Rationale and design of the prevention of respiratory infections and management in children (PRIMAKid) study

Vaccine 23 (2005) 4906–4914

Rationale and design of the prevention of respiratory infections and management in children (PRIMAKid) study A randomized controlled trial on the effectiveness and costs of combined influenza and pneumococcal vaccination in pre-school children with recurrent respiratory tract infections Y. Sch¨onbeck a,∗ , E.A.M. Sanders b , A.W. Hoes a , A.G.M. Schilder c , Th.J.M. Verheij a , E. Hak a a

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands b Department of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands c Department of Oto-rhinolaryngology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands Received 26 January 2005; received in revised form 13 May 2005; accepted 20 May 2005 Available online 13 June 2005

Abstract Health and economic burden of recurrent respiratory tract infections (RTIs) in early childhood is considerable. A systematic review of licensed influenza and pneumococcal vaccines showed substantial efficacy in children, but the health-economic impact of such vaccines among pre-school children with recurrent RTIs is unknown. We therefore, designed a double-blind randomized controlled trial to determine the effectiveness and costs of a combined influenza and pneumococcal vaccination program among a primary care based cohort of children with recurrent episodes of RTI aged between 18 and 72 months. We will enroll 690 children over three consecutive years (2003–2005) who will be randomly allocated to receive vaccinations against influenza and pneumococcal disease, influenza alone or hepatitis B in a similar schedule. Follow up by parental diaries, tympanic temperature measurements, questionnaires and interviews is planned until May 2006. Primary outcome is number of febrile RTIs. Other outcomes include duration and severity of RTI episodes, medical consumption, safety and costs. © 2005 Elsevier Ltd. All rights reserved. Keywords: Clinical trials; Infection; Respiratory tract infections; Children; Preschool children; Influenza; Streptococcus pneumoniae; Influenza vaccines; Pneumococcal vaccines

1. Introduction 1.1. Health and economic burden In the Western world, respiratory tract infections (RTIs) account for approximately 20% of all consultations in primary care and 75% of all antibiotic courses [1]. The majority of pre-school children consults a general practitioner (GP) for ∗

Corresponding author. Tel.: +31 30 2538195; fax: +31 30 2539028. E-mail address: [email protected] (Y. Sch¨onbeck).

0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.05.021

RTI at least once each year [2]. More than 10% of all young children suffer from recurrent upper and lower respiratory tract infections [3,4]. Their lack of immunologic memory to viral and bacterial pathogens puts them especially at risk. In a recent study, infants and young children were reported to have a 12-fold increased risk of hospital admission for RTIs caused by influenza compared with children aged 5–17 years [5]. Economic consequences of RTIs are major; they are the most common indication for doctor consultations, antibiotic prescription and surgery in children and lead to considerable productivity loss by parents in developed countries [6–12].

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

1.2. Treatment options Medical treatment options for RTIs are limited. Antibiotics, often unnecessarily prescribed due to the viral origin of most RTIs in children [13–15], and surgical interventions only have marginal effects on the duration and severity of these conditions [16–18]. In addition, frequent antibiotic prescriptions accelerate resistance of pathogenic bacteria against these antibiotics, which is becoming a major threat to treatment efficacy [14,19,20]. Prevention of RTIs by vaccination has therefore gained higher priority in recent years. 1.3. Influenza and Streptococcus pneumoniae infections in children Influenza A and B viruses and the bacterial pathogen Streptococcus pneumoniae (S. pneumoniae) are important causes of respiratory tract morbidity. During influenza epidemics, influenza attack rates may exceed 40% in preschool children and 30% in school-age children [8]. Importantly, viral infections predispose to bacterial super-infection. Influenza infections are known to predispose for subsequent AOM [21,22] and may directly or indirectly cause pneumonia. S. pneumoniae is the most commonly isolated bacterial pathogen in community-acquired RTIs globally, causing a variety of infections like otitis media, sinusitis and pneumonia [23]. Community-acquired pneumonia is one of the most common serious infections in young children with an annual incidence of 34–40 cases per 1000 in Europe and North America [15] and it accounts for 15/1000 GP-diagnoses in children 1–4 years of age in the Netherlands [2]. Although viruses cause most cases of pneumonia in preschool children, S. pneumoniae is the most frequent bacterial cause in this age group [15], involved in almost 30% of all episodes in ambulatory medicine [24,25]. In pneumonia requiring hospitalization, over 40% pneumococcal involvement is found [26,27]. In AOM, one of the most common infectious diseases in childhood [11], S. pneumoniae is involved in 28–55% of all cases [8,28–31] and in influenza-associated AOM the pneumococcus is a major cause of bacterial super-infection [32]. 1.4. Vaccination In the Netherlands, licensed vaccines are available against influenza A and B viruses and S. pneumoniae. A summary of previously published studies on these vaccines showed substantial clinical effectiveness among children (Table 1). A randomized controlled trial in Italy on the effects of influenza vaccination among 344 children 1–6 years of age detected a 67% reduction in influenza-like illness during an influenza epidemic [33]. A randomized trial in younger children, aged 6–24 months, failed to show significant reductions in the proportion of children under 18 months with AOM or RTI during two consecutive influenza seasons. However, the proportion of children aged 19–24 months with AOM decreased during the influenza season and the 1-year follow up in the first study

