Vaccinating children aged 6–23 months, plus all other children at high-risk, will likely be more effective than vaccinating all children against influenza.

We estimated cost-effectiveness of annually vaccinating children not at high risk with inactivated influenza vaccine (IIV) to range from US $12,000 per quality-adjusted life year (QALY) saved for children ages 6–23 months to $119,000 per QALY saved for children ages 12–17 years. For children at high risk (preexisting medical conditions) ages 6–35 months, vaccination with IIV was cost saving. For children at high risk ages 3–17 years, vaccination cost $1,000–$10,000 per QALY. Among children not at high risk ages 5–17 years, live, attenuated influenza vaccine had a similar cost-effectiveness as IIV. Risk status was more important than age in determining the economic effects of annual vaccination, and vaccination was less cost-effective as the child's age increased. Thus, routine vaccination of all children is likely less cost-effective than vaccination of all children ages 6–23 months plus all other children at high risk.

The risks of influenza, both annual epidemic and pandemic, have caused national policymakers to ask whether routine influenza vaccination should be expanded to healthy children and adults of all ages. During the 2003–04 influenza season, reports of >150 influenza-associated deaths among children and unprecedented demand for influenza vaccine highlighted the need to reevaluate the nation's influenza vaccination policies regarding children (

Should influenza vaccine be routinely used in older children without high-risk conditions? This question is especially relevant, given the introduction of live, attenuated (intranasal) influenza vaccine (LAIV) for healthy persons ages 5–49 years, which has a higher list price than the inactivated (injected) vaccine but is also potentially more effective (

Our objective in this study was to evaluate the cost-effectiveness of routine annual influenza vaccination, comparing live attenuated with inactivated vaccines, for children in varying age and risk groups from 6 months to 17 years. This is the first study to include measures of health preferences that allow results to be calculated in quality-adjusted life years (QALYs).

Using standard software (TreeAge Pro 2004 Software, release 6, Treeage Software, Williamstown, MA, USA), we created a mathematical model (decision tree) to estimate the effect of influenza vaccination on outcomes and costs among children. The decision tree evaluated 3 options: 1) no vaccination; 2) inactivated influenza vaccine (IIV); and 3) live, attenuated influenza vaccine (LAIV). It estimated costs and outcomes for influenza-related illness for children stratified into 10 subgroups by age (6–23 months, 2 years [24–35 months], 3–4 years, 5–11 years, 12–17 years) and risk status (high risk or not at high risk). Children were defined as being at high risk for influenza-related complications due to preexisting medical conditions (

Influenza cost-effectiveness model. Each health state in the model is associated with a cost and quality adjustment from

Variable | Most likely estimate | Range for sensitivity analysis | ||
---|---|---|---|---|

Influenza illness attack rate (annual) | ||||

6-23 mo | 0.157 | 0.02–0.35 | ||

2 y | 0.155 | 0.02–0.35 | ||

3–4 y | 0.155 | 0.01–0.35 | ||

5–11 y | 0.08 | 0.01–0.18 | ||

12–17 y | 0.06 | 0.01–0.14 | ||

Probability of outpatient visit for child with influenza illness‡ | ||||

6–23 mo | 0.5 | 0.17–0.83 | ||

2 y | 0.47 | 0.15–0.81 | ||

3–4 y | 0.43 | 0.12–0.78 | ||

5–11 y | 0.28 | 0.11–0.5 | ||

12–17 y | 0.24 | 0.06–0.5 | ||

Probability of otitis media for child with medically attended influenza illness | ||||

6–23 months | 0.63 | 0.33–0.8 | ||

2 y | 0.58 | 0.27–0.8 | ||

3–4 y | 0.39 | 0.17–0.6 | ||

5–11 y | 0.23 | 0.05–0.5 | ||

12–17 y | 0.15 | 0.01–0.4 | ||

Probability of nonhospitalized pneumonia or other outpatient complication for child with medically attended influenza illness§ | ||||

6–23 mo | 0.2 | 0.04–0.5 | ||

2 y | 0.15 | 0.02–0.4 | ||

3–4 y | 0.15 | 0.02–0.4 | ||

5–11 y | 0.11 | 0.02–0.3 | ||

12–17 y | 0.08 | 0.01–0.2 | ||

Hospitalizations for pneumonia or other respiratory conditions due to influenza/10,000 children not at high risk¶ | ||||

6-23 mo | 28.3 | 1.9–80.0 | ||

2 y | 17.1 | 0–56.8 | ||

3–4 y | 8.0 | 0–35.4 | ||

5–11 y | 3.1 | 0–16.0 | ||

12–17 y | 3.1 | 0–14.9 | ||

Probability of long-term sequelae following influenza-related hospitalization‡ | 0.01 | 0.001–0.03 | ||

Probability of death during influenza-related hospitalization | 0.0009 | 0–0.002 | ||

