Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. 467-472 (doi:10.1542/peds.2007-0167)
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ARTICLE

Childhood Influenza: Number Needed to Vaccinate to Prevent 1 Hospitalization or Outpatient Visit

Elizabeth N. Lewis, MDa, Marie R. Griffin, MD, MPHb,c, Peter G. Szilagyi, MD, MPHd,e, Yuwei Zhu, MD, MSf, Kathryn M. Edwards, MDg and Katherine A. Poehling, MD, MPHg

a Vanderbilt University Medical School
Departments of b Medicine
c Preventive Medicine
f Biostatistics
g Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
d Department of Pediatrics
e Strong Children's Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The goal was to assess the potential benefits of the influenza vaccine recommendations for children 6 to 59 months of age by estimating the number of children needed to be vaccinated to prevent 1 hospitalization or 1 outpatient visit attributable to influenza.

METHODS. The influenza burden was obtained from published studies in which rates for children 6 to 23 months and 24 to 59 months of age could be ascertained. We assumed a range of influenza vaccine efficacies of 25% to 75%, consistent with the literature. We estimated the number of children who needed to be vaccinated to prevent 1 influenza-attributable hospitalization or 1 outpatient visit for each age group.

RESULTS. As both vaccine efficacy and severity of the influenza season increased, the number of children who needed to be vaccinated to prevent 1 hospitalization or 1 outpatient visit decreased. The numbers of children who needed to be vaccinated to prevent 1 hospitalization in a year with 50% vaccine efficacy ranged from 1031 to 3050 for children 6 to 23 months of age and from 4255 to 6897 for children 24 to 59 months of age. For every 12 to 42 children 6 to 59 months of age vaccinated in a year with 50% vaccine efficacy, we estimated that 1 influenza-attributable outpatient visit would be prevented.

CONCLUSIONS. With 1 outpatient visit being prevented through vaccination of <50 children, influenza vaccination can reduce influenza-attributable medical visits in children significantly, even in years with modest vaccine efficacy.

Key Words: influenza • vaccine efficacy • number needed to treat • hospitalizations • outpatient visits • children

Abbreviations: ACIP—Advisory Committee on Immunization Practices

Influenza is an important cause of fever and respiratory illness in young children and is associated with many hospitalizations and outpatient visits.1–6 With increased recognition of the burden of influenza in children, the Advisory Committee on Immunization Practices (ACIP) expanded its influenza vaccine recommendations for children.7–9 In part on the basis of the inpatient burden of influenza in children, the ACIP encouraged vaccination of all children 6 to 23 months of age from 2002 to 2004 and then recommended influenza vaccination beginning with the 2004 to 2005 influenza season. In 2006, based in part on the outpatient burden of influenza, a new ACIP recommendation included all children 24 to 59 months of age.

Annual influenza vaccination is the best known method to prevent influenza infections. Vaccine efficacy for annual influenza vaccination among young children has been reported to range between 45% and 86%.10–16 This broad range is attributable, in part, to differences in the primary outcome measures of the studies (culture-confirmed influenza or serologic results), the ages of the participants, and the antigenic match of the vaccine with the circulating strain. One recent study combined the results of 13 placebo-controlled, influenza vaccine studies analyzing culture-confirmed influenza in children ≥2 years of age and reported vaccine efficacy of 65% (95% confidence interval: 45%–77%) for the inactivated vaccine and 80% (95% confidence interval: 53%–91%) for the live attenuated vaccine.17 There is considerable debate about the vaccine efficacy of inactivated vaccine in children <2 years of age; however, it is generally thought to be lower than that in older children.18,19 Although the vaccine efficacy of live attenuated influenza vaccine has not been reported separately for children <2 years of age, Vesikari et al20 reported vaccine efficacy of at least 84% (95% confidence interval: 74%–90%) against culture-confirmed influenza among children 6 to 35 months of age in each of 2 study years.

Although previous studies assessed influenza burden and vaccine efficacy, the anticipated benefits of implementing the new ACIP recommendations, with respect to influenza-related hospitalizations and outpatient visits, have not been well described. In this study, we report the potential benefit of the influenza vaccine recommendations by combining the influenza burden and estimated vaccine efficacy (ranging from 25% to 75%) into clinically relevant measures, that is, the number of children needed to be vaccinated to prevent 1 influenza-attributable hospitalization or 1 outpatient visit.21–23


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Inpatient Burden
Several studies have reported the inpatient burden of influenza in children. We limited this analysis to studies in which we could ascertain the rate per 1000 children 6 to 23 months and 24 to 59 months of age. Although the studies used varying methods, study years, and populations, the estimated rates were comparable (Table 1). Gershman24 performed a retrospective analysis of the 2004 to 2005 influenza season by using laboratory-confirmed visits (mostly rapid influenza tests, as ordered by the treating physician). O'Brien et al25 used an administrative database to estimate rates of influenza-attributable hospitalizations among children with private insurance and viral surveillance from 6 influenza seasons (1994–2000). Poehling et al6 used prospective, population-based, laboratory-confirmed surveillance of hospitalizations for an acute respiratory illness or fever over 4 influenza seasons (2000–2004).