4907

year (43 and 33% reduction, respectively). In the second year the incidence of influenza never reached epidemic proportions and no protective effect of the vaccine was observed [34]. In non-experimental studies the parenteral influenza vaccine demonstrated relative reductions in AOM incidence of 31–40% in infants and children during influenza epidemics [35,36]. The live attenuated cold-adapted trivalent intranasal influenza virus vaccine was recently shown to reduce febrile illnesses by 21% and febrile otitis media episodes by 30% in healthy children aged 15–72 months during the influenza season [37]. In otitis-prone children a 44% reduction of AOM episodes was observed [38]. Other non-experimental studies in high-risk children reported comparable effectiveness of influenza vaccination [39,40]. Although debated by some authors [41], these studies seem to justify the conclusion that the vaccine contributes to a reduction in RTIs, especially in high-risk children. The recently licensed heptavalent CRM197 pneumococcal conjugate vaccine (PVC7) showed considerable protective immunity in healthy infants and toddlers. A large-scale efficacy trial in 40,000 healthy infants found PVC7 to be at least 89% protective against all cases of invasive pneumococcal disease [42]. Efficacy against pneumonia with a positive radiograpgh ranged from 9% in children over 2 years of age to 32% in those under 1 year [43] comparable to the more recent findings of Klugman et al. who studied the effect of the nine-valent conjugate vaccine [44]. The efficacy against overall AOM episodes of 6% appears to be only marginal [42,45]. Importantly, better vaccine efficacy was observed in the prevention of recurrent AOM, ranging from 9% in the number of infants who developed four episodes per year, to 12% in those with six episodes per year. Interestingly, placement of ventilation tubes was reduced by 20% [42]. In a randomized controlled trial by Dagan et al. the nine-valent pneumococcal conjugate vaccine reduced clinically diagnosed upper and lower RTIs and otitis media episodes by 15, 16 and 17%, respectively in children aged 12–35 months attending daycare. In addition, a 17% overall reduction in antibiotic days was observed [46]. In children over 1 year of age with recurrent AOM episodes combined conjugate and polysaccharide pneumococcal vaccinations failed to reduce the occurrence of new AOM episodes [47]. At least two conjugate vaccinations seemed to be required for reduction of nasopharyngeal carriage of conjugate vaccine serotypes, also in children older than 2 years of age. The 23-valent polysaccharide vaccine did not seem to protect against nasopharyngeal carriage. A new trial with the conjugate vaccine given twice seems therefore worthwhile. A synergistic effect of influenza and pneumococcal vaccination has been demonstrated in elderly patients with chronic pulmonary disease [48]. This combination might be effective in children with a high risk for RTIs as well. From a public health perspective, children with recurrent RTIs might benefit most from the combined influenza and pneumococcal conjugate vaccines.

4908

Table 1 Summary of published trials on clinical effectiveness of influenza and pneumococcal vaccination among children Vaccine

Design

Follow up

Population

N (vacc./ctrl)

Data collection

Outcome

Vaccine effectiveness (%) [95% CI] or (p-value), (vacc. vs. ctrl)

Influenza vaccination Hoberman et al. [34]

TIV

Randomized double-blind trial

4 months

6–24 months

411/375

Follow up visits + visits in case of symptoms of respiratory infection or AOM

Children with ≥ 1 AOM episode

1999–2000: 6% (p = 0.56) (49% vs. 52%) 2000–2001: −16% (p = 0.17) (56% vs. 48%) 1999–2000: 5% (p = 0.66) (0.21 vs. 0.22 per PM) 2000–2001: −29% (p = 0.10) (0.22 vs. 0.17 per PM)

Follow up visits + visits in case of symptoms of respiratory illness Follow up visits to pediatrician Parental report of symptoms of influenza

≥ 1 AOM episodes ≥ 2 AOM episodes Febrile RTI Receipt of ≥ 1 antibiotic course Influenza like illness

67% [59–74] (12% vs. 38%)

Febrile illness

21% [11–30] (0.7 vs. 0.9)