Vaccine effectiveness in preventing influenza illness# | ||||

IIV | 0.69 | 0.4–0.9 | ||

LAIV | 0.838 | 0.6–0.96 | ||

Probability of medically attended vaccination-related adverse events | ||||

Injection site reaction | ||||

6-23 mo | 0.008 | 0.002–0.017 | ||

2 y | 0.003 | 0.001–0.006 | ||

3–4 y | 0.002 | 0.0004–0.003 | ||

5–11 y | 0.001 | 0.0002–0.002 | ||

12–17 y | 0.0003 | 0.0001–0.001 | ||

Systemic reaction (fever)** | ||||

6–23 mo | 0.013 | 0.001–0.025 | ||

2 y | 0.011 | 0.0008–0.020 | ||

3–4 y | 0.009 | 0.0007–0.016 | ||

5–11 y | 0.004 | 0.0003–0.008 | ||

12–17 y | 0.003 | 0.0002–0.005 | ||

Anaphylaxis | 0.00000025 | 0–0.000001 | ||

Guillain-Barré syndrome | 0.000001 | 0–0.00001 |

*IIV, inactivated influenza vaccine; LAIV, live, attenuated influenza vaccine.
†Refer to

Cost input | Most likely estimate | Range for sensitivity analysis | |
---|---|---|---|

Influenza-related costs | |||

OTC medications† | $3 | ||

Physician visit, uncomplicated influenza‡ | $27 | $10–$78 | |

Physician visit, otitis media§ | $78 | $23–$197 | |

Physician visit, non-hospitalized pneumonia§ | $179 | $62–$715 | |

Hospitalization¶ | $4,300 | $1,300–$34,500 | |

Long-term sequelae following influenza-related hospitalization# | $625,000 | $0–$1,000,000 | |

Vaccination costs | |||

Per dose, IIV** (children <3 y) | $9.56†† | 1×–4× base case | |

Per dose, IIV** (children >3 y) | $6.86†† | ||

Per dose, LAIV** | $12.89†† | $10–$25 | |

Administration costs (0–2 visits)¶¶ | $25 | $10–$40 | |

Parent time costs, per visit## | $32 | $0–$64 | |

Total vaccination costs*** | $30–$110 | ||

6-23 mo | $79 | ||

2 y | $66 | ||

3–4 y | $59 | ||

5–11 y | $49 | ||

12-17 y | $49 | ||

Vaccination-related adverse events | |||

Physician visit for injection site reaction††† | $61 | $30–$683 | |

Anaphylaxis‡‡‡ | $2,700 | $52–$13,754 | |

Guillain-Barré syndrome§§§ | $23,360 | $6,700–$78,900 |

*OTC, over the counter; IIV, inactivated influenza vaccine; LAIV, live, attenuated influenza vaccine.
†Vary by age, calculated by costing out recommended dose of acetaminophen for average weight in each age group.
‡Only a proportion of children with influenza illness are assumed to make a physician visit. ICD-9 codes: 487 and 487.0.
§Costs of physician visits for otitis media and nonhospitalized pneumonia vary by age group and include prescription medications and laboratory tests. Costs shown are for children 6–23 mo. See Appendix for full list of costs by age.
¶ICD-9 codes: 460-466, 471-474, 477, 478, 480-483, 490-496, 506-508, 510, 511, 514, 518, 519.
#Includes costs of lifetime care and special education.
**2 doses assumed for children <5 y receiving their first influenza vaccination.
††Vaccine dose costs are based on 2004 CDC-negotiated prices. Cost for children <3 y assumes thimerosal-free vaccine is used.
‡‡Current Procedural Terminology (CPT) codes: 99211 for an additional visit ($19.95) and 90471 for a vaccination at an existing visit ($10.37).
§§Each physician visit is assumed to take 2 hours of parent time valued at an average hourly wage rate of $15.54.
¶¶Proportion of children requiring 2 doses is 1 for 6–23 mo, 0.5 for 2 y, and 0.33 for 3–4 y. No. of additional visits needed to administer recommended number of vaccine doses is 1.07 for 6–23 mo, 0.91 for 2 y, and 0.84 for 3–4 y, and 0.75 for 5–17 y. See Appendix for more details. Total vaccination costs in

Events | Most likely estimate | Range for sensitivity analysis |
---|---|---|

Episode of influenza | 0.005 | 0.002-0.009 |

Otitis media | 0.042 | 0.023-0.065 |

Nonhospitalized complications (pneumonia) | 0.046 | 0.027-0.071 |

Hospitalization, pneumonia | 0.076 | 0.054-0.100 |

Anaphylaxis | 0.020 | 0.006-0.041 |

Guillain-Barré syndrome | 0.141 | 0.092-0.199 |

*Quality adjustments are included in model as a one-time decrement in utility for each temporary health state. For example, an episode of influenza results in a 1-time loss of 0.005 quality-adjusted life years (QALYs). Utility losses were calculated by dividing discounted time-traded off by respondent's discounted life expectancy. See appendix for references. †Average life span used to calculate total QALYs lost due to lifelong sequelae and death was 77.9–78.2 years, depending on child's current age.

