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C Viboud, P Boëlle, S Cauchemez, et al Risk factors of influenza transmission in
households
Cécile Viboud, Pierre-Yves Boëlle, Simon Cauchemez, Audrey Lavenu, Alain-Jacques Valleron, Introduction
Background: Influenza transmission in households is a subject of
renewed interest, as the vaccination of children is currently under debate
and antiviral treatments have been approved for prophylactic use.
THE epidemiology of influenza transmission in households has been the subject of great interest and investigation in Aims: To quantify the risk factors of influenza transmission in
the past, with the rationale that a better understanding of influenza transmission mechanisms could aid in the design Design of study: A prospective study conducted during the 1999 to 2000
of efficient control strategies.1 Several follow-up studies of families during one or several consecutive influenza seasons Setting: Nine hundred and forty-six households where a member, the
have described the occurrence and spread of infection in index patient, had visited their general practitioner (GP) because of an households in relation to age, family composition, crowding, influenza-like illness were enrolled in the study. Five hundred and ten of circulating viral strains, exposure in the community, and the index patients tested positive for influenza A (subtype H3N2). Astandardised daily questionnaire allowed for identification of secondary cases of influenza among their household contacts, who were followed-up The current thinking regarding influenza transmission is for 15 days. Of the 395 (77%) households that completed the that children play a major role in the early stages of the questionnaire, we selected 279 where no additional cases had occurred on epidemic, with the assumption that they are more suscepti- the day of the index patient’s visit to the GP. ble than older age groups, and that they contribute more Methods: Secondary cases of influenza were those household contacts
extensively to the spreading of the virus in the population.3 who had developed clinical influenza within 5 days of the disease onset Furthermore, children spend a great deal of time in com- in the index patient. Hazard ratios for individual clinical anddemographic characteristics of the contact and their index patient were munities where daily contact with other people is extensive; derived from a Cox regression model. for example, in schools, play groups, and daycare centres, Results: Overall in the 279 households, 131 (24.1%) secondary cases
and it is assumed that close contact favours transmission.3 occurred among the 543 household contacts. There was an increased risk However, the extent to which these mechanisms contribute of influenza transmission in preschool contacts (hazard ratio [HR] = to transmission has not been quantified.
1.85, 95% confidence interval [CI] = 1.09 to 3.26) as compared with Recently, there has been renewed interest in the study of school-age and adult contacts. There was also an increased risk in influenza transmission in families, especially in light of the contacts exposed to preschool index patients (HR = 1.93, 95% CI = 1.09to 3.42) and school-age index patients (HR = 1.68, 95% CI = 1.07 to recent debates about whether large-scale vaccination of 2.65), compared with those exposed to adult index cases. No other factor healthy children in daycare would be beneficial to other age was associated with transmission of the disease. groups,4,5 and whether contact prophylaxis with neu- Conclusion: Our results support the major role of children in the
raminidase inhibitors could effectively prevent transmis- dissemination of influenza in households. Vaccination of children or sion.6-8 However, no data are available on the quantitative prophylaxis with neuraminidase inhibitors would prevent, respectively, evaluation of the predictors of influenza transmission in 32–38% and 21–41% of secondary cases caused by exposure to a sick child in the household.
Keywords: antivirals; children; epidemiology; influenza; prospective
In this work, we analyse a prospective study of influenza studies; risk factors; vaccination. transmission in families conducted in France during the1999 to 2000 influenza season, where influenza-positiveindex patients were identified by virological tests.9 From this C Viboud, PhD, research fellow, Epidemiology and Information Sciences, study we assess the risk factors for influenza transmission Université Pierre et Marie Curie, Paris; Fogarty International Center, associated with the individual characteristics of index National Institute of Health, Bethesda; WHO Collaborating Center for Electronic Diseases Surveillance (WHO CCEDS), Paris. patients and their household contacts.
