REVIEW ARTICLES
Modifying Clinical Practices to Manage Influenza in
Children Effectively
William Paul Glezen, MD
Abstract: Children less than 5 years of age are at increased risk of
morbidity from influenza infection compared with older children
and adults aged 18 –54 years. Although much of the disease burden
can be prevented by annual vaccination, the misperception that
influenza does not result in serious illness in children, including
schoolchildren, contributes to ongoing low vaccination rates. In
conjunction with community surveillance of influenza activity, rapid
diagnostic tests can help identify influenza patients who may benefit
from initiation of antiviral therapy. Antiviral therapy is most effec-
tive when started within at least 48 hours of the onset of symptoms,
the earlier the better. The neuraminidase inhibitors oseltamivir and
zanamivir are safe and effective as first-line treatments and prophy-
laxis for influenza in children. These agents have been shown to
decrease symptoms and shorten the duration of illness, as well as to
curb the spread of influenza infection. The neuraminidase inhibitors
also have shown efficacy against influenza B infection and exhibit
less viral resistance than the older adamantane antiviral class.
Key Words: influenza in children, treatment, prevention
(Pediatr Infect Dis J 2008;27: 738 –743)
I nfluenza exacts a disproportionate health toll on children,
particularly those less than 5 years of age.1,2 Compared with
adults aged 18 –54 years, pediatric patients are at increased
risk for complications, hospitalization, emergency depart-
ment visits, and death from influenza infection.3–7 This in-
crease in risk applies to healthy children as well as those with
chronic underlying conditions, such as asthma, and during all
epidemics—moderate and severe.6,8
Much of the disease burden of influenza may be pre-
vented through annual vaccination of children ⱖ6 months of
age, as is recommended by the Centers for Disease Control
and Prevention (CDC).9 Yet, vaccination levels remain un-
acceptably low. During the 2005–2006 influenza season, the
second season for which the CDC recommended that all
Accepted for publication February 13, 2008.
From the Departments of Molecular Virology and Microbiology, and Pedi-
atrics, Baylor College of Medicine, Houston, TX.
Consultant (ad hoc) to MedImmune Vaccines, Roche, and Novartis.
MedImmune Vaccines provided vaccine for an NIH-sponsored field
trial, Control of Epidemic Influenza.
Address for correspondence: William Paul Glezen, MD, Departments of
Molecular Virology and Microbiology, and Pediatrics, Baylor College of
Medicine, One Baylor Plaza, MS: BCM-280, Houston, TX 77030.
E-mail: wglezen@bcm.tmc.edu.
Copyright © 2008 by Lippincott Williams & Wilkins
ISSN: 0891-3668/08/2708-0738
DOI: 10.1097/INF.0b013e31816d9299
738 The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
children aged 6 –23 months receive vaccination against influ-
enza, only about 20% who were previously unvaccinated
received the optimal 2 doses.10 Vaccine coverage was found
to be lower in children living below the poverty level and in
Hispanic and non-Hispanic black children.11 In addition to
promoting measures to increase vaccination levels, good
influenza management includes utilization of influenza sur-
veillance tools, swift and accurate diagnosis when influenza
is suspected, and the use of appropriate antiviral medications
for prophylaxis and treatment.
BURDEN OF INFLUENZA
The rate of hospitalization for illness attributable to
influenza is greatest in children less than 6 months of age,
remains elevated through age 6 years,12 and decreases in
older children (Table 1).1,3,6,13 When influenza viruses are in
circulation, hospitalization rates in young children are similar
to those for other groups at high risk for influenza-related
complications, including persons ⱖ65 years of age.9
Poehling et al3 conducted a year-round, population-
based surveillance of hospitalizations and outpatient visits for
laboratory-confirmed influenza from 2000 to 2004 in children
ⱕ5 years of age. Of 2797 children with acute respiratory tract
infection or fever who were hospitalized, 160 (6%) had
laboratory-confirmed influenza. The rate of hospitalization
for all children up to 5 years of age was 0.9 per 1000. Nearly
half of those hospitalized were younger than 6 months of age
and 80% were younger than 2 years. The burden was even
greater in the outpatient setting. During the influenza seasons
of 2002–2003 and 2003–2004, laboratory-confirmed influ-
enza accounted for a mean of 10.2% and 19.4% of weekly
clinic visits and 5.9% and 28.8% of weekly emergency
department visits, respectively. These average annual rates of
outpatient visits were approximately 10, 100, and 250 times
higher than the hospitalization rates for children aged 0 –5
months, 6 –23 months, and 24 –59 months, respectively.
