Incidence of Influenza-like Illness, Measured by a General Practitioner Sentinel System, Is Associated with Day-to-day Variations in Respiratory Health in Panel Studies

Saskia C. van der Zee, Gerard Hoek and Bert Brunekreef

From the Environmental and Occupational Health Group, University of Wageningen, Wageningen, Netherlands.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During three consecutive winters beginning in 1992–1993, the association between the incidence of influenza and influenza-like illness (ILI), measured by a general practitioner sentinel system, and respiratory health was investigated in an air pollution panel study. Data from 22 panels of children (7–11 years old) and adults (50–70 years old) in the Netherlands were used. ILI incidence was associated with peak expiratory flow, respiratory symptoms, and bronchodilator use. Peak ILI incidence of 122 cases/10,000 subjects was associated with a decrement in peak expiratory flow of 6% and a 3- to 4.5-fold increase in symptom reporting and bronchodilator use. In panel studies, ILI incidence might be used to adjust for confounding by acute respiratory infections. Am J Epidemiol 2000;152:389–92.

influenza; longitudinal studies; respiration; viruses

Abbreviations: ILI, influenza and influenza-like illness


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Panel studies following subjects for a certain period of time with regular observations of respiratory health status have been used frequently in air pollution epidemiology (1GoGo–3Go). Viral infections are common triggers of asthma symptoms in children and adults (4GoGoGo–7Go). Objective data on respiratory infections are not easily obtained in panel studies. For this reason, we investigated whether a surrogate variable, the incidence of influenza and influenza-like illness (ILI), registered by the Dutch network of general practitioner sentinel stations (8GoGo–10Go), was associated with indicators of respiratory health status (peak expiratory flow, respiratory symptoms, bronchodilator use) in panels of children and adults with and without chronic respiratory symptoms.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study was carried out during three consecutive winters starting in 1992–1993. Panels of children (7–11 years old) and adults (50–70 years old) with and without chronic respiratory symptoms were selected from an urban and a nonurban area on the basis of a screening questionnaire. Chronic respiratory symptoms were defined as "attacks of shortness of breath with wheezing," "dry cough at night apart from colds" (children) or "cough with phlegm 3 months in last 12 months" (adults), "doctor diagnosed asthma" (children), "current use of asthma medication" (adults), "exercise-induced shortness of breath" (adults), and "wheeze in last 12 months apart from colds" (children). The differences between the selection symptoms for children and adults were caused mainly by our use of internationally accepted questionnaires such as the European Community Respiratory Health Survey for adults and the World Health Organization questionnaire for children. During the 3-month study periods, daily measurements of peak expiratory flow were made, and the occurrence of acute respiratory symptoms and bronchodilator use was registered in a daily diary. A detailed description of the study is given elsewhere (11Go).

Data on influenza morbidity were obtained from a network of 46 sentinel general practices, covering about 1 percent of the Dutch population. The sentinel stations are spread over the country in proportion to population density. The number of new patients with ILI is registered every week from Monday to Friday. ILI must satisfy the following criteria:

  1. acute beginning, that is, a prodromal stage of no more than 3–4 days
  2. infection must be accompanied by a rectal temperature of >38°C
  3. one or more of the symptoms: cough, coryza, sore throat, frontal headache, retrosternal pain, and myalgia
Incidences were calculated according to age group per 10,000 per week. They were reported separately for the northern, eastern, southern, and western parts of the country and for three different degrees of urbanization (12Go). Because of the relatively small number of sentinel general practices in the country, no combinations of regions and degree of urbanization could be made.

For the urban areas, incidences for the highest degree of urbanization were used. For the nonurban areas, incidences were used for the appropiate regions. Age-specific incidences were used. Week-specific incidences were assigned to the 7 days of each week, assuming that the incidence on each day of the week was the same. The association between this same-day incidence of ILI (ILI0) and acute respiratory health was examined. In addition, the association between the mean ILI incidence in the preceding week, calculated as the 7-day moving average of the same day and the 6 preceding days (ILI0–6), and the weeks before that (ILI7–13 and ILI14–20) and respiratory health was evaluated.

The specification of the dependent variables obtained from the diaries (mean population peak expiratory flow deviation, prevalence of acute respiratory symptoms, and bronchodilator use) and of the modeling startegy in our panel studies is given elsewhere (11Go). All statistical analyses were conducted using SAS computer software (13Go). The minimum daily temperature, time trend, and an indicator variable for the day of the week (school/working day vs. weekend/holiday) were included in the model as potential confounders. Analyses were first performed per panel and then combined for the four groups (symptomatic and asymptomatic, children and adults).

A chi-square test was applied to test for heterogeneity in the effect estimates of the five or six panels within each of the four groups. In case of heterogeneity (defined as p < 0.25), combined effect estimates were calculated using random effects estimation (14Go). Odds ratios for the association between ILI incidence indices and the prevalence of symptoms and bronchodilator use were expressed for an increase in ILI incidence of 20 cases/10,000, for both children and adults, which is considered a relevant range (see Results).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 presents age-specific incidences of influenza and influenza-like illness (ILI0–6) reported during the study periods.


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TABLE 1. Mean, median, and range of the incidence of influenza and influenza-like illness (ILE) in the general population, registered by the Dutch network of sentinel stations, 1992–1995

 
During the winter of 1992–1993, an influenza epidemic occurred that started in the beginning of February and peaked during the third week of February, reaching maximum incidences of 67 and 65 cases/10,000 children in urban and nonurban areas, respectively. During the winter of 1993–1994, an early influenza epidemic occurred that started in the third week of November, peaked during the second week of December, and reached background values around the new year. The epidemic was more severe in the urban than in the nonurban area, reaching maximum incidences of 122 and 56 cases/10,000 children, respectively. For adults, a similar time course of ILI incidence was observed. Maximum incidences were 70 and 39 in the urban and the nonurban area, respectively. During the third winter no major influenza epidemics occurred. The maximum incidence rates were at or below 20 cases/10,000 subjects.

