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Pneumococcal vaccination does not prevent recurrence of acute otitis media in older children
EVIDENCE -BASED CLINICAL PR AC TICE
Pneumococcal vaccination does not prevent recurrence of acute otitis media in older children Abstracted from: 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: 2189^2195.
BACKGROUND Pneumococcal conjugate vaccination of children aged 2, 4, 6 and 12 to 15 months reduces the incidence of recurrent acute otitis media.The e¡ectiveness of combined pneumococcal conjugate vaccination and pneumococcal polysaccharide vaccination in preventing recurrent AOM in older children is not known.
OBJECTIVE To determine whether a combined pneumococcal conjugate (PCV7) and pneumococcal polysaccharide (PPSV23) vaccination prevents recurrent acute otitis media in children aged 41 year.
SETTING One general hospital and one tertiary care hospital in the Netherlands; April 1998 toJanuary 2002.
OUTCOMES Incidence of acute otitis media episodes during 18 month follow-up. MAIN RESULTS There was a trend towards a higher rate of recurrence of acute otitis media in the pneumococcal vaccine group than in the control vaccination group over the 18 month follow-up period (recurrence rate per-person year: 1.1 episodes with pneumococcal vaccine versus 0.83 episodes with control vaccine; RR 1.29, 95% CI 1.02 to 1.62, per-protocol analysis; RR 1.25, 95% CI 0.99 to 1.57, intention-to-treat analysis). AUTHORS’ CONCLUSIONS Combined pneumococcal conjugate and polysaccharide vaccination does not prevent recurrence of acute otitis media in children aged 1 year and over. Notes Subgroup analysis showed that pneumococcal
METHOD Double-blind randomised controlled trial.
PARTICIPANTS Three hundred and eighty-three children aged 1 to 7 years old with a history of X2 episodes of acute otitis media in the previous year. Main exclusion criteria were: primary or secondary immunode¢ciency, cystic ¢brosis, craniofacial abnormalities, chromosomal abnormalities, and history of severe adverse events during vaccination. Participants were strati¢ed according to age and number of episodes of acute otitis media in the previous year.
INTERVENTION The intervention received was age dependent. Participants in the pneumococcal group aged 12 to 24 months were immunised twice with PCV7, and 6 months later with PPSV23. Similar aged control participants were immunised with hepatitis B. Participants in the pneumococcal group aged 25 to 84 months were immunised once with PCV7 and 7 months later with PPSV23. Control participants of similar age were immunised with hepatitis A vaccine. 1462-9410/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ehbc.2003.12.010
vaccination in children aged 25 to 84 months signi¢cantly increased the rate of recurrence of AOM compared with the control vaccination (RR of recurrence rates per-person year 1.45, 95% CI 1.09 to 1.94). There was no signi¢cant di¡erence in recurrence rate of AOM in children in the 12 to 24 month age group between the pneumococcal and control vaccination groups (RR of recurrence rates per-person year 1.07, 95% CI 0.72 to 1.60).The theory behind the use of di¡erent pneumococcal and control vaccination programmes for the two age groups was not explained and may have di¡erentially in£uenced the outcomes in these two age groups. Sources offunding: This study was funded by the Netherlands Organisation for Health Research and Development ZonMw and the Netherlands Health Insurance Company Zilveren Kruis-Achmea. Correspondence to: Elisabeth Sanders, Department of Paediatric Immunology, W|lhelmina Children’s Hospital/University Medical Center Utrecht, Utrecht, Netherlands. E-mail: [email protected] Abstract provided by Bazian Ltd., London Evidence-based Healthcare (2004) 8, 55^56
55
Commentary 1 Recurrent acute bacterial otitis media is a common clinical condition, with a peak incidence in the second year of life, and usually, recurrent disease ceases within12 to18 months in the majority of children. Pneumococcus is cultured from the middle ear fluid of up to a third of children. Most cases are managed in primary care within the United Kingdom and more difficult cases are referred to ENT surgeons. Treatment with ventilation tubes is advocated in refractory cases but recurrent or persistent discharge is troublesome after surgery. The article was from workers in the Netherlands who conducted a randomized trial in 388 children aged between 1 and 7 years of age.The hypothesis was that such children affected have a subtle immune deficiency to the pneumococcal polysaccharide antigen. Unfortunately no evidence was provided to support this in the children studied. They immunized children with conjugate pneumococcal polysaccharide antigen using two strategies in two age groups of equal size. These two groups are compared with children who receive Hepatitis A or B vaccination.The children were also stratified into those who had two or three attacks prior to recruitment and those who had four or more attacks. The first group of children, while strictly recurrent, would not warrant further investigation nor treatment in the United Kingdom. The primary endpoint was the number of attacks of otitis media in an 18 -month follow-up. The diagnosis of