A similar prospective, population-based surveillance
study of children aged ⱕ5 years found that hospitalization
rates for influenza infection were 0.6 per 1000.1 Children
younger than 2 years accounted for 80% of the influenza
cases. Black and Hispanic race/ethnicity and presence of
chronic underlying illness were associated with higher rates.
Neuzil et al6 examined the effect of influenza outbreaks
on hospitalizations, outpatient visits, and number of antibiotic
prescriptions filled in otherwise healthy children over 19
consecutive years.6 The retrospective cohort study showed
that in all influenza seasons, the rates of hospitalization for
cardiopulmonary conditions in excess of the expected number
were highest for children less than 6 months of age (10.4/
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
TABLE 1. Hospitalization for Influenza Among Children
Age Children Aged
Study Period
Range ⬍6 Mo
2000 –2004 0 –⬍5 yr 4.5/1000*
49%†
2000 –2001 0 –⬍5 yr 2.4/1000*
⬇45%†
1973–1993 0 –⬍15 yr 10.4/1000*
2000 –2004 0 –ⱕ21 yr 25%†
*Average annual rate of hospitalization associated with influenza.
†
Percentage of total hospitalizations by age group.
1000 children per year), followed by those aged 6 months to
1 year (5/1000 per year). Influenza further accounted for 35%
of the excess number of outpatient visits in children ⬍3 years
of age, and for 10% to 30% of the excess use of antibiotics in
those aged ⬍15 years.
Neuzil et al8 used the same methods to measure influ-
enza burden in children with asthma or other chronic medical
conditions. Compared with healthy children, the excess hos-
pitalization rates for all children in the study were 2– 4 times
higher for those with a chronic condition. Children with
chronic pulmonary disease had the most hospitalizations.
Among children younger than 1 year who had underlying
respiratory disease, the excess hospitalization rate during
influenza season was more than twice, and outpatient visits
nearly triple, that of the cohort with other chronic diseases. In
addition, compared with healthy children, 10 –20% of high-
risk children aged ⬍15 years had an additional outpatient
visit, and 6 –14% had an antibiotic prescription filled.
A retrospective study of 745 children hospitalized with
community-acquired, laboratory-confirmed influenza during
a 4-year period included roughly half at high risk because of
a serious comorbidity.13 The incidence of community-ac-
quired, laboratory-confirmed influenza hospitalization was 7
per 10,000 child-years of observation. The median age was
1.8 years; 25% were infants ⬍6 months old, and 77% were
children ⬍5 years old. This study builds on more than 2
decades of research on the disproportionate burden of influ-
enza in young children. In the 1981–1982 and 1982–1983
influenza seasons, 2 outbreaks of influenza, which included
an outbreak of influenza B, showed the risk of hospitalization
to be greatest for those 5 years and younger, and comparable
to that of the population greater than 65 years of age.7 The
rate of hospitalizations for acute respiratory disease (includ-
ing influenza) for children less than 5 years of age was 27.9
and 37.2 per 10,000 persons in the respective seasons. The
rates of medically attended acute respiratory illness were
almost as high in school aged children as preschool; between
8 and 20 per 100 sought medical care during the epidemics.7
Mortality. Although deaths associated with influenza are
uncommon among children, they represent a substantial pro-
portion of vaccine-preventable deaths. During the 2003–2004
U.S. influenza season, 153 laboratory-confirmed deaths in
children were reported. The median age of the children was 3
years, with the mortality rate highest among children less
than 6 months of age (0.88/100,000).4 Although one-third of
© 2008 Lippincott Williams & Wilkins
Management of Influenza in Children
Children Aged Children Aged
Author
⬍2 Yr ⬍5 Yr
6 –23mo:0.9/1000* 0.9/1000* Poehling et al3
80%†
⬍1 yr:1.7/1000* 0.6/1000* Iwane et al1
80%†
6 –⬍12mo:5.0/1000* 1–⬍3 yr: 1.9/1000*; Neuzil et al6
3–⬍5 yr: 0.9/1000*
59%† 77%† Coffin et al13
the children had an underlying condition that increased their
risk of complications from influenza, 47% had been healthy.