Influenza-related outcomes included in the decision tree were episodes of influenza illness (medically attended or not), otitis media, mild pneumonia (and other complications treated on an outpatient basis), hospitalizations (with and without long term sequelae), and deaths. Event rates, by age and risk group, were derived from the published literature and were supplemented by expert opinion where data were limited or unavailable (

Inactivated vaccine was considered for all 10 subgroups, and LAIV was considered only for children not at high risk. Children 6 months to 4 years were included as a theoretical intended population for LAIV, although LAIV is currently licensed in the United States only for children 5–17 years. The most likely estimate for vaccine effectiveness against symptomatic influenza illness was lower for IIV (0.690) than the most likely estimate for LAIV (0.838) (

Adverse events attributable to influenza vaccination included in the decision tree were medically-attended episodes of injection site reactions, systemic reactions (defined as fever within 2–7 days of vaccination), anaphylaxis, and Guillain-Barré syndrome (

Costs included direct medical costs (physician visits, over-the-counter remedies, prescription drugs, diagnostic tests, and hospitalizations) and opportunity costs (parent time costs) for physician visits (

It is recommended that first-time recipients aged 6 months through 8 years receive 2 doses of influenza vaccine (

The model projected 4 different outcomes that were averted through vaccination: influenza episodes, hospitalizations, deaths, and QALYs. The QALY is a measure of net health effects that takes into account the health benefits of averted influenza cases as well as the health costs of vaccination-related adverse events. We obtained QALY valuations for each health event in the model from 2 studies (

The primary outcome measure was the incremental cost-effectiveness ratio in dollars per QALY. Secondary measures included costs and events averted per 1,000 vaccinated children, dollars per influenza-related event avoided, dollars per hospitalization avoided, and dollars per death averted. One-way sensitivity analyses were conducted on all variables, in which the impact on the average $/QALY saved was examined by altering each variable within the range of given values (

Influenza vaccination with IIV was projected to be cost saving for children ages 6–35 months at high risk and to require a net investment for all other age and risk groups. The projected benefits of vaccination decreased as age increased (

Net costs, $‡ | Influenza events averted (all) | Influenza hospitalizations averted | Deaths averted | Vaccine adverse events incurred§ | QALYs gained | |||
---|---|---|---|---|---|---|---|---|

Using inactivated influenza vaccine | ||||||||

Non-high risk | ||||||||

6–23 mo | 37,000 (–119,000 to 98,000) | 108 (16–276) | 2 (0.2–6) | 0.002 (0–0.007) | 21 (8–47) | 3.0 (0.4–9.0) | ||

2 y | 43,000 (–40,000 to 83,000) | 107 (15–276) | 1.2 (0.1–4.2) | 0.001 (0–0.005) | 14 (5–30) | 2.4 (0.3–7.3) | ||

3–4 y | 47,000 (2,000–78,000) | 107 (15–276) | 0.6 (0–2.3) | 0.0005 (0–0.0025) | 10 (3–24) | 1.7 (0.2–5.2) | ||

5–11 y | 44,000 (21,000–68,000) | 55 (8–142) | 0.2 (0–0.7) | 0.0002 (0– 0.0008) | 5 (2–11) | 0.6 (0.1–1.7) | ||

12–17 y | 44,000 (22,000– 68,000) | 41 (6–104) | 0.2 (0–0.6) | 0.0002 (0–0.0008) | 3 (1–8) | 0.4 (0–1.1) | ||

High risk | ||||||||

6–23 mo | –74,000) (–552,000 to 83,000) | 108 (16–276) | 5.5 (0.5–6.5) | 0.005 (0–0.020) | 32 (11–56) | 7.2 (0.8–23.2) | ||

2 y | –22,000) (–292,000 to 72,000) | 107 (15–276) | 3.5 (0.2–11.4) | 0.003 (0–0.013) | 25 (7–44) | 5.4 (0.6–17.2) | ||

3–4 y | 2,000 (–212,000 to 70,000) | 107 (15–276) | 2.2 (0.1–9.1) | 0.002 (0–0.010) | 19 (5–37) | 4.0 (0.4–13.1) | ||

5–11 y | 12,000 (–125,000 to 59,000) | 55 (8–142) | 1.3 (0.1–3.9) | 0.001 (0–0.005) | 9 (3–24) | 1.6 (0.2–5.6) | ||

12–17 y | 13,000 (–120,000 to 59,000) | 41 (6–104) | 1.3 (0.1–3.9) | 0.001 (0–0.005) | 6 (1–15) | 1.3 (0.1–4.5) | ||

Using LAIV¶ | ||||||||

Non-high risk | ||||||||

13 (3–32) | ||||||||

11 (2–26) | ||||||||

9 (2–23) | ||||||||

5–11 y | 48,000 (22,000–73,000) | 67 (10–166) | 0.3 (0–0.8) | 0.0002 (0–0.0010) | 4 (1–10) | 0.7 (0.1–1.9) | ||

12–17 y | 49,000 (23,000–73,000) | 50 (8–120) | 0.3 (0–0.7) | 0.0002 (0–0.0010) | 3 (0–7) | 0.5 (0.1–1.3) |

*CI, confidence interval; QALYs, quality-adjusted life years; LAIV, live, attenuated influenza vaccine. †Bootstrapped. ‡Net costs = costs of vaccination minus savings from disease averted. §Includes medically attended injection site reactions, systemic reactions, anaphylaxis, and Guillain-Barré syndrome. ¶Italics indicate that LAIV is not licensed for children <5 y.

