INFECTIOUS DISEASES IN CHILDREN March 2008
Influenza Vaccination:
Applying The Latest Data To Your Practice

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Introduction Why are we vaccinating children? What is the burden of influenza in the community? Kathryn M. Edwards, MD Emerging safety and efficacy data on the available influenza vaccines Lisa Jackson, MD, MPH Challenges in herd protection and school vaccination programs Pedro A. Piedra, MD Managing influenza vaccination in your practice Susan E. Coffin, MD, MPH

Influenza epidemics cause 36,000 deaths annually in the United States and are a tremendous burden on society. The most effective preventative measure against an influenza epidemic is vaccination. Children experience the highest rates of infection, which is, therefore, the reason why the Centers for Disease Control and Prevention recommends annual vaccination for all healthy children 6 months to 5 years of age. Recently, the Food and Drug Administration licensed cold-adapted live-attenuated influenza vaccine (LAIV) for use in children as young as 2 years.

Vindico Medical Education organized a satellite symposium during the Infectious Diseases in Children New York annual meeting in October 2007 to present pediatricians with the most recent information on influenza and influenza vaccination. This monograph is based on the proceedings from the symposium and provides the pediatrician with a review of the most current guidelines on influenza vaccination from the CDC. It examines the latest data related to vaccine safety, efficacy, and compliance. It also provides an explanation of the burden of disease, mode of transmission, and the importance of early school-based vaccination to develop herd immunity. The discussion identifies appropriate patients, suggests handling and administration protocols for your practice, and discusses dosing regimens. Finally, excerpts from the question and answer session that took place during the symposium are included.

Kathryn M. Edwards, MD
Course Director

Why are we vaccinating children? What is the burden of influenza in the community?
Kathryn M. Edwards, MD

There are several methods available for assessing the burden of influenza in the community. Large databases can provide the number of hospitalizations that occur during the times when influenza circulates and when it does not. Literature reviews of laboratory-confirmed influenza have been written. Lastly, influenza illness has been studied in schools and in population-based active surveillance providing invaluable resources for assessing the burden of influenza in the population.

Methods to assess the burden of influenza in children

Databases

A large database study in Tennessee looked at the health records of healthy children younger than 15 years of age who were enrolled in the Tennessee Medicaid database, which is half of the children in the state.¹ The children were enrolled at birth for at least 1 year, covering 20 years of consecutive data. Rates of hospitalization during flu outbreaks and during non-flu seasons were compared. Data from these studies showed hospitalization rates of 104 per 10,000 or 10 per 1,000 in children younger than 6 months of age. The rate was five per 1,000 in the 6- to 12-month age group, and lesser rates occurred in the children up to 15 years of age. However, the bulk of influenza occurred in children during the first year of life.

Another large database study at Kaiser-Permanente evaluated healthy children younger than 18 years of age and compared hospitalization rates during the influenza and peri-influenza seasons. The study covered 5 years of consecutive data.² When the hospitalization rates were compared, 14 to 19 children per 10,000 younger than 2 years of age were hospitalized. These were all non-high-risk children and did not include the most vulnerable children. The rates in this study were a log lower than what was seen in the Tennessee database study. However, based on the data from both studies, the burden of influenza was between 14 and 140 hospitalizations per 10,000 children in the youngest age group.

The Tennessee database study also provided outpatient information. The number of outpatient visits and antibiotic courses per 100 children during a typical influenza year was almost 10% for children younger than 6 months, about 15% for children 6 to 12 months of age, and about 10% of children up to 15 years of age. In addition, there were many antibiotics given during this time. In fact, as many as 50% of the children at 80% of these visits were prescribed antibiotics.¹ Similarly, a study conducted by a Massachusetts HMO showed that 10% of children had outpatient visits during the influenza season.³ Thus, the burden of influenza in the outpatient setting was even greater than the hospitalization rate.

Literature review of laboratory-confirmed influenza in children

Many reports in the literature outline rates of laboratory-confirmed influenza in various populations. A study in Review of Medical Virology⁴ found that approximately 400 papers reported confirmed cases of influenza in children. Over 6,000 children during seven influenza seasons were evaluated. During one influenza season, as many as 44% of the children were infected. The lowest attack rate reported was 8%. Overall, the attack rate for influenza was high in a population that was under laboratory surveillance for influenza.