Commentary 2 Conjugate vaccines are an important scientific achievement in child health. Young children are unable to develop immunity to polysaccharide antigen (coating of some virulent bacteria). Linking the polysaccharide to a protein helps the immune system mount a protective response. The Haemophilus influenzae type b (Hib) vaccine was the first to take advantage of this technology. Serious Hib infections are now rare in countries with universal vaccination.1 The 7-valent pneumococcal conjugate vaccine (7vPCV) provides protection against the 7 serotypes that cause most disease in children. In a large Californian randomised controlled trial (RCT), the vaccine reduced invasive disease (occult bacteraemia, bacteraemic pneumonia, and meningitis) by 94% (95% CI 80 to 99%), X-ray positive pneumonia by 18% (95% CI 5 to 29%), and otitis media episodes by 6% (95% CI 4 to 8%). Recurrent otitis media was reduced by 9% (95% CI 4 to 14%) and insertion of ventilation tubes by 23% (95% CI11 to 34%).2 Unfortunately, the vaccine is expensive. Policy-makers must weigh the potential benefits against the costs. One option is to limit the vaccine to those children who are most likely to benefit. This could mean: (i) vaccinating children from 2 months of age if they are at increased risk of pneumococcal infections; or (ii) vaccinating children as soon as they experience frequent pneumococcal infections. Although the impact of the 7vPCV on otitis media is modest, this accounts for a large proportion of the health-related cost savings.3 In the RCTreported by Veenhoven et al, children received the 7vPCV plus a booster with the 23-valent pneumococcal polysaccharide vaccine or an equivalent number of doses of the Hepatitis A or B vaccine (control group). In the 2 years after randomisation, 71% of children in the pneumococcal vaccine group experi-
56
Evidence-based Healthcare (2004) 8, 55^56
acute otitis media during the study was made using a variety of different criteria and by different personnel, which weakens the conclusions. As well as w2 and Fisher’s exact tests, Cox’s regression model was used.1 It is a survival analysis based on what happens after a length of time Fnot the primary end point of the study. The paper stated that the results of the study were analysed by intention to treat and yet some results were presented as a proportion of cases followed up. The paper demonstrated unintentionally that many cases resolve quickly and hence the mild nature of the disease in many of the cases studied. Despite this, the conclusions appear valid and immunotherapy with pneumococcal polysaccharide antigen was unhelpful in these children. This may alter practice in Europe and the USA but has little relevance to the United Kingdom where it has not gained support. Adrian Drake-Lee MMEd, PhD FRCS Queen Elizabeth Hospital, Birmingham, UK
Literature cited 1. Armitage P, Berry G. Statistical Methods in Medical Research. 3rd edn.Chapter14. Survival Analysis.14.8 Regression and proportional-hazards models. Oxford: Blackwell Science, 1994: 484 ^ 485.
enced an episode of acute otitis media compared with 72% in the control group. Surprisingly, incidence rates of acute otitis media over the same period were higher in the vaccine group (incidence rate ratio 1.11, 95% CI 0.92 to 1.33%). The study was appropriately designed and conducted. Bias is an unlikely explanation for the outcomes described.While larger studies will increase the precision of the estimates, reductions in rates of acute otitis media by more than 9% are unlikely. The 7vPCV is highly effective in preventing invasive pneumococcal disease.The impact on otitis media is modest and targeting older children does not increase the benefits. Future studies of selective immunisation should aim to identify children at risk by 3 months of age. Peter S Morris, FRACP, PhD. Menzies School of Health Research Darwin, NT, Australia
Literature cited 1. Swingler G, Fransman D, Hussey G. Conjugate vaccines for preventing Haemophilus influenzae type b infections. Cochrane Database System Rev 2003; (4): CD001729. 2. 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: 187^195. 3. Ray GT, Butler JC, Black SB, Shinefield HR, Fireman BH, Lieu TA.Observed costs and health care use of children in a randomized controlled trial of pneumococcal conjugate vaccine. Pediatr Infect Dis J 2002; 21: 361^365.