View this table:
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  		TABLE 1 Expected Reductions in Influenza-Attributable Hospitalizations and Outpatient Visits (Combined Clinic and Emergency Department Visits), According to Study, Age Group, and Vaccine Efficacy

 
Outpatient Burden
Similar to the inpatient data, the outpatient data (clinic visits and emergency department visits combined) were obtained from studies in which we could ascertain the influenza-attributable visit rate per 1000 children 6 to 23 months and 24 to 59 months of age. The outpatient studies also had comparable rates despite variations in methods, study years, and populations (Table 1). Neuzil et al26 determined the average incidence of laboratory-confirmed influenza illness from a prospective evaluation of children treated for all respiratory or febrile illnesses over 25 influenza seasons (1974–1999). Poehling et al6 used both prospective, laboratory-based surveillance of outpatient clinic and emergency department visits for an acute respiratory illness or fever and national data to estimate separately the outpatient burden during the mild season of 2002 to 2003 and the moderate season of 2003 to 2004. Season severity was determined from the Centers for Disease Control and Prevention graph of pneumonia and influenza mortality rates for 122 US cities.27 O'Brien et al25 used an administrative database to estimate the average rates of influenza-attributable outpatient visits among children with private insurance and viral surveillance from 6 influenza seasons (1994–2000).

Vaccine Efficacy
Because influenza vaccine efficacy varies depending on the degree to which the vaccine matches the circulating strains, we chose 25%, 50%, and 75% to represent the reported variation.10–16

Reduction and Number of Children Needed to Be Vaccinated
We multiplied the published rates of influenza-attributable illnesses per 1000 children for the inpatient and outpatient settings by vaccine efficacy (25%, 50%, or 75%) to compute the expected reduction in the rate of influenza-attributable disease, assuming that all children 6 to 59 months of age were vaccinated. For example, if the estimated rate of influenza-attributable visits without vaccinations was 80 visits per 1000 children, all children were vaccinated, and the vaccine efficacy was 50%, then we would expect a 50% reduction in influenza-attributable visits from 80 to 40 visits per 1000 children ([0.5 x 80]/1000). The rate reduction per 1000 children would be 80 minus 40 visits, which equals 40 visits per 1000 children. This rate attributable to vaccination was then used to compute the number needed to be vaccinated to prevent 1 influenza-attributable visit. One divided by the estimated attributable rate (1 ÷ = 25) equals the number of children needed to be vaccinated to prevent 1 influenza-attributable visit (Table 1). The variation in reported rates of influenza hospitalizations and outpatient visits and the separate outpatient visit rate estimates for mild and moderate influenza seasons in 1 study provided the opportunity to see the impact of season severity.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hospitalizations
With 50% vaccine efficacy and annual influenza-attributable hospitalization rates ranging from 0.3 to 1.9 cases per 1000 children (Table 1), we estimated that 1031 to 3050 children 6 to 23 months of age and 4255 to 6897 children 24 to 59 months of age would need to be vaccinated to prevent 1 influenza-attributable hospitalization (Fig 1). The 95% confidence intervals for the number of children who would need to be vaccinated to prevent 1 hospitalization overlapped for all ages and levels of vaccine efficacy, with the exception of children 6 to 23 months of age at 25% vaccine efficacy. As both vaccine efficacy and influenza season severity increased, the number of children who would need to be vaccinated to prevent 1 influenza-attributable hospitalization decreased.


Figure 1
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  		FIGURE 1 Estimated numbers of children (with 95% confidence intervals) needed to be vaccinated to prevent 1 influenza-attributable hospitalization, according to age group and study.

 
Outpatient Surveillance
Given outpatient visits rates that varied from 48 to 164 visits per 1000 children (Table 1), the number of children needed to be vaccinated to prevent 1 influenza-attributable hospitalization was 45-fold to >100-fold greater than that needed to prevent 1 influenza-attributable outpatient visit (Figs 1 and 2). In contrast to hospitalizations, the numbers needed to be vaccinated to prevent 1 outpatient visit were similar for children 6 to 23 months and 24 to 59 months of age. With 50% vaccine efficacy, we estimated that 12 to 42 children 6 to 59 months of age would need to be vaccinated to prevent 1 influenza-attributable outpatient visit, depending on the severity of the influenza season. The 95% confidence intervals overlapped, with the exception of the estimate for the moderate influenza season of 2003 to 2004. As both vaccine efficacy and influenza season severity increased, the number needed to be vaccinated to prevent 1 influenza-attributable outpatient visit decreased.