Study of influenza illness at one elementary school

In a study conducted in a private school in Seattle, questionnaires were sent to the families of the children during a time when influenza was at its peak (Table).⁵ The families were instructed to record the numbers of influenza illnesses in the children in the study school, their siblings, and their household members. During the 2003 to 2004 influenza season, 28 out of 100 children had illness episodes, suggesting an attack rate of nearly 30%. In total, 63 days of school were missed per 100 children. The numbers of febrile episodes were comparable to the illness episodes. Only four per 100 sought medical care. Parents and family members became ill within 3 days after the index child became ill. Therefore, children are sharing their viruses with their family members and are influenza disseminators within the community.

Table: Study of influenza illness at one elementary school in Seattle5

Population-based active surveillance

The New Vaccine Surveillance Network (NVSN) conducted population-based surveillance for acute respiratory illness (ARI) in Rochester, NY; Nashville, TN; and Cincinnati, OH. Inpatient surveillance started at the beginning of November and ended in March and evaluated patients in the hospitals that hospitalize 95% of all children in each of their respective counties.⁶ Children younger than 5 years admitted with ARI or fever were enrolled. After informed consent, parents were interviewed, a chart review was conducted, and children provided nasal and throat secretions for culture and polymerase chain reaction (PCR). The rate of culture-confirmed influenza hospitalizations per 1,000 children was 4.5 for children younger than 6 months of age, about one in the children 6 to 23 months of age, and overall about one per 1,000 in the total population of children younger than 5 years of age.

The NVSN also evaluated outpatient visits during the respiratory viral season as another means of calculating disease burden.⁶ Children younger than 12 years who were county residents were evaluated during emergency department and outpatient visits. PCR was conducted to confirm the presence of flu. The influenza incidence was calculated by weighting for non-enrollment days and using the NAMCS/NHAMCS database to estimate population-based respiratory visits. Influenza strikes every year, but the severity varies from one year to another. These studies show that the burden of disease in the outpatient was several logs greater than the inpatient data. In fact, depending upon the season, like the 2003 to 2004 season, as many as half of the children with high-risk conditions were seen in the outpatient setting during the influenza season.

Influenza morbidity and mortality in children

During the 2003 to 2004 season, 153 children younger than 18 years of age died of influenza. Their median age was 3 years with 60% younger than 5 years. Thirty percent of them died outside the hospital and within 3 days of illness onset. Twenty-four percent had bacterial co-infections with a number of those having methicillin-resistant Staphylococcus aureus. Only 33% had known high-risk conditions or chronic neurologic conditions. The highest mortality rate was seen in children younger than 6 months of age who were too young to be vaccinated.⁷ In the last several years, the mortality rate has been significantly less compared to the 2003 to 2004 season and earlier flu seasons. One important observation in the last two flu seasons (2005-2006 and 2006-2007) has been the increase in the age of children dying from disease attributed to influenza. This increase can be accounted for by the increase in MRSA-associated co-infections confirmed in older children. MRSA is an increasing problem in terms of causing disease and as a cofactor with influenza.

Each year, children have high influenza burdens, one hospitalization per 1,000 children younger than 5 years of age, between three to 16 influenza outpatient visits per 100 children a year, and between 10 and 30 influenza illnesses per 100 children per year. In addition, children also have a role in the spread of disease and the burden of influenza in the community.

References

1. Neuzil KM, Mellen BG, Wright PF, et al. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med. 2000;342(4):225-231.
2. 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):232-239.
3. Bueving HJ, van der Wouden JC, Berger MY, et al. Incidence of influenza and associated illness in children aged 0-19 years: a systematic review. Rev Med Virol. 2005;15(6):383-391.
4. O’Brien MA, Uyeki TM, Shay DK, et al. Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics. 2004;113(3 Pt 1):585-593.
5. 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):986-991.
6. Poehling KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of influenza in young children. N Engl J Med. 2006;355(1):31-40.
7. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States. N Engl J Med. 2005;353(24):2559-2567.

Emerging safety and efficacy data on the available influenza vaccines
Lisa Jackson, MD, MPH

As of September 2007, the FDA has approved the use of the live-attenuated influenza vaccine (LAIV) in children as young as 2 years through adults 49 years of age. This recommendation is based on new data about the efficacy of this vaccine, particularly in younger children.

Live-attenuated intranasal influenza vaccine

The vaccine is refrigerator stable and no longer frozen and, in fact, should not be frozen. The dose of 0.1 mL per nostril is lower than the original formulation. Contraindications are hypersensitivity to components of the vaccine and the need for ongoing aspirin therapy in children or adolescents. The vaccine is not recommended for children younger than 24 months, for whom it is not approved; patients with asthma; or young children with recurrent wheezing.