Pearson's correlations between urban and rural incidences were 0.87–0.96 during the winters of 1992–1993 and 1993–1994 but lower (0.70 for children and 0.14 for adults) in 1994–1995 when no influenza epidemics occurred. ILI0–6 was more strongly associated with respiratory health than ILI0, so only the results of the analyses with ILI0–6 are presented here.

Tables 2 (children) and 3 (adults) present the combined effect estimates for ILI0–6 and peak expiratory flow, prevalence of symptoms, and bronchodilator use. In all four groups of panels, ILI0–6 incidence was associated with a lower peak expiratory flow and with more symptoms and bronchodilator use. ILI7–13 was also associated with evening peak expiratory flow, upper respiratory symptoms, and bronchodilator use, but less so than ILI0–6. ILI14–20 was not associated with respiratory health (results not shown). When analyzed in one model, ILI0–6 and ILI7–13 were found to be independently associated with respiratory health.


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TABLE 2. Combined{dagger} effect estimates and odds ratios (ORs) with 95% confidence intervals (CIs) for the association between an increase in ILI0–6 incidence{ddagger} of 20 cases/10,000 subjects and peak expiratory flow (PEF), symptom prevalence, and bronchodilator use for children, registered by the Dutch network of sentinel stations, 1992–1995

 

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TABLE 3. Combined{dagger} effect estimates and odds ratios (ORs) with 95% confidence intervals (CIs) for the association between an increase in ILI0–6 incidence{ddagger} of 20 cases/10,000 subjects and peak expiratory flow (PEF), symptom prevalence, and bronchodilator use for adults, registered by the Dutch network of sentinel stations, 1992-1995

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The incidence of influenza and influenza-like illness, registered by general practitioner sentinel stations, was associated with respiratory health in panels of symptomatic and nonsymptomatic subjects from defined geographic areas. The combined effect estimates indicated that an increase in ILI incidence of 20 cases/10,000 subjects was associated with a 0.1–1 percent lower level of peak expiratory flow and with an increase in the prevalence of respiratory symptoms and bronchodilator use of 2–28 percent. For a major influenza epidemic reaching peak ILI incidences of 122 cases/10,000 subjects, this corresponds to peak expiratory flow decrements of up to 6 percent and an increase in symptom reporting and bronchodilator use by factors of up to 2.9 and 4.5, respectively. A positive association was found between the incidence of ILI and the prevalence of upper and lower respiratory symptoms, as expected from viral infections (15Go). Epidemiologic studies have also shown that several types of viral infection can exacerbate asthma symptoms in children (16GoGo–18Go).

Potential confounders that might bias the observed associations are meteorologic variables (mainly ambient temperature), air pollution, and long-term time trend. Air pollution is a potential confounder since it might be associated independently with both respiratory infections and respiratory health. However, exposure to low level air pollution is probably not a major determinant of respiratory infections; in addition, the correlation between particulate matter with an aerodynamic diameter of <10 µm (PM10) (as an indicator for air pollution) and ILI incidence was low. We have adjusted for ambient temperature and for long-term time trend (generally in the order of weeks) in peak expiratory flow and the prevalence of symptoms. However, those factors might be associated with respiratory infections in the panels and, thus, the potential of overadjustment exists, resulting in an underestimation of the coefficients for ILI incidence. Reporting bias might have occurred because of a subject's increased awareness of respiratory symptoms during influenza epidemics. However, it is not likely that this type of bias was an important factor because our study was focusing on the effects of air pollution. Moreover, associations between ILI incidence and respiratory health were also observed during the third winter when no influenza epidemics occurred.

The observed association between ILI incidence and respiratory health in selected panels implies that, in panel studies, the incidence of ILI might be used to adjust for the potential confounding effect of respiratory infections. For example, during investigations of the effect of ambient air pollution on respiratory health, respiratory infections can confound the association if they coincide with periods of high or low air pollution. Since the effect of air pollution on respiratory health is of the same order of magnitude or less (19Go, 20Go) than the effect of elevated ILI incidence, this might lead to substantial over- or underadjustment of the effect of air pollution. Our study has also shown that the ILI incidences of the previous week (0–6 days earlier) and of 2 weeks earlier (7–13 days earlier) were independently associated with indicators of respiratory health and, thus, should both be taken into account when adjusting for the potential confounding effect of respiratory infections.

In conclusion, the incidence of ILI, registered by the Dutch sentinel station registration network, was associated with reduced peak expiratory flow and increased reporting of symptoms and bronchodilator use in panels of symptomatic and nonsymptomatic children and adults.


    ACKNOWLEDGMENTS
 
The main study from which these data were taken was funded by the Netherlands Asthma Foundation and the Ministry of the Environment.

The authors thank the Dutch Institute of Primary Health Care (NIVEL) for providing the data on the incidence of influenza-like illness.


    NOTES
 
Correspondence to Dr. Bert Brunekreef, Department of Environmental Sciences, Environmental and Occupational Health Group, University of Wageningen, P.O. Box 238, 6700 AE Wageningen, Netherlands (e-mail: bert.brunekreef{at}staff.eoh.wau.nl).


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Received for publication July 30, 1998. Accepted for publication November 17, 1999.