Febrile OM

30% [18–45] (0.1 vs. 0.2)

Reduction of RTI

8% (56% vs. 61%)

AOM episodes

40% (19% vs. 32%)

Marchisio et al. [38]

TIV

Randomized observer-blinded trial

6 months

1–5 years with recurrent AOM

67/60

Colombo et al. [33]

TIV

Randomized trial

5 months

1–6 years

177/167

Belshe et al. [37]

LACAIV

Randomized double-blind trial

Influenza season

15–71 months

1070/532

Heikkinen et al. [35]

TIV

Clements et al. [36]

TIV

Smits et al. [40]

TIV

Pneumococcal vaccination Veenhoven et al. [47]

Klugman et al. [44]

Randomized by day-care, unblinded, controlled Prospective cohort study Retrospective study

PCV7 + PPV23

Randomized double-blind trial

PCV9

Randomized double-blind trial

6 weeks

1–3 years, day-care attendees

187/187

Follow up visits in case of fever or symptoms of RTI

RTI

44% [19–61] (36% vs. 64%) 63% (p = 0.03) (9% vs. 24%) 13% (p = 0.03) (82% vs. 96%) 39% (p = 0.07) (39% vs. 64%)

Influenza season

6 months - 5 years

94/92

Follow up visits

AOM episodes

31% [2–51] (22% vs. 36%)

2 years

0–5 years, asthmatics

98/157

Reviewing clinical databases

Acute respiratory disease

55% [20–75] (29% vs. 43%)

18 months

1–7 years, ≥2 AOM episodes in preceding year

190/193

Follow up visits + visits to physician in case of symptoms of AOM Examination at hospital admission

Rate ratio of AOM episodes

1.3 [1.0–1.6]

First episode of radiologically confirmed pneumonia

20% [2–35] (169 vs. 212)

Infants

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

Author

AOM episodes Reviewing clinical databases 18927/18941 IPD, death or end of trial PCV7 Black et al. [42]

Randomized double-blind trial

Infants

131/130 22 months PCV9 Dagan et al. [46]

Randomized double-blind trial

12–35 months, day-care attendees

831/831 Infants PCV7 Eskola et al. [45]

Vacc: vaccinated; Ctrl: controls; 95% CI: 95% confidence interval; PCV: pneumococcal conjugate vaccine; PPV23: 23-valent pneumococcal polysaccharide vaccine; LACAIV: live attenuated cold-addapted influenzavaccine; TIV: trivalent inactivated influenza vaccine; IPD: invasive pneumococcal disease; AOM: acute otitis media; OM: otitis media; URTI: upper respiratory tract infections; LRTI: lower respiratory tract infections; PM: person months; PY: person years.

6% [4–9]

Antibiotic days

OM episodes

15% [4–24] (15 vs. 18 per PM) 16% [2–28] (10 vs. 12 per 100 PM) 17% [−2–33] (6 vs. 7 per 100 PM) 17% [13–21] URTI LRTI

6% [−2–11] (44 vs. 46 per 1000 PY) 6% [−4–16] (per protocol) All pneumonia

Reviewing clinical databases Follow up visits + visits in case of symptoms of respiratory infection or AOM Follow up visits, questioning parents about illness 18926/18942

IPD, death or end of trial 24 months PCV7 Black et al. [43]

Randomized double-blind trial Randomized double-blind trial

Infants

Data collection N (vacc./ctrl) Population Follow up Design Vaccine Author

Table 1 (Continued)

AOM episodes

Vaccine effectiveness (%) [95% CI] or (p-value), (vacc. vs. ctrl) Outcome

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

4909

In this trial, the primary objective is to demonstrate a reduction in the number of febrile RTI-episodes in children who receive combined influenza and pneumococcal vaccinations, or influenza vaccinations alone compared to those who receive control vaccinations. Secondary objectives are to demonstrate a reduction in severity and duration of febrile RTI-episodes, medical consultations and treatment, day-care and school absenteeism of children, productivity loss of parents and to determine functional health status (FHS) and economic consequences of the vaccination strategies. The study is approved by the medical ethical review board of the UMC Utrecht, The Netherlands.