Efficacy of LAIV in recent placebo-controlled trials in young children

Several placebo-controlled trials comparing LAIV with placebo in young children have been conducted throughout the world. The first trial to be discussed in this article enrolled 1,616 children between the ages of 6 and 35 months attending day care in Finland, Israel, and a number of countries in Europe.¹ All of the children received two doses of vaccine or placebo in the first year of the study. In the second year, they received another dose of the same formulation. Children who were randomized to LAIV received two doses the first year and one in the second. Children randomized to placebo received placebo in both the first year and the second year. The mean age at first vaccination was 23 months. In the study, 11% of children in the placebo group were documented to have laboratory-confirmed influenza infection, compared with less than 2% in the vaccine group. Every year, the vaccine contains two A strains, H1N1 and H3N2, and a B strain. The exact strains used in the vaccines are tailored each year. The trial showed that, in the first year, there was a significant difference between the placebo group and the LAIV group with an overall vaccine efficacy of 85%. Similarly, vaccine efficacy against the H1N1 component was 92%. In this particular year of the trial, the H3N2 strain was not a significant factor, which is generally the strain that is the most virulent and changes from year to year. Vaccine efficacy against the B strain was 73% (Figure 1A). The second year of the trial showed an increase in attack rate, with an attack rate of 30% in the placebo group, compared to 11% in the first year, showing the variability of influenza circulation and infection. Again, there was a large difference between the vaccine group and the placebo group with the vaccine efficacy approaching 90%. In this second year, H3N2 was a big player and so efficacy against H3N2 could be demonstrated to be 90% (Figure 1B).

Vaccine efficacy against culture-confirmed influenza illness with vaccine-matched strains Year 1 Figure 1A. Vaccine efficacy against all strains of influenza or individual strains H1N1, H3N2, or B versus placebo after year 1 of a two dose vaccination regimen.1 Year 2 Figure 1B. Vaccine efficacy against all strains of influenza or individual strains H1N1, H3N2, or B versus placebo after year 2 of a one dose vaccination regimen with the same formulation as year 1.1

The study was also designed to look at the question of otitis media. When the definition of otitis media included events that were linked with influenza infection, there was a difference between the vaccine and placebo groups. Children who got the vaccine were less likely to have otitis media associated with influenza infection than children who did not get the vaccine. However, the influenza-associated otitis made up a relatively small proportion of all cases of otitis media (Figure 2). Overall, there was no difference in all otitis media even though there was a significant difference in influenza-related otitis. The data were similar for the first and second year of the trial. In the vaccine group, a slight fever after the first dose was reported but the differences between the vaccine group and placebo group were not significant and evened out for the second and third doses. A runny nose was also reported but was also common within the placebo group and was not significant.

Vaccine efficacy against acute otitis media—year 1 Figure 2. LAIV efficacy against the onset of influenza-associated acute otitis media (AOM) versus placebo and compared to all reports of AOM.1

The second placebo-controlled study enrolled more than 3,000 children who were 12 to 35 months of age at multiple sites in Asia.² The children received two doses of either vaccine or placebo in the first year, but in the second year they were re-randomized, so that children who received vaccine in the first year received either vaccine or placebo the second year. If they received placebo the first year, they received either vaccine or placebo the second year. The mean age in this study was 23 months and the results were similar to the previous study. In the first year, the vaccine efficacy was 73% with an attack rate of 12% in the placebo group versus 3% in the vaccine group. In the second year, the lowest attack rate was in the group that received LAIV in both year 1 and year 2. The vaccine efficacy of LAIV in year 2 was 84%. The attack rate in the group that received placebo in year 1 and a single dose of LAIV in year 2 was, however, lower than that in the group that received placebo in both years, indicating a vaccine efficacy of 60% for a single dose of LAIV (Table 1). The safety data show a statistically significant higher frequency of fever in the vaccinated group, which again was only seen after the first dose in the first year. Runny nose or nasal discharge tended to be higher in the vaccine group versus the placebo group, although the absolute differences were small.

In summary, two recent randomized placebo-controlled trials in children younger than 36 months of age have demonstrated very high levels of vaccine efficacy for LAIV against culture confirmed influenza.