P-Y Boëlle, PhD, lecturer; A-J Valleron, DRSC, director; F Carrat, MD, PhD, lec- turer, Epidemiology and Information Sciences, Université Pierre et Marie Curie, Paris; Assistance Publique des Hopitaux de Paris, Paris. S Cauchemez, MPH, research fellow; A Lavenu, MPH, research fellow, Epidemiology and Information Sciences, Université Pierre et Marie Curie, Paris. A Flahault, MD, PHD, professor; Epidemiology and Information This study, which is described in detail elsewhere,9 was Sciences, Université Pierre et Marie Curie, WHO CCEDS, Paris Assistance Publique des Hopitaux de Paris, Paris.
conducted within the framework of the French Sentinel network. The Sentinel network is a computerised public health surveillance system compiled with the voluntary and Cécile Viboud, Fogarty International Center, National Institutes of Health, 16 Center Drive Bethesda, MD 20892, USA. unpaid participation of 1790 general practitioners (GPs) located all over France. Since November 1984 it has been Submitted: 15 August 2003; Editor’s response: 18 December 2003; collecting weekly reports on 10 communicable diseases, including influenza-like illness. In addition to the continuous British Journal of General Practice, 2004, 54, 684-689.
surveillance of disease activity, the network is a setting for British Journal of General Practice, September 2004
HOW THIS FITS IN
influenza viruses is the transmission between household members. Children are more susceptible than older age groups, and they contribute more extensively to the spreading of the virus in the population.
This study quantifies the risk factors of influenza transmission in households and investigates the impact of two interventionstrategies for controlling epidemics within them. Vaccination of children or prophylaxis with neuraminidase inhibitors would prevent, respectively, 32–38% and 21–41% of secondary casescaused by exposure to a sick child.
thorough investigations conducted over limited time peri- ods.10,11 One hundred and sixty-one of the GPs from the network volunteered to participate in this specific study of influenza transmission in households. They received train-ing on the study protocol and virology sampling during a A household was enrolled when a member visited the GP and met the following inclusion criteria: the patient had hada fever >38°C within 48 hours of the visit, together with res-piratory signs; there was at least one other member in thehousehold; the consulting patient was the first case in thehousehold; the patient was not hospitalised as a result of this visit. If the inclusion criteria were met, the patient wasconsidered to be the index case of the household. Following discussion of this observational follow-up by the study sci- entific committee and jurists from the institutional sponsor, oral consent was obtained from the index patient (or the index patient’s parents if the index patient was a child). All studies conducted within the framework of the Sentinel net- work are approved by the French Commission Nationale del’Informatique et des Libertés (approval no. 471 393).
Information concerning social and demographic charac- teristics of the household was collected upon enrollment in the study. Daily details about 13 symptoms (fever >38°C; feverishness; cough; sore throat; nasal congestion, rhinor- rhea or sneezing; dysphonia; fatigue; headache; stiffness ormyalgias; otalgias; ocular symptoms; loss of appetite; sleep Figure 1. Flow diagram of the study. Dotted boxes denote subjects disturbances), medication, visits to physicians, and missed days of work of each household member, were reported in astandardised questionnaire for the 15 days following the Respiratory syncytial virus, parainfluenzae virus and aden- initial visit of the index patient to their GP. The initial visit was ovirus infections were diagnosed with the immunofluores- counted as day 0 of the follow-up. A daily severity score was cence test.9 Influenza was diagnosed where one or more calculated as the proportion of the 13 symptoms reported results with the immunofluorescence test, viral culture and on a given day (ranging from 0 to 1) as described else- the polymerase chain reaction (PCR) test were positive. Of where.9 All participants who completed the questionnaire the 946 index patients, 510 were influenza A (subtype H3N2)-positive and, of these, 395 (77%) completed the fol-low-up with their household contacts (Figure 1). The 510 influenza A-positive patients were located in 21 of the 21 Between January 2000 and March 2000, 946 index patients administrative regions of France. The median number of and their household contacts were enrolled in the study.
