Heli Silvennoinen

Burden of Influenza in Children in the Community

BACKGROUNDnInfluenza vaccination of healthy children is encouraged because children are frequently hospitalized for influenza-attributable illnesses. However, most children with influenza are treated as outpatients, and scarce data are available on the burden of influenza in these children.nnnMETHODSnWe performed a prospective study of respiratory infections in preenrolled cohorts of children < or = 13 years old during 2 consecutive respiratory seasons (2231 child-seasons of follow-up). At any sign of respiratory infection, we examined the children and obtained a nasal swab for the detection of influenza. The parents filled out daily symptom diaries. Of all the enrollees, 94% remained active participants in the study.nnnRESULTSnThe average annual rate of influenza was highest (179 cases/1000 children) among children < 3 years old. Acute otitis media developed as a complication of influenza in 39.7% of children < 3 years old. For every 100 influenza-infected children < 3 years old, there were 195 days of parental work loss (mean duration, 3.2 days).nnnCONCLUSIONSnInfluenza causes a substantial burden of illness on outpatient children and their families. Vaccination of children < 3 years old might be beneficial for reducing the direct and indirect costs of influenza in children.

Early Oseltamivir Treatment of Influenza in Children 1–3 Years of Age: A Randomized Controlled Trial

BACKGROUNDnOseltamivir provides modest clinical benefits to children with influenza when started within 48 hours of symptom onset. The effectiveness of oseltamivir could be substantially greater if the treatment were started earlier during the course of the illness.nnnMETHODSnWe carried out a randomized, double-blind, placebo-controlled trial of the efficacy of oseltamivir started within 24 hours of symptom onset in children 1-3 years of age with laboratory-confirmed influenza during the seasons of 2007-2008 and 2008-2009. Eligible children received either orally administered oseltamivir suspension or a matching placebo twice daily for 5 days. The children received clinical examinations, and the parents filled out detailed symptom diaries for 21 days.nnnRESULTSnOf 408 randomized children who received the study drug (oseltamivir, 203, and placebo, 205), 98 had laboratory-confirmed influenza (influenza A, 79, and influenza B, 19). When started within 12 hours of the onset of symptoms, oseltamivir decreased the incidence of acute otitis media by 85% (95% confidence interval, 25%-97%), but no significant reduction was observed with treatment started within 24 hours. Among children with influenza A, oseltamivir treatment started within 24 hours shortened the median time to resolution of illness by 3.5 days (3.0 vs 6.5 days; P = .006) in all children and by 4.0 days (3.4 vs 7.3; P = .006) in unvaccinated children and reduced parental work absenteeism by 3.0 days. No efficacy was demonstrated against influenza B infections.nnnCONCLUSIONSnOseltamivir treatment started within 24 hours of symptom onset provides substantial benefits to children with influenza A infection. Clinical trials registration. ClinicalTrials.gov identifier: NCT00593502.

Accuracy of Clinical Diagnosis of Influenza in Outpatient Children

In a prospective study, children < or =13 years of age with respiratory infections were examined. At each visit, a nasal swab specimen was obtained for the detection of influenza, and the physician recorded his or her opinion on whether the child had influenza. Among 2288 infections, the overall sensitivity of the clinical diagnosis of influenza was 38% and the positive predictive value was 32%.

Clinical Presentation of Influenza in Unselected Children Treated as Outpatients

Background: Influenza causes a great disease burden on children especially in the outpatient setting. The signs and symptoms of influenza in unselected children treated as outpatients have not been previously published. Methods: We assessed the clinical presentation of influenza in a prospective study of respiratory infections in preenrolled cohorts of children ≤13 years of age during 2 consecutive respiratory seasons (2231 child-seasons of follow-up). We examined the children and obtained a nasal swab for the detection of influenza during every episode of illness, regardless of the presence or absence of fever or the severity of the symptoms. Results: Influenza was virologically confirmed in 372 children, of whom 353 (95%) providing complete data on the signs and symptoms were included in the analyses. A total of 95% of these children were febrile, and 50% had fever ≥39.0°C. Among children <3 years of age, 20% had fever ≥40.0°C. Seventy-seven percent of the children had cough and 78% had rhinitis. In children 7 to 13 years of age, only 39% had headache and 13% had myalgia. Conclusions: High fever is a prominent sign of influenza in children, and the clinical presentation of influenza is most severe in children <3 years of age. Headache and myalgia are not typical features of influenza in outpatient children. Most children with influenza have rhinitis during the early phase of the illness, which makes the clinical diagnosis of influenza difficult especially in the youngest children.