Table 1: Vaccine efficacy of LAIV in a randomized trial in Asia2

Efficacy of LAIV in recent head-to-head comparisons

There are two options for influenza vaccination in children 2 years of age and older, LAIV or trivalent inactivated vaccine (TIV). A randomized trial comparing the two vaccines enrolled 2,187 children between the ages of 6 and 71 months with a median age of 38 months.³ The children received two doses of either the live or inactivated vaccine. The overall efficacy of the intranasal vaccine compared with inactivated vaccine was 53%, meaning that the attack rate of influenza in the LAIV group was about half that in the TIV group. There were no cases of H1N1 infection in this particular year in the intranasal vaccine group. So vaccine efficacy is 100%. Rates with H3N2 were relatively low, but comparable in both groups so there was no significant difference, but there was a significantly lower risk of B disease in the group that received intranasal vaccine.

A larger randomized trial enrolled over 8,000 children between the ages of 6 and 59 months with a mean age of 26 months.⁴ The children were randomized to receive either intranasal vaccine or injected inactivated vaccine. Any children with a recent episode of wheezing or who were defined as having severe asthma were excluded from participation, but children with a history of wheezing or with mild to moderate asthma were included in the study population. If the children were vaccine naïve, they received two doses of the vaccine they were randomized to. If they had been previously vaccinated, they received one. During the course of the trial, there was an overall attack rate of about 9% in children who received inactivated vaccine and 4% in children who received a live vaccine (Figure 3).

Kaplan-Meier Curves for the time to the first culture-confirmed report of influenza in the two vaccine groups Figure 3. Percentage of children reported to have influenza after receiving either the live-attenuated influenza vaccine (LAIV) or the inactivated vaccine (TIV) over an 8-month period. (Belshe RB, Edwards KM, Vesikari T. N Engl J Med. 2007;356:685-696. Copyright ©2007 Massachusetts Medical Society. All rights reserved.)

This trial also allowed the ability to look at viral strains that were not well-matched to the vaccine. The conclusion was that there was a significant difference between LAIV and TIV, with an attack rate of about 1% with mismatched strains in the intranasal vaccine group versus 4.5% in the inactivated vaccinated group. These results replicate what was previously seen in studies performed in the United States where it appeared that giving children the live vaccine better protected against strains of influenza that were not matched to the ones that were chosen to be included in the vaccine.

The study also addressed the issue of medically significant wheezing. The child was examined by the provider who then determined whether the child needed a bronchodilator, had retractions or was hypoxic or needed to be hospitalized. Any of those criteria classified the event as medically significant wheezing. Based on that definition, in this study, children 6 to 23 months of age were more likely to have medically significant wheezing in the 42 days after live intranasal vaccine than following inactivated vaccine and the difference was 3.2% versus 2%, so 1.2% absolute risk difference for this event. However, in children older than 24 months, there was no difference in the risk of medically significant wheezing following LAIV versus inactivated vaccine.

In summary, the head-to-head comparisons of the trials of inactivated versus LAIV showed that children who received the live-attenuated intranasal vaccine were at significantly lower risk of influenza infection, both with matched strains and with mismatched strains, compared to those who received inactivated vaccine. Further, there was no evidence for an increased risk of wheezing when the studies looked at children 24 months of age and older.

Observational studies of TIV effectiveness

The data from randomized trials on inactivated vaccine, specifically in young children around 2 years of age, are relatively limited because vaccination is routinely recommended for children 6 months of age and older. However, observational studies have been conducted comparing children who received inactivated versus those who did not and examining the risk of outcomes such as influenza infection or illnesses that may be due to influenza.

Three observational studies were conducted during the 2003 to 2004 influenza season, in which there was a very early peak of influenza and an unusual number of deaths in children. The first study examined an outcome of laboratory-confirmed influenza.⁵ This study was conducted in a large pediatric practice in Atlanta. The pediatricians in the practice attempted to identify documented influenza infections in children in their practice by performing rapid tests or sending nasal cultures to be tested for influenza. In all, during this influenza season, 290 children were documented to have had laboratory-confirmed influenza infection. The investigators then matched those children with 580 control children from the same practice. When the prevalence of vaccination was compared between the children who got influenza and those who did not, they found that there was a difference in risk of influenza when fully vaccinated children were compared to unvaccinated. A fully vaccinated child was defined as a patient who had received two doses, or one dose if they were recommended to receive only one dose. The risk of documented influenza infection was about 50% lower in the fully vaccinated group compared to the unvaccinated group. So it appeared that TIV reduced the risk of documented influenza infection by half when children got the proper number of doses of influenza vaccine. However, in the partially vaccinated group versus unvaccinated group, there was no significant difference in risk of influenza infection for children 6 to 23 months old, whereas there was a significant difference between these groups in children 24 to 59 months old (Table 2).