Pneumococcal vaccination does not prevent recurrence of acute otitis media in older children Abstracted from: 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: 2189^2195.
BACKGROUND Pneumococcal conjugate vaccination of children aged 2, 4, 6 and 12 to 15 months reduces the incidence of recurrent acute otitis media.The e¡ectiveness of combined pneumococcal conjugate vaccination and pneumococcal polysaccharide vaccination in preventing recurrent AOM in older children is not known.
OBJECTIVE To determine whether a combined pneumococcal conjugate (PCV7) and pneumococcal polysaccharide (PPSV23) vaccination prevents recurrent acute otitis media in children aged 41 year.
SETTING One general hospital and one tertiary care hospital in the Netherlands; April 1998 toJanuary 2002.
OUTCOMES Incidence of acute otitis media episodes during 18 month follow-up. MAIN RESULTS There was a trend towards a higher rate of recurrence of acute otitis media in the pneumococcal vaccine group than in the control vaccination group over the 18 month follow-up period (recurrence rate per-person year: 1.1 episodes with pneumococcal vaccine versus 0.83 episodes with control vaccine; RR 1.29, 95% CI 1.02 to 1.62, per-protocol analysis; RR 1.25, 95% CI 0.99 to 1.57, intention-to-treat analysis). AUTHORS’ CONCLUSIONS Combined pneumococcal conjugate and polysaccharide vaccination does not prevent recurrence of acute otitis media in children aged 1 year and over. Notes Subgroup analysis showed that pneumococcal
METHOD Double-blind randomised controlled trial.
PARTICIPANTS Three hundred and eighty-three children aged 1 to 7 years old with a history of X2 episodes of acute otitis media in the previous year. Main exclusion criteria were: primary or secondary immunode¢ciency, cystic ¢brosis, craniofacial abnormalities, chromosomal abnormalities, and history of severe adverse events during vaccination. Participants were strati¢ed according to age and number of episodes of acute otitis media in the previous year.
INTERVENTION The intervention received was age dependent. Participants in the pneumococcal group aged 12 to 24 months were immunised twice with PCV7, and 6 months later with PPSV23. Similar aged control participants were immunised with hepatitis B. Participants in the pneumococcal group aged 25 to 84 months were immunised once with PCV7 and 7 months later with PPSV23. Control participants of similar age were immunised with hepatitis A vaccine. 1462-9410/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ehbc.2003.12.010
vaccination in children aged 25 to 84 months signi¢cantly increased the rate of recurrence of AOM compared with the control vaccination (RR of recurrence rates per-person year 1.45, 95% CI 1.09 to 1.94). There was no signi¢cant di¡erence in recurrence rate of AOM in children in the 12 to 24 month age group between the pneumococcal and control vaccination groups (RR of recurrence rates per-person year 1.07, 95% CI 0.72 to 1.60).The theory behind the use of di¡erent pneumococcal and control vaccination programmes for the two age groups was not explained and may have di¡erentially in£uenced the outcomes in these two age groups. Sources offunding: This study was funded by the Netherlands Organisation for Health Research and Development ZonMw and the Netherlands Health Insurance Company Zilveren Kruis-Achmea. Correspondence to: Elisabeth Sanders, Department of Paediatric Immunology, W|lhelmina Children’s Hospital/University Medical Center Utrecht, Utrecht, Netherlands. E-mail: [email protected] Abstract provided by Bazian Ltd., London Evidence-based Healthcare (2004) 8, 55^56
55
Commentary 1 Recurrent acute bacterial otitis media is a common clinical condition, with a peak incidence in the second year of life, and usually, recurrent disease ceases within12 to18 months in the majority of children. Pneumococcus is cultured from the middle ear fluid of up to a third of children. Most cases are managed in primary care within the United Kingdom and more difficult cases are referred to ENT surgeons. Treatment with ventilation tubes is advocated in refractory cases but recurrent or persistent discharge is troublesome after surgery. The article was from workers in the Netherlands who conducted a randomized trial in 388 children aged between 1 and 7 years of age.The hypothesis was that such children affected have a subtle immune deficiency to the pneumococcal polysaccharide antigen. Unfortunately no evidence was provided to support this in the children studied. They immunized children with conjugate pneumococcal polysaccharide antigen using two strategies in two age groups of equal size. These two groups are compared with children who receive Hepatitis A or B vaccination.The children were also stratified into those who had two or three attacks prior to recruitment and those who had four or more attacks. The first group of children, while strictly recurrent, would not warrant further investigation nor treatment in the United Kingdom. The primary endpoint was the number of attacks of otitis media in an 18 -month follow-up. The diagnosis of