Admission diagnoses of children 0–16 years of age hospitalized with influenza

The prompt diagnosis of influenza enables the institution of antiviral therapy and adequate cohorting of patients, but scarce data are available to help clinicians correctly suspect influenza in children at the time of admission. This 16-year retrospective study assessed the main admission diagnoses of 401 children aged ≤16xa0years hospitalized with virologically confirmed influenza. The clinical data were derived from a systematic review of the medical records of the children. Sepsis-like illness was the main reason for admission in 52% of infants aged <6xa0months and in 7–16% of the older children. Respiratory symptoms accounted for 38% of admissions, and 15% of children were hospitalized due to acute neurologic conditions, primarily febrile convulsions. Wheezing or exacerbation of asthma was the primary reason for admission in 14% of children aged <3xa0years. No differences were observed in the admission diagnoses between children with influenza A and B infections. The main admission diagnoses vary widely in different age groups of children with influenza, and only a minority of children are hospitalized for respiratory symptoms. The leading role of sepsis-like illness in infants aged <6xa0months calls for increased efforts to find protective measures against influenza in this age group.

Feasibility of diagnosing influenza within 24 hours of symptom onset in children 1?3 years of age

Diagnosing influenza at an early stage of illness is important for the initiation of effective antiviral treatment. However, especially in young children, influenza often commences with an abrupt onset of fever, with full-blown respiratory symptoms developing only later. We determined the feasibility of diagnosing influenza in young children already during the first signs of the illness. During confirmed influenza activity, we obtained nasal swabs from children aged 1–3xa0years who presented as outpatients within 24 hours of the onset of fever (≥38.0°C). The specimens were tested for influenza viruses with viral culture, antigen detection, PCR, and a rapid point-of-care test (Actim Influenza A&B, Medix Biochemica, Finland). In addition, follow-up specimens were obtained from a proportion of children 3–7xa0days later. Influenza virus was detected already within 24 hours of symptom onset in 56 of 61 (92%; 95% CI 82–97%) children in whom influenza was eventually confirmed in the laboratory. A total of 158 rapid tests performed within 24 hours of symptom onset yielded a sensitivity of 90% (95% CI 74–98%) for influenza A viruses but only 25% (95% CI 3–61%) for influenza B viruses (Pu2009<u20090.001), resulting in an overall sensitivity of 77% (95% CI 61–89%) and specificity of 99% (95% CI 95–100%) for all influenza viruses. In most young children, influenza can already be accurately diagnosed within 24 hours of symptom onset. The rapid point-of-care test used was sensitive and specific for diagnosing influenza A, but its sensitivity for influenza B was limited.

Comparison of spectral gradient acoustic reflectometry and tympanometry for detection of middle-ear effusion in children.

Background: Spectral gradient acoustic reflectometry (SGAR) and tympanometry are handy methods to aid in the diagnostics of middle-ear diseases, but no prior studies have directly assessed the correlation between SGAR and tympanometry readings in children. Methods: We compared SGAR and tympanometry in 2152 otoscopic examinations among 600 children aged 0.6–14 years, who were examined for signs and symptoms of respiratory infection in a primary care setting; 677 (31.5%) of the ear examinations were in children <3 years of age. We further determined the test characteristics of these methods for the detection of middle-ear effusion (MEE) using pneumatic otoscopy as the gold standard. All examinations were performed by trained physicians. Results: SGAR and tympanometry indicated probable absence of MEE in 1896 (88.1%) and 1937 (90.0%) of the 2152 ears, respectively. SGAR levels 1–2 were observed in 95.7% of ears with type A/As tympanogram and in 58.1% of ears with type B tympanogram. The frequency of type B tympanogram increased with increasing SGAR levels, from 4.8% at SGAR level 1 to 67.7% at SGAR level 5. The observed agreement between the 2 methods was 86%. The test characteristics of SGAR and tympanometry for the detection of MEE diagnosed by pneumatic otoscopy were comparable. Conclusions: The high specificities and negative predictive values of SGAR and tympanometry make them useful aids particularly in ruling out MEE in children with respiratory infections. The low cost, easy portability and absence of need for an airtight seal support the use of SGAR also for screening purposes at home.