2. Materials and methods 2.1. Study population For this randomized double-blind controlled trial, children 18–72 months of age with recurrent GP-diagnosed RTIs are selected from GP practices in the Netherlands (see for inclusion and exclusion criteria Table 2). Cohorts of eligible children are recruited in the years 2003, 2004 and 2005. GP-diagnosed RTIs are defined according to the International Classification of Primary Care (ICPC) (see Table 3) [49,50]. 2.2. Vaccines After written parental informed consent, children are randomly allocated to one of the three study groups. The first group receives the trivalent inactivated influenza vaccine (Influvac® , Solvay) twice in the first year and once in the second year combined with twice the heptavalent pneumococcal conjugate vaccine (Prevnar® , Wyeth; containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F); the second group receives the influenza vaccine and placebo (0.9% NaCl phosphate buffered, Solvay); the control group receives hepatitis B vaccinations (Engerix-B junior® , GSK), which is commonly used as a control vaccine [47], and placebo. Vaccination schedule is similar in all three comparison groups (Table 4). Vaccinations are postponed in case of a febrile illness or if the child has received antibiotic treatment within 48 h of vaccination. The second dose is administered within 60 days after the first dose. Adverse reactions within 7 days after vaccination are recorded in diaries. 2.3. Data collection 2.3.1. Baseline risk of comparison groups Data on possible predictors of RTI-occurrence such as age, gender, RTI-history including number of RTI-related GP consultations, previous medical treatment and ENT-surgery, family composition, day-care attendance, passive exposure to smoking, breastfeeding and allergy/atopy in the family are collected from GP medical record forms and selfadministered parental questionnaires [51].

4910

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

Table 2 Inclusion and exclusion criteria for the PRIMAKid-trial Inclusion criteria

Exclusion criteria

Age 18–72 months Two or more GP-diagnosed RTIs in 12 months before inclusion Mastery of the Dutch language Written informed consent signed by parents/guardians and researcher

Asthma or recurrent wheezing chronically threated with inhaling corticostero¨ıds Other disorders predisposing for RTIs such as Down’s syndrome, cystic fibrosis, cranio-facial malformations, known immuno-deficiency other than low IgA or IgG2 or hematological disorders Indication for influenza, pneumococcal or hepatitis B vaccination Ever had a influenza, pneumococcal or hepatitis B vaccination Clinically significant hypersensitivity to eggs Previous severe adverse reactions to vaccines

Table 3 Definition of ICPC-codes for respiratory tract infections ICPC-code

Description

Criteria

H71

Acute otitis media

R05 R74

R75

Cough (with fever) Upper respiratory infection acute (including pharyngitis and common cold) Sinusitis acute/chronic

recent perforation of the tympanic membrane discharging pus; or inflamed and bulging tympanic membrane; or one ear drum more red than the other; or red tympanic membrane, with ear pain; or bullae on the tympanic membrane includes: cough (dry or moist) evidence of acute inflammation of nasal or pharyngeal mucosa with absence of criteria for more specifically defined acute respiratory infection classified in this section

R76

Tonsillitis acute

R77

Laryngitis/tracheitis acute

R78

Acute bronchitis/bronchiolitis

R80

Influenza

R81 R82

Pneumonia Pleurisy/pleural effusion

R83

Respiratory infection other

purulent nasal/post-nasal discharge, or previous medically treated episodes of sinusitis, plus tenderness over one/more sinuses, or deep-seated aching facial pain aggravated by dependency of head, or opacity on transillumination; or imaging evidence of sinusitis; or pus obtained from the sinus sore throat or fever with reddening of tonsil(s) more than the posterior pharyngeal wall, and either pus on swollen tonsil(s) or enlarged tender regional lymph nodes hoarseness/stridor with/without respiratory distress, or deep dry painful cough (barking in children), and normal chest signs in children and adults: cough and fever with scattered or generalized abnormal chest signs: wheeze, coarse rales, rhonchi or moist sounds; in infants (bronchiolitis): dyspnoea and hyperinflation myalgia and cough without abnormal respiratory physical signs other than inflammation of nasal mucous membrane and throat, plus three or more of the following: sudden onset (within 12 h); rigors/chills/fever; prostration and weakness; influenza in close contacts; influenza epidemic; or viral culture/serological evidence of influenza virus infection evidence of pulmonary consolidation clinical evidence of pleural exudate; or pleuritic pain accompanied by pleural friction rub; or investigative evidence of inflammatory pleural exudate includes: chronic nasopharyngitis, chronic pharyngitis, chronic rhinitis NOS, diphtheria, empyema, epiglottitis, fungal respiratory infection, lung abscess, protozoal infection (without pneumonia)

2.3.2. Primary outcome measure The primary outcome is the occurrence of febrile RTIs. Follow up for each participant starts 14 days after receipt of the second set of vaccinations and continues for 6–19 months, depending on the year of inclusion (see also Table 4). A febrile

RTI is defined as fever (tympanic temperature ≥ 38.0 ◦ C) for at least two consecutive days accompanied by one or more of the following signs or symptoms of RTI: general weakness/malaise, rhinitis, sore throat, earache, coughing, wheezing/shortness of breath or muscle ache, with a severity