Figure 2
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  		FIGURE 2 Estimated numbers of children (with 95% confidence intervals) needed to be vaccinated to prevent 1 influenza-attributable outpatient visit, according to age group and study.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The number of children needed to be vaccinated to prevent 1 influenza-attributable visit combines the burden of disease and vaccine efficacy into a single, clinically relevant measure. The number needed to be treated to prevent 1 event was used previously in studies such as those evaluating the effectiveness of lipid-lowering agents, the benefits of thrombolytic therapy in acute stroke, and the advantages of radiation therapy after prostatectomy.28–30 To our knowledge, this study is the first to use the number needed to be vaccinated to estimate the potential reduction of influenza-attributable hospitalizations or outpatient visits, given the current influenza vaccination recommendations for young children. Reflecting the greater burden of disease in the outpatient setting, we estimated that the number of children needed to be vaccinated to prevent 1 influenza-attributable hospitalization was 45-fold to >100-fold greater than the number needed to be vaccinated to prevent 1 influenza-attributable outpatient visit.

Influenza epidemiologic features make prediction of the benefits of vaccination in any given year difficult. First, the influenza burden varies each year with the severity of the season. Therefore, we included studies that encompassed multiple seasons (>20 years for inpatient studies and >30 years for outpatient studies), to reflect typical benefits. Second, vaccine efficacy varies each year. To account for this known variation, we assumed conservatively 3 levels of vaccine efficacy (25%, 50%, and 75%). Finally, the severity of the influenza season varies according to geographic region; therefore, in a given year, benefits may vary according to location.

Because we sought to make conservative estimates of the potential benefits of influenza vaccination, we assumed no indirect or "herd" effects, which, if present, would increase the benefits of vaccination for both older and younger populations. Because influenza virus is highly contagious,31 herd effects from influenza vaccination have been assessed in a number of publications. In Japan, a threefold to fourfold decrease in excess deaths resulting from pneumonia and influenza was observed after the introduction of an influenza vaccination program for schoolchildren and disappeared when that vaccination program was discontinued.32 Monto et al33 showed that there were fewer respiratory visits in a town in which school-aged children were vaccinated against influenza than in a town without vaccinated children. Similarly, King et al34 performed a trial of school-based influenza vaccination among 11 elementary schools and found that households from intervention schools had fewer influenza-like symptoms during a recall week. Glezen35 showed recently that children and adults had fewer respiratory illnesses in a town in which <20% of children received nasal influenza vaccine, compared with a town without a nasal influenza vaccination program. If influenza vaccination among young children results in herd effects, then we have underestimated the true impact of vaccination and overestimated the number of children needed to be vaccinated to prevent 1 hospitalization or outpatient visit.

We estimated conservatively the direct effects (ie, assuming no herd immunity) that a vaccination program for children 6 to 59 months of age would have on the influenza burden in young children. For every 12 to 42 children 6 to 59 months of age vaccinated in a year in which the influenza vaccine has 50% vaccine efficacy, 1 outpatient visit should be prevented. Extrapolated to a national level, the impact of one half of the 18 million US children 6 to 59 months of age being fully vaccinated in a year with 50% vaccine efficacy would be ~2250 fewer hospitalizations and 270000 to 650000 fewer outpatient visits for influenza-attributable illnesses. The impact with the same parameters and 75% vaccine efficacy would be ~3250 fewer hospitalizations and 400000 to 975000 fewer outpatient visits for influenza-attributable illnesses. We conclude that influenza vaccination can reduce influenza-attributable medical visits for children significantly, even in years with modest vaccine efficacy.


   ACKNOWLEDGMENTS
 
Dr Poehling received support, in part, from the Robert Wood Johnson Generalist Physician Faculty Scholars Program and National Institute of Allergy and Infectious Diseases grant K23 AI065805.

We thank Verlinda Miner and Kim Crews for their assistance in preparing this manuscript. We appreciate the contributions of the reviewers, whose comments and suggestions led to significant improvements in this manuscript.


   FOOTNOTES
 
Accepted Apr 24, 2007.

Address correspondence to Katherine A. Poehling, MD, MPH, Department of Pediatrics, Wake Forest University Medical Center, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: kpoehlin{at}wfubmc.edu

Financial Disclosure: Dr Griffin received grant funding from Medimmune. Dr Edwards received grant funding from Sanofi, acted as a consultant for Medimmune, and is a consultant for PATH. All other authors have indicated they have no financial relationships relevant to this article to disclose.

Dr Lewis’ current affiliation is Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts.

Dr Poehling's current affiliation is Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC.


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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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