All vaccination strategies had net positive QALYs gained, which indicated that the health benefits of vaccination outweighed the risks (

IIV use was cost saving among children at high risk ages 6 months to 2 years (

Age group | Using inactivated influenza vaccine | Using live, attenuated influenza vaccine† | ||
---|---|---|---|---|

Children not at high risk | Children at high risk | Children not at high risk | ||

$ per influenza episode averted‡ | ||||

6–23 mo | 340 (CS–4,690) | CS (CS–4,090) | ||

2 y | 400 (CS–3,990) | CS (CS–3,620) | ||

3–4 y | 440 (10–3,590) | 20 (CS–3,410) | ||

5–11 y | 800 (180–5,850) | 210 (CS–5,560) | 720 (170–5,290) | |

12–17 y | 1,070 (250–7,780) | 310 (CS–7,360) | 980 (240–7,070) | |

$ per hospitalization averted‡ | ||||

6-23 mo | 19,000 (CS–350,000) | CS (CS–132,000) | ||

2 y | 37,000 (CS–633,000) | CS (CS–232,000) | ||

3–4 y | 84,000 (1,000–2,587,000) | 1,000 (CS–750,000) | 74,000 (CS–2,227,000) | |

5–11 y | 202,000 (38,000–1,929,000) | 9,000 (CS–310,000) | 184,000 (35,000–1,629,000) | |

12–17 y | 206,000 (43,000–1,768,000) | 10,000 (CS–304,000) | 188,000 (40,000–1,575,000) | |

$ per death averted‡ | ||||

6–23 mo | 22 m (CS–1,109 m) | CS (CS–342 m) | ||

2 y | 42 m (CS–1,762 m) | CS (CS–591 m) | ||

3–4 y | 98 m (1 m–6,840 m) | 1 m (CS–1,873 m) | ||

5–11 y | 234 m (32 m–5,993 m) | 10 m (CS–876 m) | 212 m (32 m–5,331 m) | |

12–17 y | 238 m (37 m–5,607 m) | 12 m (CS–892 m) | 217 m (34 m–5,007 m) | |

$ per quality-adjusted life-year saved | ||||

6–23 mo | 12,000 (CS–208,000) | CS (CS–85,000) | ||

2 y | 18,000 (CS–217,000) | CS (CS–100,000) | ||

3–4 y | 28,000 (1,000–290,000) | 1,000 (CS–130,000) | ||

5–11 y | 79,000 (15,000–682,000) | 7,000 (CS–260,000) | 72,000 (14,000–592,000) | |

12–17 y | 119,000 (24,000–1,040,000) | 10,000 (CS–367,000) | 109,000 (22,000–888,000) |

*CS, cost savings; m, million. †Numerator does not include productivity losses. ‡Italics indicate that live, attenuated influenza vaccine is not licensed for children <5 y.

Using base-case vaccine purchase prices for LAIV and IIV (

Probabilistic sensitivity analysis provided confidence intervals for projected costs and events averted and quasi-confidence intervals for cost-effectiveness ratios. By using base case assumptions, results for LAIV are slightly more favorable than IIV (compared to no vaccination), and vaccination with LAIV is the preferred strategy. However, probabilistic sensitivity analysis indicated projected results were similar for IIV and LAIV.

Cost-effectiveness acceptability curves generated through probabilistic sensitivity analysis are very similar for IIV and LAIV (

Cost-effectiveness acceptability curves for inactivated influenza vaccine compared with no vaccination (A, children not a high risk; B, children at high risk). Cost-effective acceptability curves for live, attenuated vaccine compared with no vaccine (C, children not at high risk only). Box indicates the mean cost-effectiveness ratio.

In 1-way sensitivity analyses, cost-effectiveness ratios were most sensitive to changes in influenza illness attack rate, hospitalization rates, total vaccination costs, and vaccine effectiveness (

One-way sensitivity analyses on selected variables for children ages 6–23 months not at high risk, in dollars per quality-adjusted life years gained. This figure reports variables to which the results were most sensitive. Variables not reported here had less effect on results than those included above. Base case=$12,300.

Two-way sensitivity analysis on influenza illness rate and vaccine effectiveness (IIV) resulted in changes in the cost-effectiveness ratio from a decrease in 11% for a season with a high influenza illness rate (35%) and high vaccine effectiveness (IIV) to an increase of more than a factor of 30 for seasons with a low influenza illness rate and low vaccine effectiveness (IIV). Combining a high influenza illness rate (35%) with low vaccine effectiveness (IIV) resulted in cost-effectiveness ratio ≈3 times base case results ($43,000/QALY) for children not at high risk ages 6–23 months. Two-way sensitivity analyses on influenza illness rate and total vaccination costs (IIV) had similar results, ranging from a decrease in 6% in the cost-effectiveness ratio to an increase 25 times as high as the base case for seasons with low influenza illness rate and high vaccination costs (IIV). Two-way sensitivity analyses for vaccination costs and effectiveness yielded a 20% lower cost-effectiveness ratio for low costs and high effectiveness of vaccination (IIV) to 7 times the base case for high costs and low vaccine effectiveness (IIV).

We found that influenza vaccination of children, both those at high risk and those not at high risk, in all age groups would have health benefits that outweigh vaccine adverse events as measured by QALYs for both IIV and LAIV. For children not at high risk ages 6 months–4 years, we estimated that influenza vaccination with IIV would cost <$25,000 per QALY saved. In comparison, other routinely-used preventive interventions, such as pneumococcal conjugate vaccination, cost an average of $7,000/QALY for children <2 years (

Live, attenuated influenza vaccine is currently approved for children >5 years of age who are not at high risk, but not for children <5 years or for children at high risk. At a price per dose <$20, its cost-effectiveness ratios are similar to those for IIV. This analysis likely presents a relatively conservative estimate of the potential benefits of LAIV, because we did not include its potentially greater effectiveness against antigenically drifted strains or likely higher effectiveness with 1 dose of vaccine in previously unvaccinated children <9 years (