index cases per region was 16, with a range of 2–61. At Nasal swabs were obtained from all index patients.
inclusion, the only difference between households that com- British Journal of General Practice, September 2004
C Viboud, P Boëlle, S Cauchemez, et al pleted the study (n = 395) and those lost to follow-up (n = 115) was in the sex of the index patient: 19% of the Although occurrence of secondary transmission is the ult- households with a female index patient and 26% of those imate outcome of interest in this work, time to transmission with a male index patient were lost to follow-up (P = 0.04).
is important as well, because the level of exposure to In particular, there was no difference regarding variables influenza in the household is not constant over time.
such as the age of the index patient, severity of the disease Household members became sick and recovered during on the first day of illness, body temperature, and inclusion the study follow-up. Adjustment for factors that varied between households; for example, exposure to influenza We used a clinical definition of influenza, without labo- and household structure, was needed to assess the true ratory testing, to identify secondary patients. Clinical role of individual predictors of transmission. The Cox model influenza was defined as the presence of a fever >38°C, or is a popular regression model used to assess the relation of feverishness when the temperature was not taken, or at explanatory covariates to the time of occurrence of events, least two of the following symptoms: cough; sore throat; which in this study is the onset of clinical influenza in con- nasal congestion, rhinorrhoea, or sneezing; fatigue; tacts. This model allows adjustment for time-dependent headache; stiffness; myalgias. This definition is based on covariates; for example, the level of exposure to influenza in the criteria that define influenza-like illness in clinical trials of neuraminidase inhibitors.7,8,13 Household contacts who Extensions to the Cox model exist that deal with the developed clinical influenza within 5 days of the initial visit dependence between observations, in particular for correlat- of the index patient were classified as secondary patients.
ed household members. In this study, dependence between To avoid ambiguity about the true introducer of infection in household contacts is due to shared household structure the household, we excluded households in which one or and exposure to the same index patient.17 Household con- more contacts had developed clinical influenza on the day tacts who had not developed clinical influenza within 5 days of the initial GP visit of the index patient (day 0) from the (412/543 [75.9%]) were considered as censored (for these main analysis. The incubation period of influenza is contacts, transmission events had not occurred within around 1–1.5 days,14,15 therefore this procedure minimises the probability that the household members (index patient Similarly to previous studies of influenza transmission in and contacts) were infected from a common source from families,18 we distinguished between preschool children outside the household and not by transmission within the (0–5 years old), school-age children (6–15 years old), and household. Among the 395 households that completed adults (>15 years) to quantify the effect of age. Size limita- the study, 116 reported potential co-existing primary tion did not allow for more refined subcategories, such as patients and were excluded from the main analysis. We infants or adolescents. We included the following covariates subsequently performed sensitivity analyses with an separately in the model: age of the household contact (0–5, extended dataset that included those households where 6–15, >15 years); influenza vaccination of the contact; co-existing primary cases were reported on the day of the influenza-like illness of the contact in the previous year; his- initial visit, and also a more specific definition of clinical tory of chronic disease and tobacco consumption of the influenza based on the combined presence of fever >38°C contact; duration of illness of the index patient (above or below the median); and severity of disease of the index In the remaining 279 of households, the mean number of patient on the first day of symptoms (above or below the children per household under 15 years of age was 0.71. This median). We also adjusted for three household-specific is in line with the national figure of 0.68 for French house- parameters that could confound individual characteristics: holds of two or more members.12 The mean age of index the number of children ≤15 years in the household, the num- patients was 38.4 years (standard deviation [SD] = 19.4), ber of adults, and the level of exposure to influenza infection 241 (86.4%) of them were adults (mean age = 43.1 years, in the household. We used a daily index, calculated as the SD = 16.6) and 38 (13.6%) were children aged ≤15 years sum of the severity scores of the household members (the (mean age = 9.1 years, SD = 4.7) of whom 10 (3.6%) were daily severity score was the proportion of symptoms report- <5 years of age. Ten per cent of the index patients were ed on a given day among the 13 listed in the questionnaire vaccinated against influenza, and 14% had experienced and ranged from 0 to 1) as a proxy for the level of exposure clinical influenza in the preceding year.