Table 2: Inactivated influenza vaccine efficacy against laboratory-confirmed influenza

The next two studies were similar in design but did not evaluate documented influenza infection. In these studies, databases were used to identify medical encounters associated with diagnosis codes that might indicate influenza, like febrile illnesses, respiratory infections, and pneumonia.^6,7 The first study was conducted in a practice in Denver and enrolled children 6 to 21 months of age.⁶ A computerized billing database was used to identify children with outpatient visits associated with diagnosis codes for influenza-like illnesses or pneumonia. The results were similar to the previous study and used similar definitions of fully vaccinated and partially vaccinated versus unvaccinated. In the younger group, 6 to 21 months of age, the risk was reduced by 69% in the fully vaccinated compared with unvaccinated, but no difference in the partially vaccinated versus unvaccinated. Similarly, for the outcome of pneumonia or influenza, risk was reduced 87% with fully vaccinated children, but no difference with partially vaccinated.

The last of the studies included children 6 months through 8 years of age enrolled in Kaiser Colorado. Kaiser databases were used to identify children with outpatient visits associated with diagnosis codes for influenza-like illnesses or pneumonia. The results are similar to the other two studies. Fully vaccinated children were at a 23% lower risk, but partially vaccinated children showed a 7% reduced risk. Significant reductions in risk for pneumonia and influenza were observed in both fully vaccinated and partially vaccinated patients compared with unvaccinated.

The recent observational studies suggest that TIV reduces the risk of laboratory-confirmed influenza infection, as well as medically attended influenza-like illness. It appears that this benefit may be reduced in children who receive only one dose of vaccine in the first year that they are vaccinated.

References

1. Vesikari T, Fleming DM, Aristegui JF, et al. Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care. Pediatrics. 2006;118(6):2298-2312.
2. Tam JS, Capeding MR, Lum LC, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J. 2007;26(7):619-628.
3. Ashkenazi S, Vertruyen A, Arístegui J, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J. 2006;25(10):870-879.
4. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007 Feb 15;356(7):685-696.
5. Shuler CM, Iwamoto M, Bridges CB, et al. Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004. Pediatrics. 2007;119(3):e587-e595.
6. Allison MA, Daley MF, Crane LA, et al. Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season. J Pediatr. 2006;149(6):755-762.
7. Ritzwoller DP, Bridges CB, Shetterly S, et al. Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses. Pediatrics. 2005;116(1):153-159.

Challenges in herd protection and school vaccination programs
Pedro A. Piedra, MD

The tremendous burden that influenza causes to our community and to the United States is underestimated, and alternative strategies to the current risk-based approach for controlling influenza need to be considered. Influenza is the number one vaccine-preventable cause of death each year in the United States, Europe, and other countries.

There are on average 36,000 deaths per year during a 3-month period during the flu season. In the United States, 5% to 20% of the population during each influenza season will become infected with influenza, which is about 31 million cases. Compared to other well-recognized binfectious diseases, the influenza burden is very high (Table 1).^1-4

Table 1: Estimated vaccine-preventable disease and deaths in the United States *Stochastic simulation model of influenza transmission, which translates into an average annual influenza attack rate of 11%.

Based on the 2003 U.S. population, there was an estimated 600,000 life years lost, 3.1 million hospitalized days, and 31.4 million outpatient visits during an average influenza season. Direct medical costs were more than $10 billion and, when projected earning loss was included, it went up to $16 billion. An estimate of the total economic burden during a flu season was more than $87 billion.⁵

“Healthy People 2010”: Objectives for influenza vaccination

The Centers for Disease Control and Prevention has tried to reduce mortality and morbidity associated with influenza but without much success; however, the CDC has set goals to improve vaccination coverage of high-risk populations. In both institutionalized and non-institutionalized adults, the goal is to achieve a coverage of 90% or greater by 2010 and, in all other risk groups, a 60% coverage.⁶ Attempts at reaching that goal are falling short. Data collected from the CDC indicate that the overall percentage of high-risk individuals who receive influenza vaccination is less than 20% (Figure 1).^6,7 Reported vaccination levels are low among children at increased risk for influenza complications and an analysis of patients in HMOs reported influenza vaccination percentages ranging from 9% to 10% among children with asthma.⁸ A 25% vaccination level was reported among children with severe to moderate asthma who attended an allergy and immunology clinic.⁹ However, a study conducted in a pediatric clinic demonstrated the vaccination percentage of children with asthma or reactive airway disease increased from 5% to 32% after implementing a reminder/recall system.¹⁰ A study by Marshall and colleagues reported 79% vaccination coverage among children attending a cystic fibrosis treatment center.¹¹ Increasing vaccination coverage among people who have high-risk conditions, including children at high risk, is the highest priority for expanding influenza vaccine use.

