Several studies carried out in recent years have provided increasing evidence for the great disease burden of influenza in children.1–6 During annual outbreaks, the attack rates of influenza are consistently highest in children.7 Influenza frequently gives rise to bacterial complications such as acute otitis media,3,4,8,9 and young children are hospitalized for influenza-related illnesses at rates comparable to those seen in the elderly.1,2,5,10,11 Children also have a central role in the spread of influenza in the community,12–15 and the socioeconomic impact of pediatric influenza on children and on their household members is substantial.16,17
The great impact of influenza on children calls for increased attention to effective management of this illness in the youngest age groups. Influenza vaccination of young children is currently recommended in some countries (eg, the United States, Canada, and Finland) but despite the recommendations the vaccination rates remain low in many areas.18 For the treatment of influenza, the neuraminidase inhibitor oseltamivir is licensed for use in children 1 year of age or older. When started within 48 hours of the onset of symptoms, oseltamivir treatment shortens the duration of influenza by 1.5 days and reduces the development of acute otitis media as a complication by more than 40%.19,20 Neuraminidase inhibitors are also effective for postcontact prophylaxis of influenza in the family setting.21,22
The difficulty of diagnosing influenza on clinical grounds alone is an important limiting factor for the institution of antiviral treatment in young children.23,24 This is particularly true for the primary care where the routine use of influenza rapid tests for all febrile patients during a busy epidemic period may not be feasible. Most of our knowledge about the clinical presentation of influenza in children is derived from studies on hospitalized children with severe forms of influenza,25 which can distort our concept about the signs and symptoms of influenza in the average child. The aim of this study was to assess the clinical presentation of influenza in various age groups of unselected children seen in the primary care setting.
MATERIALS AND METHODS
This prospective cohort study was carried out in Turku, Finland, during 2 consecutive winter seasons of 2000 to 2002.4 Children younger than 13 years of age were enrolled in the study cohorts before the start of each respiratory season; no exclusion criteria were used. The numbers of children followed-up throughout each respiratory season (October through May) were 1338 and 893, respectively; 758 children who were followed-up during the first season continued in the study during the second season also. Overall, the study comprised 2231 child-seasons of follow-up.
The study protocol was approved by the Ethics Committee of Turku University Hospital. Written, informed consent was obtained from the parents of all participating children.
The parents were instructed to bring their children to the study clinic at any signs of fever or respiratory infection. The study clinic was open everyday. No charge was made for any of the visits, and the families were not compensated for their travel costs or time lost from work. At each visit, the children were thoroughly examined by a study physician, and a standardized case record form was filled out for each child during every visit. The case record form contained detailed questions about the presence and duration of preceding signs and symptoms of the child (rhinitis, cough, sore throat, fever, earache, headache, myalgia, sleep disturbance, vomiting, diarrhea, and any other symptoms), detailed findings during the clinical examination, results of any laboratory tests or radiographs, and the diagnosis and treatment. The children were routinely re-examined after 5 to 7 days, but for the purposes of this analysis, only signs and symptoms recorded at the initial visit to the study clinic were included.
During each episode of respiratory infection, a nasal swab was obtained for determination of the viral etiology of the illness. The specimen was obtained from a depth of 2–3 cm in the nostril using a sterile cotton swab that was then inserted into a vial containing viral transport medium.26 Detection of influenza viruses in the specimens was based on viral culture in Madin-Darby canine kidney cell line and subsequent immunoperoxidase staining with monoclonal antibodies.27
Gastrointestinal symptoms included vomiting, diarrhea, and abdominal pain. Conjunctivitis was defined as distinct redness of the conjunctivae or purulent discharge from the eyes. The diagnosis of acute otitis media was based on signs and symptoms of acute infection, together with the presence of middle ear fluid detected by pneumatic otoscopy. The diagnoses of pneumonia and sinusitis were based on radiologic confirmation of the condition in an acutely ill child.
For continuous data, the groups were compared by the t test or by the Mann-Whitney U test in the case of failed normality test. Comparison of proportions between the groups was performed by the standard χ2 test. A P value <0.05 was considered to indicate statistical significance.
A total of 372 episodes of culture-confirmed influenza were diagnosed; 262 episodes during the first season and 110 during the second. Two children were excluded from the analyses because of confirmed double viral infection (1 with adenovirus and another with parainfluenza virus). Seventeen children had incomplete data on the degree or duration of fever, and they were also excluded from the analyses. Of the 353 episodes included in the final analyses, 101 (29%) occurred in children younger than 3 years of age, 160 (45%) in children 3 to 6 years of age, and 92 (26%) in children 7 to 13 years of age (Table 1). The youngest infant included was 7 months of age. Influenza A was detected in 286 (81%) and influenza B in 58 (16%) cases; in 9 cases (3%), the viruses were untyped.
Clinical Findings in Different Age Groups
The rates of various signs, symptoms, and clinical diagnoses in different age groups of children at the first visit are shown in Table 2. The median duration of any symptom of illness before the initial visit to the study clinic was 3 days in children younger than 7 years of age and 2 days in children 7 to 13 years of age. Fever was the most prominent sign, occurring in 95% of all children. Fifty-nine percent of children <3 years of age had fever ≥39.0°C. Fever ≥40.0°C was observed in 20% of children <3 years of age, 12% of children 3 to 6 years of age, and 4% of children 7 to 13 years of age (P = 0.005). On the other hand, 19 (5%) of the 353 children had had no fever by the time of the initial visit for influenza. There were no significant differences in the duration of preceding symptoms between the febrile and afebrile children (median, 3 days for both groups; P = 0.86).