In the 279 households there were 615 contact members.
Upon completion of the study and data entry by trained We disregarded 72 contacts with insufficient information on personnel, less than 4% of the information was missing.
clinical follow-up, and in the final analysis included 543 con- Because of the low rate of missing values, these values tacts, with a mean age of 32.1 years (SD = 19.9), compris- were not replaced. All statistical analyses were carried out ing 401 (73.8%) adults (mean age = 40.4 years, SD = 16.3) and 142 (26.2%) children (mean age = 8.7 years,SD = 4.1) of whom 36 (6.6%) were below 5 years of age.
The proportion of children among the 72 contacts who didnot fully complete the questionnaire was 26%. Seven per cent of the household contacts were vaccinated against Overall, 131 (24.1%) of the 543 contacts developed symp- influenza, and 9% had experienced clinical influenza in the toms of influenza within 5 days of the onset of disease in the index patient, and hence were considered as secondary British Journal of General Practice, September 2004
Table 1. Comparison of demographic data for household contacts (n = 543), grouped by secondary cases and non-case contacts. Chronic diseases (n [%]) 45 (10.9) aP for trend = 0.06. SD = standard deviation.
Table 2. Hazard ratios for individual predictors of influenza Figure 2. Number of secondary cases of influenza by day of household transmission, adjusted on a daily score for exposure to household outbreak. Overall there were 131 secondary cases. Day influenza infection, the number of children under 15 years old and 0 is the day of onset of influenza A (H3N2) illness in the index case the number of adults in the household. = day of the visit to the general practitioner. cases. Influenza transmission was observed in 97 (35%) households. Of the 97 households, 67 (69.1%) reported one secondary case, 26 (26.8%) reported two, and four (4.1%) reported three. The median time lag between the onset of influenza in the index patient and the onset of symptoms in the secondary patient was 2 days (range = 1–5 days) (Figure 2). The demographic and medical data for the secondary patients and non-case household contacts are presented in Table 1. We found no significant differences in the individual characteristics of these two groups of contacts with regard to age, sex, smoking status, history of chronic disease, influenza vaccination, or previous influenza-like ill- ness. However, clinical influenza was reported in 38.5% (10/26) of contacts in households where the index patient belonged to the 0–5 years age group, in 33.7% (28/83) of the 6–15 years age group and in 21.4% (93/434) of adults, (Cochran-Armitage trend test, P = 0.004). Note that these estimates are not adjusted on household structure.
Households in which the index patient was a child had more children than those where the index patient was an adult The median severity of disease on day 0 (proportion of 13 clinical symptoms reported on the day of the visit to the general practitioner) was (respective median number of children = 2 versus 1, 0.65 for index cases (range = 0–1). bThe median duration of disease was 8 days in index cases (range = 0–15). CI = confidence interval.
Risk factors of influenza transmission in 1.68, 95% CI = 1.07 to 2.65), compared with those exposed The Cox statistical analysis showed that transmission of to adult index patients. No other factor related either to the influenza was clearly associated with the age of both the contact or to the index patient was associated with influenza index patient and the contact. We found an increased risk of clinical influenza in preschool contacts compared with We tested the effect of discarding the households where adults, with a hazard ratio (HR) of 1.85, 95% confidence co-existing primary cases were reported on the day of the interval (CI) = 1.09 to 3.26. There was no increased risk in initial visit to the GP from the analysis. We repeated the ini- school-age contacts (HR = 1.12, 95% CI = 0.73 to 1.71).
tial statistical analysis with an extended dataset comprising There was also an increased risk of clinical influenza in con- all households (n = 395), in which 313 secondary cases tacts exposed to preschool index patients (HR = 1.93, 95% were reported (secondary attack rate in contacts = 38.3%).
