symptom profiles and the asymptomatic fraction in household contacts. Among these, the SIR and household serial interval are relatively imprecise in that they are influenced by transmissions both in household and community settings, as well as preexisting immunity among contacts. We therefore conducted metaregression analysis to identify potential factors associated with higher or lower household SIRs (Table 2).
There were substantial heterogeneities in estimated SIRs from the various studies, with point estimates of the SIR based on RT-PCR–confirmed secondary cases ranging from 3% to 38% (Fig. 2). Estimates were similarly heterogeneous when based on febrile acute respiratory illness (Fig. 3) and acute respiratory illness (eFigure 2, http://links.lww.com/EDE/A584). The intrinsic transmissibility of the pH1N1 virus is not thought to have varied substantially in different countries; indeed, a recent review identified similarity in the estimates of the reproduction number from a range of studies.9 A review of serologic studies also found similar estimates of cumulative incidence of infection over the first pH1N1 wave in several countries.49
A number of factors may have led to the observed differences in estimated household SIRs. Metaregression analyses revealed that rigorous case ascertainment with RT-PCR testing for all contacts (including asymptomatic contacts), elevated the SIRPCR, whereas the SIRFARI was unaffected (Table 2, Fig. 4). Although rigorous testing undoubtedly increases the cost, our results indicate that studies that tested all household contacts by RT-PCR, regardless of illness, identified more infections. Studies that test only symptomatic contacts will not identify all infected contacts, nor will they achieve a timely collection of specimens within 3 days of onset (when RT-PCR sensitivity is highest50). It might be expected that studies with longer durations of follow-up would pick up not only those transmissions within households but also those from the community; our findings were consistent with increases in SIRPCR and SIRFARI with longer follow-up.
The highest SIRs were observed in Chile,37 Australia,29 and Canada.35,39 Among these, 2 studies with differing SIRs (estimated SIRPCR of 33% and 15%) were reported from Victoria, Australia at similar times.29,44 The study with the larger SIR estimate recruited subjects by 31 August 2009, and the other ended on 3 June 2009; the proportion of child index cases (≥5 years of age) was 86% in the study with SIRPCR = 15%, compared with 37% in the other study. These are consistent with our findings from metaregression (Table 2); the smaller SIRPCR in studies with a greater proportion of child index cases may also suggest case ascertainment bias. The Chilean and Canadian studies enrolled households during peak periods of pH1N1 activity, and household contacts were followed up for 2 weeks37,39 and 3–4 weeks,35 potentially increasing the risk of misclassifying infections from the community or household tertiary cases as household secondary cases.
In comparison, studies that report interpandemic influenza transmission in households have also reported widely varying SIRs, from 7% to 31%.22,47,51 – 55 It is likely that factors that led to the significant variation and heterogeneity among the studies in this review of the SIR of pH1N1 also affected the SIR of interpandemic influenza. Only 3 studies directly compared the household transmission of interpandemic and pandemic influenza concurrently during a single season in a single population, and each reported comparable SIRs between interpandemic and pandemic strains.22,31,40 One study that was excluded from our review also reported similar secondary-infection risks for interpandemic and pandemic influenza based on serologic evidence from a cohort study in 2008–2009, explicitly estimating the risks of infections directly caused by household index cases.56 The variations in SIRs for both pH1N1 and interpandemic influenza highlight a critical need to formulate guidelines for conducting household studies of influenza so that we can gain more explicit insights into the natural history as well as the transmission within households.
Household serial interval estimates were reported in 18 of the 27 studies (67%) included in our review, with most point estimates falling in the range 2.8–3.5 days (Fig. 5). Correction for multiple chains of transmission (eg, tertiary cases) could reduce serial interval estimates and shorten the estimated mean to 2.5 days.9 The household serial interval is not a biologic constant but instead reflects a combination of the infectivity profile of index cases, contact patterns within households, transmission dynamics in the community, and incubation period—and these may vary in different settings and by individual characteristics such as age.57 – 59 Although estimates of the household serial interval have been used to infer the reproduction number from exponential growth rate of cases,60 further studies are needed to estimate the serial interval in various settings. For example, one recent study in the United States estimated that the serial interval of pH1N1 in schools had a mean of just 1.1 days.57
Some household studies permitted estimation of the fraction of virologically confirmed pH1N1 infections with asymptomatic illness at 7%–11%, and the profile of signs and symptoms associated with pH1N1 infection (Table 3). Estimation of the asymptomatic fraction was achieved by studies that collected specimens from contacts regardless of the presence or absence of symptoms.22,35,40,41,43 Only 5 of the 27 studies included in this review reported serologic data.21,22,26,35,40 The inclusion of serology can provide additional information on asymptomatic infections and on the degree of protection associated with higher baseline humoral antibody titers. There is currently no consensus on the definition of asymptomatic infections versus subclinical infections. The proportion of pH1N1 infections associated with afebrile illness could be a reasonable definition of the subclinical fraction, with estimates ranging from 33% to 47% (Table 3). Only a small fraction of confirmed infections were completely asymptomatic.22,26,35,41
Two major technical problems have yet to be solved regarding the analysis of data from household transmission studies. The first is the unobservable nature of infection events. In many studies, household follow-up was truncated at 7–9 days after illness onset of the index case, after which little primary household transmission occurs.61 Although not explicitly mentioned, the cut-off point should be set at a reasonable length to exclude tertiary cases and those acquiring infection in the community (based on the right tail of the serial interval distribution). Except for one study,20 the reviewed studies did not explicitly address decomposition of secondary, tertiary, and community infections when estimating the SIR. However, 2 other studies used viral sequencing to confirm homology between the strains infecting the index cases and corresponding secondary cases in households.35,62 Given that the larger SIRs and longer mean serial interval in some studies35,37 are suggestive of the presence of chains of transmission or community infections and consequent overestimation of the SIR, it is important to try to identify transmissions that occur only within households. Although several statistical methods are available to address this point at least partially (using either SIR stratified by household size or observed serial interval distribution59,63), those datasets were unfortunately fairly scarce, and irregular timing of observation during the course of an epidemic has made it difficult to remove the coprimary cases from the observed serial intervals. Furthermore, considering the dependent nature of household and community infection risks,64 we refrained from imposing strong epidemiologic assumptions to build a simplistic statistical model, and also from decomposing the observed data into those attributable to transmissions in the household and community. To address these issues, influence of household study characteristics on the estimate of SIR (including the length of follow-up and the timing of observation) were examined instead, demonstrating that the study design—most notably case ascertainment—was an important source of heterogeneity (Table 2). In particular, our meta-analysis has demonstrated that household studies can provide invaluable data on influenza infection; in studies that used febrile illness reports, the resulting estimates of the SIR could underestimate the true SIR (Fig. 4) because a substantial fraction of influenza infections are not associated with febrile illness (Table 3).