Underimmunization is a problem in all risk categories Figure 1. Tiers 1, 2, and 3 represent percentage of people immunized based on risk. Tier 1 is the highest risk and tier 3 the lowest (CDC. MMWR Morb Mortal Wkly Rep. 2005;54[30]:749-750; Harper SA, et al. MMWR Recomm Rep. 2004;53[RR-6]:1-40).

Achievement of vaccination of health care personnel must be better than the current 40% to 45% coverage, given that influenza causes significant disease in our community.^6,7 Health care providers need to inform the public and their patients of the need for vaccination, because, if the health care professional does not advocate vaccinating or preventing or treating flu, it sends the message that influenza is not relevant. Currently, about 70% of the U.S. population fits into an at-risk group to receive a flu vaccine. There is only enough vaccine made to vaccinate 60% of the population for which it is recommended. Millions of doses are thrown away each year, even during vaccine shortage years.

Age distribution of influenza-positive infections during epidemics: 1974-1981

Data compiled from years of influenza seasons looked at the proportion of people infected by age group according to the timing in the influenza season.¹² Early into the season, the majority of patients who were infected were children between 5 years and 19 years of age. As the flu season progressed, older age groups and infants became infected and, by the end of the flu season, children played a lesser role in disease burden (Figure 2). The data suggest that children play an important role early in the season in spreading the flu to family members and to the community. Because children are considered excellent vectors for flu transmission, new vaccination strategies for targeting children should be conceived. Targeting children for vaccination not only would provide direct benefit against flu in children, but also would be a means to control the spread of flu.

Age distribution of influenza-positive infections during epidemics: 1974-1981 Figure 2. Children ages 5 to 19 contribute the highest percentage of influenza infections early in the season. The number of older adults with influenza increases as the flu season progresses with the percentage of children with disease decreasing. (Glezen WP. Serious morbidity and mortality associated with influenza epidemics. Epidemiol Rev. 1982;4:25-44, by permission of the Oxford University Press.)

A complementary universal approach to influenza vaccination of children will provide a direct benefit to children and, as a secondary outcome, help control the spread of influenza so that morbidity among all age groups in the community is reduced. The first proof of concept to demonstrate this occurred during the Hong Kong pandemic in 1968.¹³ Vaccination of 86% of children reduced 26% of all respiratory illnesses during the pandemic flu season, indicating influenza causes a major burden of respiratory illness during the influenza season. Another study in Australia found that communities that had the highest vaccination coverage demonstrated lower attack rates compared to communities that were not vaccinated.¹⁴

Effectiveness of mass vaccination in children

Several studies have looked at a school-based vaccination program showing the beneficial impact that vaccinating school children has on providing direct benefit to the child, as well as decreasing illness in the family and among the teachers. After the Asian pandemic, Japan initiated a policy that required vaccination of school-aged children rather than using an at-risk or risk-based approach like the vaccination of elderly adults in the United States. During a 10-year period from 1977 through 1987, 80% of school-aged children were vaccinated and, as a result, each year, there was a decrease by 37,000 to 49,000 deaths associated with flu.¹⁵ When that program was rescinded, the rates started to increase.

An ongoing community-based influenza vaccination study in Central Texas is vaccinating children to control seasonal influenza.^16-18 Temple-Belton are the intervention communities and Waco, Bryan, and College Station are the comparison cities. This ongoing program of 10 years vaccinates children with either live vaccine or inactivated vaccine according to the health status of the patient. Healthy patients receive the live-attenuated influenza vaccine. If they have an at-risk medical condition, they receive the inactivated influenza vaccine. During a 4-year period from 1998 to 2002, healthy children ages 1.5 to 19 years were vaccinated with the live-attenuated influenza vaccine, which was still investigational rather than licensed at that time. One of the challenges to vaccinating the children in the community was raising awareness of the impact of influenza on children and the community. To overcome this, a major health care provider clinic opened and offered influenza vaccine to all children. As the community became more aware of flu, the influenza clinic was expanded to the mall and to other outreach areas and schools which became a major site for vaccination. In 2007, our research program provided influenza vaccines primarily through school-based clinics. The schools have become more comfortable with the approach of influenza vaccination in school-based clinics. They realized that vaccination of the children reduced absenteeism of the children, teachers, and staff from illness associated with flu. Providing vaccination in schools opens up the community spectrum of ethnic groups and high-risk children that we are able to reach and vaccinate.