Signs and symptoms predicting influenza in children: a matched case–control analysis of prospectively collected clinical data

We aimed to determine whether there are signs or symptoms that could help clinicians to distinguish between influenza and other respiratory infections. The clinical data for this matched case–control analysis were derived from a 2-year prospective cohort study of respiratory infections among children aged ≤13xa0years. At any signs of respiratory infection, the children were examined and nasal swabs were obtained for virologic analyses. Cases were 353 children with laboratory-confirmed influenza and controls were 353 children with respiratory symptoms who tested negative for influenza. Cases and controls were matched for gender, age, and timing of the visit. In the multivariate conditional logistic regression analyses, fever was the only sign that independently predicted influenza virus infection, with odds ratios ranging from 13.55 (95% confidence interval [CI], 6.90–26.63) to 50.10 (95% CI, 16.25–154.45), depending on the degree of fever. In all analyses, the predictive capability of fever increased with incremental elevations in the child’s temperature. The likelihood ratio of fever ≥40.0°C in predicting influenza was 6.00 (95% CI, 2.80–12.96). Among unselected children seen as outpatients during influenza outbreaks, fever is the only reliable predictor of influenza virus infection. The optimal use of influenza-specific antiviral drugs in children may require virologic confirmation.

Comparative Burden of Influenza A/H1N1, A/H3N2 and B Infections in Children Treated as Outpatients.

Background: Few studies have directly compared the clinical impact of different types and subtypes of influenza viruses in children. Methods: In a prospective study of respiratory infections in preenrolled cohorts of children ⩽13 years of age, we compared the clinical features and the overall burden of illness between outpatient children with A/H1N1, A/H3N2 and B infections. The data were derived from structured medical records filled out by study physicians and from daily symptom diaries filled out by the parents throughout the follow-up period. Results: Of 358 children included in the analyses, 203 (57%) had influenza A/H1N1, 96 (27%) had A/H3N2, and 59 (16%) had influenza B infection. Children with influenza A/H3N2 were significantly younger (median, 3.2 years) than those with A/H1N1 (median, 4.8 years) or B (median, 5.1 years) infections (P < 0.0001). When adjusted for age, children 3–6 years of age with A/H3N2 infection had a higher frequency of fever ≥39.0°C (67% vs. 38%; P = 0.002), longer duration of fever (median, 4 vs. 3 days; P = 0.02) and more antibiotic treatments (43% vs. 20%; P = 0.004) than did children with A/H1N1 infections. Overall, the clinical presentation, duration of illness, frequency of complications, children’s absenteeism from day care or school and parental work absenteeism were comparable between children with A/H1N1, A/H3N2 and B infections. Conclusions: Adjusted for age, the clinical manifestations and the burden of illness are largely comparable between children with influenza A/H1N1, A/H3N2 and B infections.

Clinical and socioeconomic impact of moderate-to-severe versus mild influenza in children.

Some studies have assessed the efficacy of influenza vaccination in children separately for moderate-to-severe and any influenza, but the definition used for identifying children with moderate-to-severe illness has not been validated. We analyzed clinical and socioeconomic data from two prospective cohort studies of respiratory infections among children aged ≤13xa0years (four influenza seasons, 3,416 child-seasons of follow-up). We categorized children with laboratory-confirmed influenza into two mutually exclusive groups of moderate-to-severe and mild influenza using the previously proposed criteria. We obtained the data for the analyses from structured medical records filled out by the study physicians and from daily symptom cards filled out by the parents. Of 434 cases of influenza, 217 (50xa0%) were classified as moderate-to-severe and 217 (50xa0%) as mild. The mean duration of fever was 4.0xa0days in children with moderate-to-severe influenza and 3.1xa0days in those with milder illness (Pu2009<u20090.0001). Antibiotics were prescribed to 111 (51xa0%) children with moderate-to-severe and to ten (5xa0%) children with mild influenza (Pu2009<u20090.0001). The rates of parental work absenteeism were 184xa0days per 100 children with moderate-to-severe influenza and 135xa0days per 100 children with mild influenza (Pu2009=u20090.02). The corresponding rates of children’s own absenteeism from day care or school were 297 and 233xa0days respectively per 100 children (Pu2009=u20090.006). Categorization of children into groups with moderate-to-severe and mild influenza is meaningful, and it identifies children in whom the clinical and socioeconomic impact of influenza is highest. Illness severity should be considered when assessing influenza vaccine effectiveness in children.