CI = 1.09 to 3.42) and school-age index patients (HR = We retrieved similar results, but all hazard ratio estimates British Journal of General Practice, September 2004
C Viboud, P Boëlle, S Cauchemez, et al were somewhat closer to one than those of the main analy- combination of cough and fever as case definition,16 we sis. There was an increased risk of clinical influenza in found risk estimates consistent with those derived from our preschool contacts (HR = 1.90, 95% CI = 1.35 to 2.67) but original broader definition, although some of our risk est- not in school-age contacts (HR = 0.94, 95% CI = 0.71 to imates were no longer significant due to lack of statistical 1.26). There was also an increased risk of clinical influenza in contacts exposed to young index patients, with a hazard The choice of a time period of 1–5 days from the inclusion ratio of 1.62, 95% CI = 1.31 to 2.00 for preschool index of index patients to the onset of symptoms in secondary patients and a hazard ratio of 1.27, 95% CI = 1.03 to 1.57 for patients (mean delay = 2.4 days) minimised the risk of infections from non-influenza pathogens and from extra- The additional sensitivity analysis using a more specific household sources. Indeed, in the present study, we found definition of clinical influenza (based on fever and cough) influenza transmission in 24.1% of the household contacts gave results in line with those from the main analysis. The and in 34.8% of the households. These figures are within the secondary attack rate in contacts was 18.1%. There was an range of previously published estimates in comparable increased risk of clinical influenza in preschool contacts (HR = 2.28, 95% CI = 1.46 to 3.59) but not in school-age con- Overall, although we do not know the exact proportion of tacts (HR = 0.61, 95% CI = 0.37 to 1.01). Although no more patients with influenza among the contacts showing symp- significant, the magnitude of risk and confidence intervals toms of clinical influenza, we can provide an estimate. It has associated with the age of the index patient was consistent been reported that 75–80% of household transmissions with the previous estimates (HR = 1.03, 95% CI = 0.42 to occur directly from the influenza-positive index patient or 2.54) for preschool index patients and HR = 1.44, 95% CI = from the same source of infection as the index patient.7,8 In 0.83 to 2.51 for school-age index patients. this group, all of the clinical secondary cases have aninfluenza aetiology. The remaining 20–25% are due to trans- Discussion
mission from the community at large.7,8 In this second The present study identifies age of index patients and age of group, the probability of infection by influenza equals the contacts as the main predictors of influenza transmission in prevalence of influenza in the community. From the propor- families. These factors appear to be more important than tion of influenza infections in index patients at inclusion we other individual variables, whether they are related to the estimate the prevalence of influenza in the community at contact person or to the index patient. Based on our risk 54% in this study. A plausible range estimate of the propor- estimates, 40–48% of the secondary cases exposed to a tion of influenza infection among secondary patients is child sick with influenza in the household are attributable to Reasons for increased transmission from children The role of children in the dissemination of influenza is com- Two factors may have harmed the validity of our results. The monly accepted,2,3 and can be explained by three different first is that the household contacts were not tested for and possibly complementary mechanisms. First, children are influenza infection to limit intervention bias.9 It is therefore believed to experience a large number of extra-household possible that some of the clinical infections detected here contacts with their peers in schools or daycare centres, may be due to respiratory viruses other than influenza.
although very little quantitative information is available on the However, there was little circulation of other respiratory subject. Our study was not designed to test this mechanism.