The sensitivity of the results to the influenza illness attack rate (which varies from season to season and from community to community) and to vaccine effectiveness indicates that the cost-effectiveness of influenza vaccination can vary considerably from year to year. In seasons with a low influenza attack rate, the cost-effectiveness of vaccination with IIV would be dramatically higher than in the base case (

Our study contributes valuable new information because it incorporates survey-based health state preferences for influenza-related illness and vaccine adverse events. These preferences, which are expressed as QALYs saved, are important for 2 reasons. First, we were able to evaluate the net health benefits of vaccination by subtracting the QALYs lost due to vaccine adverse events from the QALYs gained due to averted influenza cases. The results suggest that vaccination of all children is desirable from a health standpoint. Second, the outcome measure of dollars per QALY saved allows policymakers to compare the cost-effectiveness of influenza vaccination of children with other potential investments in preventive health services.

Authors of other economic analyses of influenza vaccination in children concluded that vaccination was more cost-effective than we found in our study (

In a recent study that used cost-benefit analysis to evaluate the economics of influenza vaccination in children, Meltzer et al. arrived at conclusions similar to this analysis for many of the age/risk groups under consideration (

Some studies that used mathematical models have suggested substantial community herd immunity effects from vaccinating school-aged children (

A recent randomized trial suggests that influenza vaccination has little, if any, effect on otitis media in children (

The time-tradeoff questions we used to elicit preferences for health states differ from that commonly used for adult illnesses because the loss of quality of life for both parent and child are explicitly included. In addition, parents were asked to include the value of productivity losses to paid or unpaid work for caring for a child with influenza in the time-tradeoff amount; therefore, productivity losses were included in the health state quality adjustments, whereas parent time costs for vaccination were included as dollar costs. As a result, the time-tradeoff amounts presented here are not directly comparable to utility values from generic utility instruments for measuring reductions in quality-of-life for chronic health states, such as the Health Utilities Index (

Recent data show that some influenza-related deaths in children may occur outside the medical setting (

Few data are available to guide assumptions on what proportion of children who experience mild systemic symptoms after vaccination, such as fever or respiratory symptoms, will see a physician. In the absence of reliable data, we selected an assumption that would be more likely to bias against vaccination rather than for and assumed it would be the same as the proportion of children who would visit a physician due to influenza illness. If the number of medically attended, vaccination-related adverse events were lower, the cost-effectiveness ratios would also be slightly lower, but cost-effectiveness results are not very sensitive to this parameter. We did not include any quality adjustment for vaccination itself aside from negative effects of vaccination-related adverse events. If vaccination itself were associated with a decrease in quality of life, cost-effectiveness ratios would be less favorable than in the current analysis. Previous analyses of other vaccinations, which included a quality adjustment for fever and fussiness following vaccination, were not sensitive to this parameter (

Routine annual influenza vaccination using IIV for children age >2 years not at high risk is likely to result in net health benefits, but cost-effectiveness ratios are likely to be less favorable than for children ages 6–23 months and children of any age with a high-risk condition. Cost-effectiveness among children decreases with increasing age, although risk status is more important than age in determining the economic impact of annual influenza vaccination. Further work is needed to assess the potential impact of herd immunity on the cost-effectiveness of expanding influenza vaccine recommendations.

Suggested citation: Prosser LA, Bridges CB, Uyeki TM, Hinrichsen VL, Meltzer MI, Molinari N-AM, et al. Health benefits, risks, and cost-effectiveness of influenza vaccination of children. Emerg Infect Dis [serial on the Internet]. 2006 Oct [date cited].

We thank the external members of our expert panel (Kathryn Edwards, Arnold Monto, and Marie Griffin) for assisting in the development of input assumptions for the model; Kakoli Roy, Peter Szilagyi, James Singleton, and Jonathan Finkelstein for providing important data for this study; and Andra Barnette for outstanding administrative assistance.

This research was supported by the Vaccine Safety Datalink Project and the Joint Initiative for Vaccine Economics of the National Immunization Program, Centers for Disease Control and Prevention. Dr. Lieu's effort was supported in part by a Mid-Career Investigator Award in Patient-Oriented Research from the National Institute of Child Health and Human Development (K24 HD047667).

Health Benefits, Risks, and Cost-Effectiveness of Influenza Vaccination in Children

This appendix provides additional information on methods and data and is intended to supplement the corresponding article.

Equation for Calculating Cost-Effectiveness (CE) Ratios

Variable | Most likely estimate | Range for sensitivity analysis | Source | Type of distribution | Distribution parameter 1 | Distribution parameter 2 | |
---|---|---|---|---|---|---|---|

Influenza illness attack rate (annual) | (1–10) | ||||||

6–23 mo | 0.157 | 0.02–0.35 | β^{1} | 2.2 | 11.8 | ||

2 y | 0.155 | 0.02–0.35 | Derived^{2} | ||||

3–4 y | 0.155 | 0.02–0.35 | Derived | ||||

5–11 y | 0.08 | 0.01–0.18 | Derived | ||||

12–17 y | 0.06 | 0.01–0.14 | Derived | ||||

Probability of an outpatient visit for child with influenza illness^{3} | (5,11,12)4 | ||||||