Table 4 Vaccination schedule Group

1 2 3

N

Visit 1

Visit 2

Visit 3

Visit 4

230 230 230

C1: October 2003 C2: October 2004 C3: October 2005 IV + PCV IV + placebo Hep B + placebo

C1: November 2003 C2: November 2004 C3: November 2005 IV + PCV IV + placebo Hep B + placebo

C1: September 2004 C2: September 2005 C3: IV IV Hep B

C1: June 2005 C2: June 2006 C3: June 2006 Final visit Final visit Final visit

C1: first cohort; C2: second cohort; C3: third cohort; IV: trivalent inactivated influenza vaccine, Influvac® , Solvay; PCV: heptavalent pneumococcal conjugate vaccine, Prevnar® , Wyeth; Hep B: hepatitis B vaccine Engerix-B junior® (GSK); Placebo: 0.9% NaCl.

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

score of 2 or 3 on a scale ranging from 1 (mild) to 3 (severe). In very young children signs or symptoms like sore throat and muscle ache will be difficult or impossible to assess. We believe these complaints will present as general weakness/malaise in such children and instruct parents who are uncertain about the presence or absence of these signs or symptoms not to report these. Body temperature and presence of RTI-associated signs and symptoms are recorded daily in parent-reported diaries. Parents are instructed to measure the child’s body temperature (preferably at the end of the day) with a validated tympanic thermometer [52] provided by the trial center if clinical signs or symptoms associated with RTI are present. At the first vaccination visit parents are instructed on how to use the tympanic thermometer correctly. At the second vaccination visit the first measurements are evaluated and further instructions are provided if necessary. New RTIepisodes are those occurring after a sign and symptom free period of at least 14 days. 2.3.3. Secondary clinical outcome measures Secondary clinical outcomes are severity and duration of febrile RTIs, number of GP consultations for RTIs, prescription of antibiotics, diagnostic tests, referral to medical specialists, ENT-surgery (adenoidectomy, tonsillectomy, ventilation tube placement), hospitalization, use of over-thecounter medication, day-care and school absenteeism of children and productivity loss of parents during follow up. These data are extracted from the parent-reported diaries, GP-forms filled out in case of GP consultations for RTI during follow up and by telephone interviews with parents in case of a RTI reported in the diary. General FHS and disease specific FHS are measured at baseline, at 12 months and at the end of follow up by the Dutch ‘RAND general health rating index for children’ (RAND-GHRI) [53], the Otitis Media-6 (OM-6) [54] and the newly developed six-item RTI-6, respectively. The Dutch RAND-GHRI, derived from a child FHS instrument developed at the RAND cooperation [55], has shown high validity and reliability for assessment of general FHS in children aged 6 months to 12 years with asthma [53]. Both the English and Dutch OM-6 have shown high validity and reliability for assessment of disease specific FHS in children with recurrent AOM of the same age [54,56]. The validity and responsiveness of the RTI-6 will be assessed during the study. 2.3.4. Virological outcome measure To verify whether the clinically defined influenza cases are true influenza cases, nasopharyngeal swabs are taken during influenza epidemics. Parents are asked to contact the trial center during an influenza epidemic as indicated by data from the National Influenza Center if their child has had fever for more than 1 day accompanied by at least one RTI-associated sign or symptom. Within 4 days after onset of such complaints nasopharyngeal swabs for viral determination are taken by a trained research assistant [57]. The samples will be analyzed by multiplex PCR-analysis for presence of influenza virus A and B.

4911

2.3.5. Economical outcome measure To establish the economical consequences of the different vaccination strategies from a societal perspective, incremental direct and indirect costs for relevant cost-drivers will be calculated. Direct costs include those of vaccines, vaccine administration, side effects, GP or specialist consultations for RTIs, medication, surgical procedures, hospitalization and additional laboratory tests. Indirect costs include those of productivity loss by parents and day-care and school absenteeism of children due to vaccination and RTIs [7,9]. Data on these volumina will be extracted from the parent-reported diaries, GP medical record forms and telephone interviews. Costs per volumina will be based on national guidelines. 2.3.6. Sample size calculation We expect 65% of the children in the control group to experience a febrile RTI in 12 months. To demonstrate a statistically significant and clinically relevant reduction in the occurrence of this outcome by influenza and pneumococcal vaccination combined (estimated at 22%) 690 children are needed, assuming a type I error of 5%, a power of 80% and a loss-to-follow up of 15%. 2.3.7. Statistical analysis Statistical analysis will be performed using SPSS version 12.0 for Windows. Univariate analysis will be used to compare outcomes between the groups using Student’s ttest or Mann–Whitney U-test for continuous variables and chi-square tests for categorical variables. Point estimates of efficacy will be calculated as 1 − RR × 100%. In addition, effect modification due to number of previous RTI episodes (number of annual RTI-episodes < 4 or ≥ 4) and age (categorized as 1 21 to 2 or 2–5 years) will be addressed. To assess the additive effect of the influenza vaccine to the pneumococcal vaccine, occurrence of RTI-episodes will be considered separately during influenza seasons and other seasons. Univariate and multivariate Cox-regression analysis will be conducted to adjust for time and within person dependency. 2.3.8. Economical analysis Economical analysis using medical decision modeling will be performed to estimate the costs or savings per RTIepisode from a societal perspective. Estimations of costs (savings) are derived for each vaccination strategy by distracting the savings resulting from prevention of disease from the costs of the pertaining vaccination strategy. Monte Carlo simulation will be conducted to estimate the sensitivity of the outcome parameters to several effect and cost input variables.