The second technical problem is the lack of an ideal approach to recruitment and follow-up of households during the course of an epidemic. Studies conducted during the early stages of the pandemic can provide timely estimates of epidemiologic characteristics, such as the SIR and serial interval, but the community risk of infection varies throughout the course of the epidemic, and the risk of infection within the household could be influenced by many factors, such as changing contact behavior on diagnosis. In one study, households recruited were quarantined and advised to remain at home; in such situations, there could be a higher degree of household contact leading to elevated SIRs.29 However, sampling households only around the peak period of the pandemic could lead to confusion of community infections as secondary cases from within the household, as well as to inclusion of some contacts that have already been infected and are immune. Furthermore, the sources and characteristics of index cases may affect subsequent transmission dynamics as discussed earlier. All these reservations likely apply equally to household studies of interpandemic influenza in households.
Based on our review, we have formulated some recommendations for household transmission study protocols for future studies of pandemic and interpandemic influenza. First, although many studies were conducted within a few months of the initial World Health Organization global pandemic alert in April 2009, other studies were delayed by requirements for protocol development, ethical approval, and funding. Some of the earliest studies were conducted as part of containment measures or routine public health investigations, and these studies often had the most haphazard approaches to recruitment and follow-up of households. The First Few 100 study conducted in the United Kingdom36 provides an excellent model of a household transmission study that was prepared in advance of the pandemic with a detailed protocol, relevant approvals, and funding in place before the pandemic.
Second, laboratory outcome measures are preferable in community-based studies of influenza because many other cocirculating pathogens are associated with upper respiratory tract infections.65 Febrile acute respiratory infections among contacts provided fairly specific criteria for confirmed pH1N1 infection, and estimates based on febrile acute respiratory infections could be corrected for the fraction of infections developing such illness to provide more reasonable estimates of the SIR. Given the technical issue discussed earlier regarding the direct interpretation of point estimates of overall SIRs and the heterogeneity reported in our meta-analysis (Figs. 2, 3), the most important information provided by household transmission studies may be on differences in infectivity and susceptibility by age, and the effects of specific interventions, such as antiviral use. Household SIRs have been used to provide these estimates in the literature because the exposure of household contacts to a single index case permits fairly straightforward analysis.66
Third, it must be remembered that the household SIR is theoretically defined to reflect the risk of infection among “susceptible” contacts,5 whereas many older adults are likely to have been partially or fully immune to pH1N1.67 Inclusion of serology in household studies could provide information on humoral immunity. With adequate laboratory capacity, other correlates of protection, such as cell-mediated and mucosal immunity, can be assessed through collection of whole blood and nasal washes.
Finally, there was considerable uncertainty in the early stages of the pandemic regarding the fraction of infections that were asymptomatic or subclinical. Along with well-designed prospective symptom diaries, collection of acute and convalescent serology from household contacts in household transmission studies could provide key information on asymptomatic cases, which is essential to interpreting epidemic curves of symptomatic cases and forecasting the course of the pandemic. One potential limiting factor, however, is the availability of validated serologic assays early in the next pandemic.
Household transmission studies can provide important information on influenza epidemiology. However, our review suggests that interpretation and comparison of estimates of the SIR from individual studies are substantially affected by differential diagnostic methods and case ascertainment. Furthermore, the unbiased risk of household secondary infection is only approximated by the crude household SIR, and it remains technically challenging to estimate the fraction of secondary cases that were directly infected by the index case. By building a consensus on the appropriate approaches to studying transmission in households (via, eg, common survey protocols), it is likely that household transmission studies could be greatly improved and provide valuable insights into the epidemiology of pandemic and interpandemic influenza.
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We thank Mark Simmerman and Dale Carcione for providing detailed breakdowns of the data on pH1N1 transmission from studies in Bangkok and Australia, respectively. We thank Richard Pebody for clarification on the data included in the series of publications based on the First Few 100 study in the United Kingdom. We thank Vicky Fang for technical assistance, and Katie Glass, Geoff Mercer, and Peter Horby for helpful discussions.© 2012 Lippincott Williams & Wilkins, Inc.