6–23 mo | 0.5 | 0.17–0.83 | β | 3.3 | 3.5 | ||

2 y | 0.47 | 0.15–0.81 | β | 3.29 | 3.71 | ||

3–4 y | 0.43 | 0.12–0.78 | β | 3.01 | 3.99 | ||

5–11 y | 0.28 | 0.11–0.5 | β | 5.6 | 14.4 | ||

12–17 y | 0.24 | 0.06–0.5 | β | 2.88 | 19.12 | ||

Probability of otitis media for a child with medically attended influenza illness | (13–16), expert panel | ||||||

6–23 mo | 0.63 | 0.33–0.8 | β | 6.3 | 3.7 | ||

2 y | 0.58 | 0.27–0.8 | β | 5.22 | 3.78 | ||

3–4 y | 0.39 | 0.17–0.6 | β | 6.24 | 9.76 | ||

5–11 y | 0.23 | 0.05–0.5 | β | 2.53 | 8.47 | ||

12–17 y | 0.15 | 0.01–0.4 | β | 1.5 | 8.5 | ||

Probability of nonhospitalized pneumonia or other outpatient complication for child with medically attended influenza illness^{5} | (11,12); expert panel | ||||||

6–23 mo | 0.2 | 0.04–0.5 | β | 2.6 | 10.4 | ||

2 y | 0.15 | 0.02–0.4 | β | 1.95 | 11.05 | ||

3–4 y | 0.15 | 0.02–0.4 | β | 1.95 | 11.05 | ||

5–11 y | 0.11 | 0.02–0.3 | β | 2.2 | 17.8 | ||

12–17 y | 0.08 | 0.01–0.2 | β | 2.16 | 24.84 | ||

Hospitalizations for pneumonia or other respiratory conditions due to influenza per 10,000 children not at high risk^{6} | (7,11,17); W. Thompson, pers. comm.) | ||||||

6–23 mo | 28.3 | 1.9–80.0 | β | 5.5 | 244.5 | ||

2 y | 17.1 | 0–56.8 | β | 3.4 | 246.6 | ||

3–4 y | 8.0 | 0–35.4 | β | 1.6 | 248.4 | ||

5–11 y | 3.1 | 0–16.0 | β | 7.95 | 1,492.1 | ||

12–17 y | 3.1 | 0–14.9 | β | 10.5 | 1,489.5 | ||

Probability of long-term sequelae after influenza-related hospitalization^{2} | 0.01 | 0.001–0.03 | Expert panel | β | 1.3 | 11.7 | |

Probability of death during influenza-related hospitalization | 0.0009 | 0–0.002 | (18)4 | β | 1.7 | 18.3 | |

Vaccine effectiveness in preventing influenza illness9 | |||||||

IIV | 0.69 | 0.4–0.9 | (19)4 | β | 7.59 | 3.41 | |

LAIV | 0.838 | 0.6–0.96 | (20)4 | β | 16.76 | 3.24 | |

Probability of medically attended vaccination-related adverse events | |||||||

Injection site reaction | |||||||

6–23 mo | 0.008 | 0.002–0.017 | (8) | β | 4.0 | 46.0 | |

2 y | 0.003 | Derived^{10} | |||||

3–4 y | 0.002 | Derived | |||||

5–11 y | 0.001 | Derived | |||||

12–17 y | 0.0003 | Derived | |||||

Systemic reaction (fever)11 | |||||||

6–23 mo | 0.013 | 0.001–0.025 | (20) | β | 5.2 | 194.8 | |

2 y | 0.011 | Derived | |||||

3–4 y | 0.009 | Derived | |||||

5–11 y | 0.004 | Derived | |||||

12–17 y | 0.003 | Derived | |||||

Anaphylaxis | 0.00000025 | 0–0.000001 | Expert panel | β^{12} | 0.5 | 19.5 | |

Guillain-Barré syndrome | 0.000001 | 0–0.00001 | Expert panel | Triangular | 0.000001 (most likely) | 0 (min), 0.000002 (max) | |

Influenza-related costs | |||||||

OTC medications^{13} | $3 | (21,22); J. Finkelstein, pers. comm.; expert panel | |||||

Physician visit for uncomplicated influenza^{14} | $27 | $0–$180 | Marketscan database15 | Lognormal^{16} | 32 | 27 | |

Physician visit for otitis media | |||||||

6–3 mo | $78 | $23–$197 | Marketscan database^{17} | Lognormal | 98 | 78 | |

2–4 y | $83 | $23–$200 | Marketscan database^{17} | Lognormal | 100 | 83 | |

5–17 y | $94 | $31–$245 | Marketscan database^{17} | Lognormal | 117 | 94 | |

Physician visit for nonhospitalized pneumonia | |||||||

6–23 mo | $179 | $62–$715 | Marketscan database^{17} | Lognormal | 252 | 179 | |

2–4 y | $88 | $27–$333 | Marketscan database^{17} | Lognormal | 130 | 88 | |

5–17 y | $109 | $34–$503 | Marketscan database^{17} | Lognormal | 187 | 109 | |

Hospitalization^{18} | |||||||

6–23 mo | $4,306 | $1,307–$34,473 | Marketscan database^{17} | Lognormal | 13194 | 4306 | |

3–4 y | $4,180 | $1,292–$32,030 | Marketscan database^{17} | Lognormal | 10000 | 4180 | |

5–17 y | $5,135 | $1,373–$42,990 | Marketscan database^{17} | Lognormal | 14956 | 5135 | |

Long-term sequelae following influenza-related hospitalization^{19} | $625,000 | $0–$1,000,000 | (23) | ||||