The impact the Texas study has had on the intervention community compared to the comparison community shows that the highest coverage rates were achieved in children ages 5 to 11 and 12 to 17 years when we offered the influenza vaccines in schools (Figure 3). The vaccination program increased vaccination coverage by about 2.5-fold to threefold compared to the comparison community within the school-aged group. Possible models to improve vaccination coverage in children include private provider–based models, long-term care facilities, and/or community clinics. A public health–based model would involve the city health department’s setting up influenza clinics or a mixture where a private provider–based model is used initially and then expanded to the schools with county or city health clinics. To set up programs to vaccinate children in schools, the community must be educated about influenza and the burden associated with flu. The school and the parents need to trust and work with the programs supported by the public and/or private health care providers. Both the live and inactivated influenza vaccines should be offered to all people in the schools. Consent needs to be streamlined, and outcomes such as student absenteeism, influenza-like illness, and teacher and staff absenteeism need to be monitored.

Influenza vaccination coverage in SWC population in the intervention cities Figure 3. Percentage of influenza vaccines administered during an 8-year period. In 2003, the LAIV vaccine was approved for use in healthy individuals 5 to 49 years old. During 2003, there was a sharp rise in 5- to 11-year-olds and 12- to 17-year-olds vaccinated, along with the elderly showing the highest coverage rates.17

Annual school-based influenza vaccination of school children will improve the health and wellness in schools, maximize school attendance, and reduce the burden of influenza. Curtailing influenza will also improve student learning, increase the allocations of funds from state and federal sources, and decrease school and employment absenteeism. In conclusion, a universal vaccination program in children may help control seasonal influenza and should be considered in the pandemic preparedness plan.

References

1. Weycker D, Edelsberg J, Halloran ME, et al. Population-wide benefits of routine vaccination of children against influenza. Vaccine. 2005;23(10):1284-1293.
2. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179-186.
3. CDC. Pink Book. 9th Edition. Available at www.cdc.gov/nip/publications/pink/2006.
4. American Cancer Society. Cancer Facts and Figures 2004. www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf.
5. Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086-5096.
6. Harper SA et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2004;53(RR-6):1-40.
7. Centers for Disease Control and Prevention (CDC). Tiered use of inactivated influenza vaccine in the event of a vaccine shortage. MMWR Morb Mortal Wkly Rep. 2005;54(30):749-750.
8. Kramarz P, DeStefano F, Gargiullo PM, et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Arch Fam Med. 2000;9(7):617-623.
9. Chung EK, Casey R, Pinto-Martin JA, et al. Routine and influenza vaccination rates in children with asthma. Ann Allergy Asthma Immunol. 1998;80(4):318-322.
10. Gaglani M, Riggs M, Kamenicky C, et al. A computerized reminder strategy is effective for annual influenza immunization of children with asthma or reactive airway disease. Pediatr Infect Dis J. 2001;20(12):1155-1160.
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Managing influenza vaccination in your practice
Susan E. Coffin, MD, MPH

The ultimate goal in reducing the burden of influenza in the community is to vaccinate the children. Streamlining the process of vaccinating large numbers of children in a short period in a private practice setting is the first step to meeting that goal.

Challenges

Several logistical challenges need to be overcome to vaccinate a large population of children. The window in which the influenza vaccine can be administered is short and vaccinating a large number of children during this small window of opportunity is challenging. Also, the date of delivery from the manufacturer is unpredictable. Some years, the vaccine may arrive in September. Other years, it may arrive later in the season which makes the logistics of scheduling staff time and scheduling patient visits difficult. Another challenge is the need to stock multiple products. This results in a challenge in terms of ordering each season, tracking supply, and reordering and replenishing supply.

Another area people struggle with is how to plan and create a sense of anticipation among the families about coming back for a special visit just to receive influenza vaccine. It is a challenge for practitioners to find good methods to identify patients who need to be called back for influenza vaccine when it becomes available. Many parents have a limited understanding of how serious influenza is in children. Lastly, parents have concerns about vaccine safety, need for vaccination, and tension between the desire for natural immunity versus artificial immunity. Parents who are hesitant about their child receiving vaccines that are required for school entry are likely to become even more hesitant or less interested in having them receive influenza vaccine.