3. Baseline characteristics of cohort 2003 Mean age of the 171 children included in the first cohort in 2003 is 3.3 years (standard deviation (S.D.) 1.3 years), two-thirds (67%) is male. Twenty-five percent of the participating families had one child, 67% had two to three and 7%

4912

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

had four or more children. Three-quarters of the children in the cohort had attended day-care in the year prior to inclusion. Thirteen percent of the participants were exposed to indoor tobacco smoking at least once a week. The median number of physician-diagnosed RTI episodes in the year prior to inclusion was 3, ranging from 1 to 12. Fifty percent of the children consulted their GP two to three times in the year preceding inclusion, 23% four to five times and 15% visited the GP five times or over. Since there was a time lag between recruitment and actual vaccination, 12% of the children visited their GP only once in the year preceding inclusion. Six percent of the children had a birth weight below 2500 g, 38% had atopic disease (eczema, recurrent wheezing) and 29% had had previous ear-nose-throat-surgery (23% of the children had adenoidectomy, 8% tonsillectomy, 16% ventilation tube placement). Age and gender of the children in the first cohort was similar to corresponding figures for all eligible children. The mean number of GP consultations was statistically significant higher in the study population than the reference population (2.6 versus 2.4 episodes per year), but this difference may not be clinically relevant.

serotypes [47]. However, from a public health perspective a reduction in the overall number of RTI episodes is most relevant. We therefore evaluate the clinical effect of the vaccines on all episodes of RTIs. Substantial health and economic benefits of vaccination can be obtained by reducing the number of serious RTI-episodes and therefore two consecutive days of fever associated with signs or symptoms with a severity score of 2 or 3 on a scale ranging from 1 (mild) to 3 (severe) were defined as a clinically relevant episode of RTI. In this trial we focus on children between 18 and 72 months of age, since they have a high medical consumption, including GP-consultations, antibiotic prescriptions and surgical procedures like adenoidectomy, tonsillectomy and insertion of ventilation tubes. The baseline characteristics of the first randomized cohort demonstrate that one in three of these children have already undergone such surgical procedures. Children participating in the study had a slightly higher mean number of GP consultations in the year prior to inclusion than the eligible population. This is not surprising, since parents whose children are more affected by RTIs can be expected to be more likely to participate. However, differences were small and we therefore expect that the results of the trial will be applicable to all children with recurrent RTIs.

4. Discussion Due to its considerable health and economic burden and the progressive resistance to antibiotic treatment, there is an urgent need for cost-effective preventive measures in children with recurrent RTIs. With this randomized double-blind trial among a general practice-based cohort of children with recurrent RTIs the clinical effects and cost-effectiveness of readily available vaccines against influenza A and B virus and S. pneumoniae will be established. To our knowledge, this is the first randomized, controlled trial to study the effect of combined influenza and pneumococcal vaccination. The combination of these vaccinations might be especially important during influenza epidemics to prevent bacterial super-infection. Recently, an intranasal influenza vaccine has become available in the United States for children. Although such a vaccine is preferable for children, it has not yet been licensed for use in Europe. We therefore choose to evaluate the conventional intra-muscular subunit influenza vaccine which has been shown to be effective in children. The vaccination schedule includes influenza vaccination twice in the first year according to standard guidelines for children under 6 years. With respect to the pneumococcal conjugate vaccinations, we have chosen to immunize the children twice with the conjugate vaccine, since we have shown that two vaccinations are required for effective reduction of vaccine type pneumococcal carriage in the nasopharynx, also in children over 2 years of age [58]. The additional effect of pneumococcal vaccination besides influenza vaccination has to be shown by comparing those who receive influenza vaccination alone to those who receive both vaccines. Vaccination may decrease the number of RTIs caused by vaccine serotypes, but increase those caused by non-vaccine

Acknowledgements We thank Mrs. Nelly van Eden for administrative and coordinative support and Mrs. Hanneke den Breeijen for datamanagement. Funding: The Netherlands Organization for Health Research and Development ZONMW (grant number 2200.0121).