Vaccination costs | |||||||

Per dose, IIV^{20} (children <3 y) | $9.56^{21} | 1×–4× base case | (21) | ||||

Per dose, IIV (children >3 y) | $6.86^{21} | 1×–4× base case | (21) | ||||

Per dose, LAIV^{20} | $12.89^{22} | $10–$25 | (24,25) | ||||

Administration (0–2 visits)^{23} | $25 | $10–$40 | (26) | ||||

Parent time costs^{24} | $32 | $0–$62 | (27), expert panel | ||||

Total vaccination costs | $30–$110 | ||||||

6–23 mo | $79 | ||||||

2 y | $66 | ||||||

3–4 y | $59 | ||||||

5–11 y | $49 | ||||||

12–17 y | $49 | ||||||

Vaccination-related adverse events | |||||||

Physician visit for injection site reaction^{25} | $61 | $30–$-683 | Marketscan database^{26} | Lognormal^{16} | 202 | 61 | |

Anaphylaxis^{27} | $2,699 | $52–$13,754 | Marketscan database^{28} | Lognormal^{16} | 4527 | 2699 | |

Guillain-Barré syndrome^{29} | $23,359 | $6,663–$78,912 | Marketscan database^{28} | Lognormal^{16} | 32196 | 23359 | |

Quality adjustments^{30,31} (disutility associated with an event) | |||||||

Episode of influenza | 0.005 | 0.002–0.009 | ( | β | 7.35 | 1492.65 | |

Otitis media | 0.042 | 0.023–0.065 | ( | β | 14.56 | 335.44 | |

Nonhospitalized complications (pneumonia) | 0.046 | 0.027–0.071 | (28) | β | 16.21 | 333.8 | |

Hospitalization, pneumonia | 0.076 | 0.054–0.100 | (28) | β | 37.85 | 462.15 | |

Anaphylaxis | 0.02 | 0.006–0.041 | (27) | β | 4.53 | 225.47 | |

Guillain-Barré syndrome | 0.141 | 0.092–0.199 | (27) | β | 22.53 | 137.47 |

IIV, inactivated influenza vaccine; LAIV, live, attenuated influenza vaccine; OTC, over the counter.
^{1}Distributions for transition probabilities were assigned using most likely values and ranges identified in the literature and/or expert panel. For these parameters, primary data were not available and beta distributions were assigned to match the values identified in the table.
^{2}Distributions for age groups other than 6–23 mo are based on the 6- to 23-mo distribution multiplied by the ratio of the most likely estimates for the age group in question to children 6–23 mo (e.g., the distribution for 2 y is calculated by multiplying the distribution for 6–23 mo by 0.155/0.157).
^{3}Estimates for healthy children are shown in Table. Probabilities are estimated to be twice as high for children at high risk for influenza-related complications.
^{4}Range for sensitivity analysis determined by expert opinion.
^{5}Estimates for healthy children shown in Table. Probabilities are estimated to be up to 5 times as high for children at high risk for influenza-related complications. Base case estimates for children at high risk are 1.6 times as high as for healthy children.
^{6}Children at high risk are estimated to be hospitalized at 3–6 times the rate of healthy children.
^{7}Probability from distribution divided by 10.
^{8}Probability from distribution divided by 100.
^{9}Assumes vaccine is poorly matched with circulating virus 1 in 10 years (i.e., vaccine effectiveness is assumed to be 0 in years with a poor match).
^{10}Distributions for age groups other than 6–23 mo are based on the 6- to 23-mo distribution multiplied by the ratio of the most likely estimates for the age group in question to children ages 6–23 mo (e.g., the distribution for 2 years is calculated by multiplying the distribution for 6–23 mo by 0.003/0.008).
^{11}Definitions and follow-up for incidence of fever following vaccination vary by study. Rates are 2× higher for high-risk subgroups.
^{12}Probability from distribution divided by 100,000.
^{13}Vary by age, calculated by costing out recommended dose of acetaminophen for average weight in each age group.
^{14}Only a proportion of children with influenza illness are assumed to make a physician visit. ICD-9 codes: 487 and 487.0.
^{15}1993–1997 Marketscan database, The Medstat Group, Ann Arbor, MI, USA.
^{16}Lognormal distributions are approximated using the mean and median in Treeage. In this table, parameter 1 is the mean and parameter 2 is the median for each distribution.
^{17}2001-2003 Marketscan database, The Medstat Group, Ann Arbor, MI.
^{18}ICD-9 codes: 460-466, 471-474, 477, 478, 480-483, 490-496, 506-508, 510, 511, 514, 518, 519. 2001-2003 Marketscan database.
^{19}Includes costs of lifetime care and special education.
^{20}Assumed 2 doses will be required for children <5 years receiving their first influenza vaccination.
^{21}Vaccine dose costs are based on 2004 CDC negotiated prices. Cost for children <3 years assumes thimerosal-free vaccine is used.
^{22}Based on 2004 CDC negotiated price.
^{23}Common Procedural Terminology (CPT) codes: 99211, 90471. Physician costs for vaccine administration at existing visit is $10.37 (90471); $19.95 for vaccine administration requiring a separate visit (99211).
^{24}Each physician visit is assumed to take 2 hours of parent time valued at an average hourly wage rate of $15.54.
^{25}5- minute visit, CPT code 99211.
^{26} 2001–2003 Marketscan database.
^{27}ICD-9 codes: 999.4, 995.0, 995.6x.
^{28}2001-2003 Marketscan database.
^{29}ICD-9 code: 357.0.
^{30}Quality adjustments are included in the model as a one-time decrement in utility for each temporary health state. For example, an episode of influenza results in a one-time loss of 0.005 quality-adjusted life years (QALYs). Utility losses were calculated by dividing the discounted time-traded off by the respondent’s discounted life expectancy.
^{31}Average life span used to calculate total QALYs lost due to life-long sequelae and death was 77.9–78.2 y, depending on child’s current age. See