Commentary 2 Conjugate vaccines are an important scientific achievement in child health. Young children are unable to develop immunity to polysaccharide antigen (coating of some virulent bacteria). Linking the polysaccharide to a protein helps the immune system mount a protective response. The Haemophilus influenzae type b (Hib) vaccine was the first to take advantage of this technology. Serious Hib infections are now rare in countries with universal vaccination.1 The 7-valent pneumococcal conjugate vaccine (7vPCV) provides protection against the 7 serotypes that cause most disease in children. In a large Californian randomised controlled trial (RCT), the vaccine reduced invasive disease (occult bacteraemia, bacteraemic pneumonia, and meningitis) by 94% (95% CI 80 to 99%), X-ray positive pneumonia by 18% (95% CI 5 to 29%), and otitis media episodes by 6% (95% CI 4 to 8%). Recurrent otitis media was reduced by 9% (95% CI 4 to 14%) and insertion of ventilation tubes by 23% (95% CI11 to 34%).2 Unfortunately, the vaccine is expensive. Policy-makers must weigh the potential benefits against the costs. One option is to limit the vaccine to those children who are most likely to benefit. This could mean: (i) vaccinating children from 2 months of age if they are at increased risk of pneumococcal infections; or (ii) vaccinating children as soon as they experience frequent pneumococcal infections. Although the impact of the 7vPCV on otitis media is modest, this accounts for a large proportion of the health-related cost savings.3 In the RCTreported by Veenhoven et al, children received the 7vPCV plus a booster with the 23-valent pneumococcal polysaccharide vaccine or an equivalent number of doses of the Hepatitis A or B vaccine (control group). In the 2 years after randomisation, 71% of children in the pneumococcal vaccine group experi-
56
Evidence-based Healthcare (2004) 8, 55^56
acute otitis media during the study was made using a variety of different criteria and by different personnel, which weakens the conclusions. As well as w2 and Fisher’s exact tests, Cox’s regression model was used.1 It is a survival analysis based on what happens after a length of time Fnot the primary end point of the study. The paper stated that the results of the study were analysed by intention to treat and yet some results were presented as a proportion of cases followed up. The paper demonstrated unintentionally that many cases resolve quickly and hence the mild nature of the disease in many of the cases studied. Despite this, the conclusions appear valid and immunotherapy with pneumococcal polysaccharide antigen was unhelpful in these children. This may alter practice in Europe and the USA but has little relevance to the United Kingdom where it has not gained support. Adrian Drake-Lee MMEd, PhD FRCS Queen Elizabeth Hospital, Birmingham, UK
Literature cited 1. Armitage P, Berry G. Statistical Methods in Medical Research. 3rd edn.Chapter14. Survival Analysis.14.8 Regression and proportional-hazards models. Oxford: Blackwell Science, 1994: 484 ^ 485.
enced an episode of acute otitis media compared with 72% in the control group. Surprisingly, incidence rates of acute otitis media over the same period were higher in the vaccine group (incidence rate ratio 1.11, 95% CI 0.92 to 1.33%). The study was appropriately designed and conducted. Bias is an unlikely explanation for the outcomes described.While larger studies will increase the precision of the estimates, reductions in rates of acute otitis media by more than 9% are unlikely. The 7vPCV is highly effective in preventing invasive pneumococcal disease.The impact on otitis media is modest and targeting older children does not increase the benefits. Future studies of selective immunisation should aim to identify children at risk by 3 months of age. Peter S Morris, FRACP, PhD. Menzies School of Health Research Darwin, NT, Australia
Literature cited 1. Swingler G, Fransman D, Hussey G. Conjugate vaccines for preventing Haemophilus influenzae type b infections. Cochrane Database System Rev 2003; (4): CD001729. 2. 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: 187^195. 3. Ray GT, Butler JC, Black SB, Shinefield HR, Fireman BH, Lieu TA.Observed costs and health care use of children in a randomized controlled trial of pneumococcal conjugate vaccine. Pediatr Infect Dis J 2002; 21: 361^365.