References [1] Acute respiratory infections: the forgotten pandemic. Communique from the International Conference on Acute Respiratory Infections, held in Canberra, Australia, 7–10 July 1997. Int J Tuberc Lung Dis 1998;2(1):2–4. [2] van der Linden MW, Westert GP, de Bakker DH, Schellevis FG. Second Dutch National Study on Geral Practice [Tweede nationale studie naar ziekten en verrichtingen in de huisartspraktijk; Klachten en aandoeningen in de bevolking en in de huisartspraktijk] [Dutch]. Utrecht/Bilthoven: NIVEL/RIVM 2004. [3] Hak E, Rovers MM, Sachs AP, Stalman WA, Verheij TJ. Is asthma in 2–12 year-old children associated with physicianattended recurrent upper respiratory tract infections. Eur J Epidemiol 2003;18(9):899–902. [4] Niemela M, Uhari M, Mottonen M. A pacifier increases the risk of recurrent acute otitis media in children in day care centers. Pediatrics 1995;96(5 Pt 1):884–8. [5] Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342(4):232–9. [6] Heikkinen T, Silvennoinen H, Peltola V, et al. Burden of influenza in children in the community. J Infect Dis 2004;190(8):1369–73.

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914 [7] Neuzil KM, Hohlbein C, Zhu Y. Illness among schoolchildren during influenza season: effect on school absenteeism, parental absenteeism from work, and secondary illness in families. Arch Pediatr Adolesc Med 2002;156(10):986–91. [8] Neuzil KM, Mellen BG, Wright PF, Mitchel Jr EF, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342(4):225– 31. [9] White T, Lavoie S, Nettleman MD. Potential cost savings attributable to influenza vaccination of school-aged children. Pediatrics 1999;103(6):e73. [10] Freid VM, Makuc DM, Rooks RN. Ambulatory health care visits by children: principal diagnosis and place of visit. Vital Health Stat 1998;13(137):1–23. [11] McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995;273(3):214–9. [12] Hall MJ, Kozak LJ, Gillum BS. National Survey of Ambulatory Surgery: 1994. Stat Bull Metrop Insur Co 1997;78(3):18–27. [13] Monto AS, Sullivan KM. Acute respiratory illness in the community. Frequency of illness and the agents involved. Epidemiol Infect 1993;110(1):145–60. [14] Ruoff G. Upper respiratory tract infections in family practice. Pediatr Infect Dis J 1998;17(8 Suppl):S73–8. [15] Ostapchuk M, Roberts DM, Haddy R. Community-acquired pneumonia in infants and children. Am Fam Physician 2004;70(5):899– 908. [16] Klein JO. Clinical implications of antibiotic resistance for management of acute otitis media. Pediatr Infect Dis J 1998;17(11):1084–9. [17] Paradise JL, Feldman HM, Campbell TF, et al. Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years. N Engl J Med 2001;344(16):1179–87. [18] Paradise JL, Bluestone CD, Colborn DK, et al. Adenoidectomy and adenotonsillectomy for recurrent acute otitis media: parallel randomized clinical trials in children not previously treated with tympanostomy tubes. JAMA 1999;282(10):945–53. [19] del Castillo F, Baquero-Artigao F, Garcia-Perea A. Influence of recent antibiotic therapy on antimicrobial resistance of Streptococcus pneumoniae in children with acute otitis media in Spain. Pediatr Infect Dis J 1998;17(2):94–7. [20] Cappelletty D. Microbiology of bacterial respiratory infections. Pediatr Infect Dis J 1998;17(8 Suppl):S55–61. [21] Neuzil KM, Zhu Y, Griffin MR, et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis 2002;185(2):147–52. [22] Ruuskanen O, Arola M, Putto-Laurila A, et al. Acute otitis media and respiratory virus infections. Pediatr Infect Dis J 1989;8(2):94–9. [23] Posfay-Barbe KM, Wald ER. Pneumococcal vaccines: do they prevent infection and how. Curr Opin Infect Dis 2004;17(3):177–84. [24] Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J 1998;17(11):986–91. [25] Wubbel L, Muniz L, Ahmed A, et al. Etiology and treatment of community-acquired pneumonia in ambulatory children. Pediatr Infect Dis J 1999;18(2):98–104. [26] Juven T, Mertsola J, Waris M, et al. Etiology of communityacquired pneumonia in 254 hospitalized children. Pediatr Infect Dis J 2000;19(4):293–8. [27] Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004;113(4):701–7. [28] Block SL, Hedrick JA, Smith RA. Pathogens of acute otitis media in a pediatric population: /=48 months [Abstract K23]. 1996. [29] Bluestone CD, Stephenson JS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J 1992;11(8 Suppl):S7–11.