A total of 77% of the children had cough and 78% had rhinitis. Rhinitis was significantly more common in children <3 years of age (86%) than in the older age groups (75% and 73%; P = 0.048). Gastrointestinal symptoms were present in 9% of all children, and the general condition was impaired in 10% of the children.
Among children 7 to 13 years of age, 39% had headache and 13% complained of myalgia. Eight of the 12 (67%) children with myalgia had fever ≥39.0°C. One child with myalgia was afebrile. The highest measured temperatures in febrile children 7 to 13 years of age were not significantly different between children with or without myalgia (mean, 38.9°C vs. 38.7°C, P = 0.22).
Three percent of all influenza-positive children presented with acute expiratory wheezing or exacerbation of asthma. Acute otitis media was the most frequent complication, and it was diagnosed at the first visit in 19% of children <3 years of age. None of the children was diagnosed with a febrile seizure.
Clinical Findings in Influenza A and B Virus Infections
The rates of clinical signs and symptoms were further analyzed according to the type of influenza virus; 9 children with untyped influenza viruses were excluded from these analyses. Influenza A viruses were found in 87 (88%) and influenza B viruses in 12 (12%) children <3 years of age. In children 3 to 6 years of age, influenza A accounted for 128 (83%) and influenza B for 26 (17%) of the cases, and in children 7 to 13 years of age the corresponding figures were 71 (78%) and 20 (22%), respectively. No significant differences were observed in any signs or symptoms between children with influenza A or B virus infections within the different age groups. Figure 1 shows the rates of various signs and symptoms in the entire group of 344 children (influenza A, 286 [83%]; influenza B, 58 [17%]). In this combined group, none of the differences between influenza A and B viruses reached statistical significance.
This prospective cohort study provides new information about the clinical presentation of influenza in different age groups of unselected children treated in the primary care. Our study had 2 particular strengths. First, the study cohorts included large numbers of normal children who were enrolled without using any exclusion criteria, so the study participants likely represent the normal pediatric population that is seen by primary care physicians during annual influenza epidemics. Secondly, we obtained samples for viral detection during every episode of illness seen at the study clinic, regardless of the presence or absence of fever or the severity of the symptoms. Thereby, we avoided any bias caused by sampling only a selected population of children.
We believe that this is the first study to assess the signs and symptoms of laboratory-confirmed influenza in unselected children with respiratory infections. Friedman and Attia28 studied 128 children <17 years of age (mean age, 6 years) who were selected from emergency department patients at a tertiary pediatric center according to predetermined criteria indicating influenza infection. In that selected population, 55% of all children had fever ≥39.0°C, 83% had cough, and 60% had rhinitis.
Fever was clearly the most remarkable sign of influenza in all age groups of children, as has been reported also earlier by other investigators.5 Only 5% of all children and 2% of those less than 3 years of age were afebrile. The highest fevers were observed most frequently in the youngest children, but it is noteworthy that approximately 40% of school-aged children had fever of 39.0°C or more.
In adults, 70% to 91% of influenza-infected patients have headache and 60% to 94% myalgia.29–31 In our population, headache and myalgia were present in a minority of school-aged children who could be expected to express their subjective symptoms when asked. It appears that headache and myalgia, which are often considered as almost pathognomonic symptoms of early influenza in adults, are not essential features of influenza in pediatric patients.
In previous studies, approximately one-third of children who were either hospitalized or seen in emergency departments had gastrointestinal symptoms.25,28 In our outpatient population, the presence of gastrointestinal symptoms was substantially lower, although approximately every 10th child with influenza had some gastrointestinal complaints.
Acute expiratory wheezing was rarely associated with influenza in our study. In a recent study among outpatient children, bronchiolitis was observed in only 0.2% of influenza-positive children, which rate was significantly lower than that seen in influenza-negative children.17 These results are in agreement with the study of Jartti et al32 who demonstrated that influenza viruses are minor players in the etiology of acute expiratory wheezing in children. Although laryngitis associated with influenza was also a relatively infrequent finding in our study, the clinical presentation of croup caused by influenza viruses is much more severe than that caused by parainfluenza viruses.33
Influenza viruses are among the leading respiratory viruses predisposing a child to acute otitis media.3,4,8,9,34 In our study, 19% of children <3 years of age had acute otitis media at their first visit to the study clinic for influenza. It is important to note, however, that approximately half of all episodes of acute otitis media develop after 3 to 4 days of the onset of upper respiratory tract infection.35,36 This was also true for the present study cohorts, in which the total rate of acute otitis media in children <3 years of age was 40%.4
Although the presence of fever and cough together with the absence of rhinitis are often regarded as typical symptoms of early influenza,30,37 a substantial proportion of children with influenza do not fulfill these criteria. Approximately one-fourth of the children in our cohorts did not have cough. On the other hand, most children had rhinitis during the first days of influenza. The clinical diagnosis of influenza is very difficult especially in young children,24,37 and our findings underline the importance of microbiologic diagnosis of influenza in the youngest age groups. Several rapid diagnostic tests for influenza are available and they are reasonably accurate for detecting influenza in children.38,39 Several factors such as the cost of the tests and the lack of time to run the tests in a busy outpatient clinic are often cited as reasons for the infrequent use of rapid diagnostic tests for influenza in children.
Our study demonstrates that the clinical presentation of influenza in unselected outpatient children differs in many aspects from the conventional concept of influenza symptomatology. This study also indicates that the signs and symptoms of influenza are most severe in the youngest children. These findings corroborate the view that young children would benefit most from vaccination against influenza.
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