Solutions

One solution to compliance is to offer flu vaccine at well and sick visits as soon as the vaccine becomes available. Another approach is to encourage the use of the intranasal influenza vaccine since it shortens the time needed to immunize and leverages the efficiency of delivering vaccine.

Standing orders for influenza vaccination have become part and parcel of adult hospitalization orders but can be used effectively in the private practice setting. A nurse would no longer need to find a physician to sign an order to deliver influenza vaccine. A child who is at the pediatrician’s office for a height and weight check can be given vaccine at that point. Most importantly and probably most effective, would be setting aside time, space, and personnel specifically for influenza vaccination clinics.

Flu vaccine clinics

In order to set up influenza vaccine clinics prior to the start of the flu season, several important steps have to be taken to ensure the clinics run efficiently. The first step is to start planning and start planning early. This is important particularly for the staff. The staff will not want to hear in the middle of October that they have to volunteer for one Saturday morning in the month of November to staff an influenza vaccine clinic. Planning ahead for scheduled time for the staff to be at the clinics will have better acceptance and commitments from staff to work at scheduled vaccine clinics. Dedicate time, space, and staff to flu vaccine clinics.

It is important to gather information about which patients are going to need to be vaccinated prior to opening up an influenza vaccine clinic. One approach is to ask parents to identify their child as needing vaccine because of age or high-risk conditions. Parents may feel committed to having their child vaccinated against influenza regardless of the child’s health status. Sign-up sheets can be placed in the exam rooms as early as June mentioning that the parents will receive a call when the influenza vaccine becomes available or parents can pre-address reminder postcards.

Some practices have found ways to streamline flu vaccine clinics. The purpose of the visit is to either put the needle in the arm or give the nose spray to the patient, so using a single-dose syringe or intranasal spray is going to be faster than drawing up doses from multidose vials. Preregistering patients and having staff dedicated to completing paperwork after the inoculation is given will expedite the process. Some practices have chosen to waive the visit fee because the visit can be shortened if a check-out time is not used and, in fact, it is believed that the remuneration received from the vaccination itself is sufficient. When the parent visits the clinic, he or she should bring all eligible siblings at the same time, as a way to streamline the visit. A phone call to the parent prior to the visit will allow the clinic to screen for any egg allergies, ask about vaccine preference, and even do a quick education about the fact that there now is more choice than there has been previously. It can be recommended to the parents that they review the vaccine information sheets and, most importantly, the practitioner can spend a moment setting the expectations for the visit.

Additional options

Practices with electronic medical records have potential to leverage their resources to identify children who need to be vaccinated. The difficulty is finding the appropriate skilled manpower to create the programs necessary to gather the information to guide vaccination; however, with these programs, children with high-risk conditions would be identified and labeled as an “influenza risk.” Electronic prompts could then be built into the program that would automatically flag these children during the influenza season. The system could be leveraged to print out labels for reminder postcards and query the system in early December to identify unvaccinated high-risk children.

Common misconceptions

There are several misconceptions among the public and practitioners about the administration of the influenza vaccine. The first is that live-attenuated influenza vaccine cannot be given with other vaccines. Another misconception is that all vaccine needs to be given before the winter holidays. It is optimum to give the vaccine prior to the start of the flu season, but influenza vaccine can produce demonstrable efficacy and can have an impact on a family and on community if delivered after December. If influenza is circulating in the community at any time throughout the flu season, there is a chance that an immunization given at that moment will provide some meaningful protection to the child who is vaccinated and those in close contact with that child.

Possible alternatives

The most important goal before and during the flu season is to vaccinate as many children as possible. Opening up vaccination to children at alternative sites other than designated flu clinics would increase the number of opportunities to vaccinate more children. The most obvious alternative sites would be schools and day cares. Grocery stores and pharmacies are another possibility. These alternative sites could expand their immunization offering to healthy children as well as to older adults. Hospitals can play a role in offering flu vaccination. For example, emergency departments can offer a place to deliver the vaccine. This practice is underutilized in most communities. Specialist offices are another site for offering vaccination to chronically ill children. Children with chronic illnesses are in and out of specialist offices more commonly than they are in a general pediatrician’s office. However, some specialists do not fully embrace the idea of administering vaccine voicing that vaccination falls in the purview of general pediatricians. However, by offering vaccination, these practices can reach the children not generally seen at the pediatrician. Finally, home health agencies could also be responsible for delivering vaccination.