Age group | No extra visits required | One extra visit required | Two extra visits required |
---|---|---|---|

6–23 mo | 0.27 | 0.39 | 0.34 |

2 y | 0.26 | 0.57 | 0.17 |

3–4 y | 0.26 | 0.64 | 0.10 |

5–11 y | 0.25 | 0.75 | – |

12–17 y | 0.25 | 0.75 | – |

Per 1,000 children | |||||||||
---|---|---|---|---|---|---|---|---|---|

Cost of vaccination program§ | Savings from influenza disease averted | Net costs | Influenza events averted (all) | Influenza hospitalizations averted | Deaths averted | Vaccine adverse events incurred (medically attended)¶ | QALYs gained (95% CI^{32}) | ||

Healthy | Using inactivated influenza vaccine | ||||||||

6–23 mo | $79,000 | $42,000 | 37,000 (–119,000 to 98,000) | 108 (16–276) | 2 (0.2–6) | 0.002 (0–0.007) | 21 (8–47) | 3.0 (0.4–9.0) | |

2 y | $66,000 | $23,000 | 43,000 (–40,000 to 83,000) | 107 (15–276) | 1.2 (0.1–4.2) | 0.001 (0–0.005) | 14 (5–30) | 2.4 (0.3–7.3) | |

3–4 y | $59,000 | $12,000 | 47,000 (2,000–78,000) | 107 (15–276) | 0.6 (0; 2.3) | 0.0005 (0–0.0025) | 10 (3–24) | 1.7 (0.2–5.2) | |

5–11 y | $49,000 | $5,000 | 44,000 (21,000–68,000) | 55 (8–142) | 0.2 (0–0.7) | 0.0002 (0–0.0008) | 0.6 (0.1–1.7) | ||

12–17 y | $49,000 | $5,000 | 44,000 (22,000–68,000) | 41 (6–104) | 0.2 (0–0.6) | 0.0002 (0–0.0008) | 0.4 (0–1.1) | ||

High risk: | Using inactivated influenza vaccine | ||||||||

6–23 mo | $79,000 | $153,000 | –74,000) (–552,000 to 83,000) | 108 (16–276) | 5.5 (0.5–6.5) | 0.005 (0–0.020) | 32 (11–56) | 7.2 (0.8–23.2) | |

2 y | $66,000 | $88,000 | –22,000) (–292,000 to 72,000) | 107 (15–276) | 3.5 (0.2–11.4) | 0.003 (0–0.013) | 25 (7–44) | 5.4 (0.6–17.2) | |

3–4 y | $59,000 | $57,000 | 2,000 (–212,000 to 70,000) | 107 (15–276) | 2.2 (0.1–9.1) | 0.002 (0–0.010) | 19 (5–37) | 4.0 (0.4–13.1) | |

5–11 y | $49,000 | $37,000 | 12,000 (–125,000 to 59,000) | 55 (8–142) | 1.3 (0.1–3.9) | 0.001 (0–0.005) | 9 (3–24) | 1.6 (0.2–5.6) | |

12–17 y | $49,000 | $36,000 | 13,000 (–120,000 to 59,000) | 41 ( | 1.3 (0.1–3.9) | 0.001 (0–0.005) | 1.3 (0.1–4.5) | ||

Healthy | Using live attenuated influenza vaccine | ||||||||

6–23 mo | $99,000 | $63,000 | |||||||

2 y | $80,000 | $35,000 | |||||||

3–4 y | $74,000 | $21,000 | |||||||

5–11 y | $61,000 | $11,000 | 48,000 (22,000–73,000) | 67 (10–166) | 0.3 (0–0.8) | 0.0002 (0–0.0010) | 0.7 (0.1–1.9) | ||

12–17 y | $61,000 | $10,000 | 49,000 (23,000–73,000) | 50 (8–120) | 0.3 (0–0.7) | 0.00002 (0–0.0010) | 3 (0–7) | 0.5 (0.1–1.3) |

*CI, confidence interval; QALYS, quality-adjusted life years; italics indicate that live, attenuated influenza vaccine is not licensed for children <5 y. †Bootstrapped. ‡Figures may not sum due to rounding. §Includes time costs associated with vaccination. ¶Includes injection site reactions, systemic reactions, anaphylaxis, and Guillain-Barré syndrome.

Scatterplot of incremental costs and quality-adjusted life years (QALYs) for children ages 6–23 months not at high risk from probabilistic sensitivity analysis.

Dr Prosser is an assistant professor in the Department of Ambulatory Care and Prevention at Harvard Medical School and Harvard Pilgrim Health Care. Her research interests include conducting economic evaluations of health interventions and improving methods for valuing children's health benefits for cost-effectiveness analysis. Her current research focuses on the cost-effectiveness of childhood interventions, including newborn screening for metabolic disorders, influenza vaccination, and child maltreatment.