METHODS

Children, aged 1–7 years, with two or more previous wheezing episodes, were enrolled from a paediatric community practice and an emergency department during two consecutive winters (1997/1998, 1998/1999) into this concurrent case–control study.

Cases had previous wheezing and current symptoms of an upper respiratory infection and acute wheezing (clinical score of at least 1). Controls had previous wheezing and current symptoms of an upper respiratory tract infection, without acute wheezing (clinical score of 0) at the time of enrolment or within the week following enrolment. Children were excluded if they had received immunisation for influenza in the year of enrolment. The study was approved by the Hospital for Sick Children Research Ethics Board, and informed parental consent was obtained.

Baseline characteristics were collected and wheezing severity was graded using a clinical score (minimum to maximum range: 0–10). Nasopharyngeal swab specimens were collected and examined for influenza viruses A and B and RSV by immunofluorescence microscopy (antibodies from Light Diagnostics, Temecula, CA) and cell culture (RMK cells: Viromed Diagnostics, Minniapolis, MN; and MDCK cells: American Type Culture Collection, Rockwood, MD).

The odds ratio and 95% confidence interval were determined for influenza virus and RSV in children with acute wheezing (cases) relative to children with upper respiratory symptoms alone (controls). Separate analyses were undertaken for community cases versus controls, and all cases (community and emergency cases) versus controls.

RESULTS

Table 1 shows baseline characteristics. Table 2 shows the association between acute wheezing and virus infection. For influenza virus, the odds ratio indicates that infection is not associated with acute wheezing. The adjusted odds ratio (all cases versus controls) for the risk of acute wheezing in those with influenza was 0.52 (95% confidence interval, 0.27 to 1.03). For RSV, the odds ratio indicates that infection is associated with a threefold increase in the risk of acute wheezing.

Children with influenza virus (n = 43) and RSV (n = 58) were compared. Children with influenza virus were older (median age 3.6 years v 2.4 years, p = 0.002), had a lower median clinical score (0 v 2, p < 0.001), were more likely to be recruited from the community practice (87% v 59%, p = 0.003), and were less likely to be wheezing acutely (47% v 81%, p = 0.0003), compared to children with RSV. There were no differences in sex, history of smoke exposure, family history of asthma, and history of atopy.

DISCUSSION

When cases and controls were analysed for the viral aetiology of their respiratory illness, cases were three times as likely to be infected with RSV, but almost half as likely to be infected with influenza virus compared with controls. This finding existed in both the community and emergency department setting.

An extensive body of literature, summarised by Pattemore and colleagues,² has found that influenza virus and RSV are commonly identified in wheezing illnesses and asthma exacerbations occurring in childhood. The interpretation of these studies is compromised in that control groups were not included for comparison. The unique contribution of our study was the inclusion of a control group, to allow for an estimate of the strength of the association.

Our study may be limited by the case–control study design. Although a prospective cohort study would be appropriate, this would be an intensive and invasive process, requiring participants to undergo repeated nasopharyngeal swabs, both when symptomatic (wheezing) and asymptomatic (not wheezing). Therefore, we designed a case–control study, in which controls were chosen to be free of wheezing (outcome) but comparable to cases with respect to risk of exposure. Thus, controls were selected from those individuals seeking care for broadly defined symptoms of an upper respiratory infection. A strength of the design was the inclusion of both community and emergency department controls. Furthermore, determination of outcome (wheezing) and exposure (virus infection) was conducted concurrently.

An unexpected finding was the trend of the association between influenza virus and wheezing, suggesting that infection might actually be associated with a reduced risk of wheezing (adjusted odds ratio 0.52, 95% confidence interval, 0.27 to 1.03). While this may have been a chance finding, it contrasts with previous studies, which have found a high influenza virus related morbidity in children with recurrent wheezing and asthma.³

New hypotheses have emerged regarding the role of viruses in promoting or preventing the development of persistent wheezing and asthma.⁴ Exposure to older children at home, children at day care, and repeated viral infections (other than lower respiratory tract infections) are thought to be protective.^5,6

Understanding the role of respiratory viruses in triggering acute wheezing, and in the long term development or prevention of recurrent wheezing, will be important when considering strategies such as immunisation and antiviral therapy. In this context, we conclude that in our study the role of influenza virus in triggering acute wheezing in young susceptible children less than 7 years of age was weak, while the role of RSV in these children was strong.