viruses in the community during the study period: only 25 of Second, children are assumed to be more susceptible to the 946 (2.6%) index patients tested positive for respiratory influenza infection because of lower immunity, although it syncytial virus and none were found to be positive for depends on virus (sub)types and setting.3,21 Accordingly, we parainfluenzae virus or adenovirus. Furthermore, a recent found evidence of increased susceptibility to clinical influen- investigation of the genetic sequences of influenza viruses za in preschool children. We have no clear explanation as to recovered in families suggested that transmission from com- why there was no increased susceptibility in school-age chil- munity sources was rare in families where an index patient dren, but influenza A (H3N2) infections usually have a wider distribution of age-specific attack rates than influenza A Instead of laboratory tests, we used a broad clinical defin- (H1N1) or influenza B infections.18 It is also possible that few ition based on fever or respiratory signs to identify sec- differences in susceptibility between adults and school-age ondary cases. Indeed, 38% of contacts classified as sec- children occurred in this particular year, due to the circulation ondary patients did not report a fever. In patients consulting of the same influenza viruses (A/Sydney/5/97-like viruses, physicians for a respiratory illness during an influenza epi- A/H3N2 subtype) for the third consecutive winter. Third, chil- demic period, the relative risk that fever >37.8°C is associ- dren could also be more infectious both because of an ated with an influenza diagnosis was 2.5 in one study (4.6 for increased amount of virus shedding and an increased dura- influenza A [H3N2] specifically),20 and 3.3 in another.16 tion of the infectious period, as reported in recent clinical However, syndromes associated with true influenza infection studies.22,7 Our results are in line with these findings.
do not necessarily always include fever. In the latter studies,30–40% of patients with respiratory syndromes caused by Strategies for limiting secondary transmission of influenza were afebrile. Furthermore, by applying a specific British Journal of General Practice, September 2004
This work provides a quantification of the major role of chil- symptoms predicting influenza infection. dren, and particularly younger children, in the transmission Extending the Cox model. New York: Springer- of influenza in families. Based on attributable fractions of exposure to sick children in the household of around 18. Monto AS, Sullivan KM. Acute respiratory illness in the community.
40–48% we can assess the potential impact of two interven- Frequency of illness and the agents involved. tion strategies. The first is the vaccination of children in 19. Gubareva LV, Novikov DV, Hayden FG. Assessment of advance of the epidemic season. The efficacy of influenza hemagglutinin sequence heterogeneity during influenza virus vaccine has been estimated to be around 80% in preventing 20. Carrat F, Tachet A, Rouzioux C, et al. Evaluation of clinical case the disease in children.23 Thus, 32–38% of the secondary definitions of influenza: detailed investigation of patients during the household cases from exposure to a sick child could be 21. Longini IM Jr, Koopman JS, Haber M, Cotsonis GA. Statistical averted by vaccinating children. The second is the prophy- inference for infectious diseases. Risk-specific household and lactic treatment of household contacts with neuraminidase inhibitors after exposure to a child sick with influenza.
22. Nicholson K, Webster RG, Hay A. Textbook on influenza. Oxford: Parents usually consult a GP or a paediatrician if their child has symptoms of influenza-like illness, so the diagnostic of 23. Nicholson KG, Wood JM, Zambon M. Influenza. influenza needs to be established. Using rapid influenza 24. Uyeki TM, Fukuda K, Cox NJ. Influenza surveillance with rapid tests during the visit would allow identification of 72–95% of children truly sick with influenza.24 If the time since onset ofsymptoms in the child diagnosed with influenza is less than Acknowledgments
48 hours, then prophylaxis of contacts can be initiated with We thank the patients, their families and the 161 GPs of the French an efficacy of around 74–89% in preventing the disease.23 Sentinelles network who participated in the study. This study was partly This strategy would prevent 21–41% of cases in exposed supported by a grant from GlaxoSmithKline, Marly-Le-Roi, France.
Cécile Viboud was supported by a grant from the French Ministry of household contacts. These figures should help clinicians Education and Research and the Fondation pour la Recherche choose adequate strategies for controlling the size of Médicale at the time of this study.
influenza epidemics within households.
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