4913

[30] Luotonen J, Herva E, Karma P, Timonen M, Leinonen M, Makela PH. The bacteriology of acute otitis media in children with special reference to Streptococcus pneumoniae as studied by bacteriological and antigen detection methods. Scand J Infect Dis 1981;13(3):177–83. [31] Johnson CE, Carlin SA, Super DM, et al. Cefixime compared with amoxicillin for treatment of acute otitis media. J Pediatr 1991;119(1 (Pt 1)):117–22. [32] Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340(4):260–4. [33] Colombo C, Argiolas L, La Vecchia C, Negri E, Meloni G, Meloni T. Influenza vaccine in healthy preschool children. Rev Epidemiol Sante Publique 2001;49(2):157–62. [34] Hoberman A, Greenberg DP, Paradise JL, et al. Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA 2003;290(12):1608–16. [35] Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 1991;145(4):445–8. [36] Clements DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995;149(10):1113–7. [37] Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 1998;338(20):1405–12. [38] Marchisio P, Cavagna R, Maspes B, et al. Efficacy of intranasal virosomal influenza vaccine in the prevention of recurrent acute otitis media in children. Clin Infect Dis 2002;35(2):168– 74. [39] Sugaya N, Nerome K, Ishida M, Matsumoto M, Mitamura K, Nirasawa M. Efficacy of inactivated vaccine in preventing antigenically drifted influenza type A and well-matched type B. JAMA 1994;272(14):1122–6. [40] Smits AJ, Hak E, Stalman WA, van Essen GA, Hoes AW, Verheij TJ. Clinical effectiveness of conventional influenza vaccination in asthmatic children. Epidemiol Infect 2002;128(2):205–11. [41] Pitkaranta A, Hayden FG. Respiratory viruses and acute otitis media. N Engl J Med 1999;340(25):2001–2. [42] Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19(3):187–95. [43] Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21(9):810–5. [44] Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349(14):1341–8. [45] Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344(6):403–9. [46] Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001;20(10):951–8. [47] Veenhoven R, Bogaert D, Uiterwaal C, et al. Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study. Lancet 2003;361(9376):2189–95. [48] Nichol KL, Baken L, Wuorenma J, Nelson A. The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 1999;159(20):2437–42.

4914

Y. Sch¨onbeck et al. / Vaccine 23 (2005) 4906–4914

[49] Prepared by the International Classification Committee of WONCA. ICPC-2. International Classification of Primary Care. Second ed. Oxford: Oxford University Press; 1998. [50] Okkes I, Jamoulle M, Lamberts H, Bentzen N. ICPC-2-E: the electronic version of ICPC-2. Differences from the printed version and the consequences. Fam Pract 2000;17(2):101–7. [51] Forssell G, Hakansson A, Mansson NO. Risk factors for respiratory tract infections in children aged 2–5 years. Scand J Prim Health Care 2001;19(2):122–5. [52] van Staaij BK, Rovers MM, Schilder AG, Hoes AW. Accuracy and feasibility of daily infrared tympanic membrane temperature measurements in the identification of fever in children. Int J Pediatr Otorhinolaryngol 2003;67(10):1091–7. [53] Post MW, Kuyvenhoven MM, Verheij MJ, de Melker RA, Hoes AW. The Dutch Rand General Health Rating Index for Children: a questionnaire measuring the general health status of children [Dutch]. Ned Tijdschr Geneeskd 1998;142(49):2680–3.

[54] Rosenfeld RM, Goldsmith AJ, Tetlus L, Balzano A. Quality of life for children with otitis media. Arch Otolaryngol Head Neck Surg 1997;123(10):1049–54. [55] Lewis CC, Pantell RH, Kieckhefer GM. Assessment of children’s health status. Field test of new approaches. Med Care 1989;27(3 Suppl):S54–65. [56] Brouwer, C.N.M. Health-related quality of life in children with recurrent acute otitis media 2003; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht. [57] Rebelo-de-Andrade H, Zambon MC. Different diagnostic methods for detection of influenza epidemics. Epidemiol Infect 2000;124(3):515–22. [58] Veenhoven RH, Bogaert D, Schilder AG, et al. Nasopharyngeal pneumococcal carriage after combined pneumococcal conjugate and polysaccharide vaccination in children with a history of recurrent acute otitis media. Clin Infect Dis 2004;39(7): 911–9.