These findings demonstrate that younger children are at
increased risk of influenza-related death. Yet, reported labo-
ratory-confirmed deaths represent only a fraction of the total
that occur each year. During the relatively mild season,
2006 –2007, a total of 68 laboratory-confirmed pediatric
deaths—mostly schoolchildren—were reported to the CDC.14
DIAGNOSIS
Prompt and accurate diagnosis of influenza is essential
to initiate antiviral therapy, limit the spread of the virus, and
avoid unnecessary antibiotic prescriptions. Yet, fewer than
half of children with fever and respiratory symptoms who are
hospitalized during influenza season receive a clinical diag-
nostic test for influenza.3,15 Delays in obtaining results from
viral culture and the limited availability and expense of
reverse transcription polymerase chain reaction (RT-PCR)
tests make these methods impractical for clinical decision
making. Relatively, inexpensive rapid influenza antigen de-
tection tests that provide a quick turnaround are an alternative
diagnostic tool. The wide availability and rapid results of
these tests has led the CDC and World Health Organization
(WHO) to deem them useful in establishing an influenza
diagnosis during outbreaks of acute respiratory disease and in
selected patients presenting with compatible symptoms.16,17
The reliability of the rapid tests varies, however, and results
should be interpreted in conjunction with information about
the clinical presentation and demographics of patients com-
bined with surveillance reports of influenza activity in the
community.
Grijalva et al15 correlated the predictive value of rapid
tests to the degree of severity of influenza outbreaks. They
accessed the New Vaccine Surveillance Network, which
enrolls children aged ⬍5 years prospectively, who are hos-
pitalized with respiratory symptoms or fever in 3 U.S. coun-
ties, and identified 270 children who received a rapid influ-
enza test during 4 influenza seasons from 2000 to 2004. Of
the 41 children who received a rapid test and subsequently
had influenza confirmed by viral culture or RT-PCR, 26 were
positive by rapid test (sensitivity, 63%). Among 229 children
who were influenza-negative on viral culture or RT-PCR, 223
were judged negative with a rapid test (specificity, 97%). The
predictive value of the rapid tests was improved in the context
739
Glezen The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
of higher prevalence of influenza in the community. When
prevalence of influenza among children with compatible
symptoms in outpatient surveillance sites was 5%, the pre-
dictive value of the rapid tests was found to be about 50%. In
contrast, when community prevalence was 21%, the predic-
tive value of the rapid tests was 85%. Influenza surveillance
is conducted by many large academic medical centers and
state and local health departments; local information is most
relevant for the clinician. In addition, CDC tracks regional
influenza activity from October to May on its Web site
(www.CDC.gov/flu), and Roche Laboratories has established
a comprehensive influenza surveillance network (www.
flustar.com).
PREVENTION
In light of the excessive and serious burden of influenza
in children, the ACIP in 2007 recommended annual vaccina-
tion for children 6 –59 months of age and their household
contacts including older siblings.9 In February 2008, the
ACIP extended coverage to all school children 5–18 years of
age to be fully implemented in 2009. Injectable trivalent
inactivated influenza vaccine is well tolerated and accounts
for the majority of vaccine doses given each year, but has an
overall effectiveness of ⬍50% in young children.18 A newer
live attenuated intranasal vaccine (LAIV) has been shown to
be more effective in children, especially in those younger
than 5 years of age, than is the inactivated vaccine.19 –21
However, LAIV is not yet available for children younger than
2 years of age.
Vaccine effectiveness is optimized when 2 separate
doses are given to influenza vaccine-naive children. There-
fore, it is recommended that children ⬍9 years of age who
have not been vaccinated previously receive 2 doses sepa-
rated by ⱖ4 weeks. If children miss the second dose of
vaccine in their first year, 2 doses are recommended for the
following season. If the second dose is missed again, then 1
annual dose should be provided thereafter.9 Unfortunately,
the percentage of influenza vaccine-naive children receiving
the recommended 2 doses is small. In 1 private practice, 19%
of children aged 6 to 23 months and 6% of those aged 24 –59
months who had never received influenza vaccine received
both doses for the 2003–2004 influenza season.18 A retro-
spective cohort study of children 6 months to 8 years of age
found that 7.5% of all children were fully vaccinated and
9.9% were partially vaccinated against influenza by the start
of peak influenza activity.22 In contrast to the data on use of
the inactivated vaccine, a single dose of LAIV has been found
to be effective in children— even those 1.5– 4 years of age.23,24
Variations between viral strains circulating in the com-
munity and those in that season’s vaccine can decrease
vaccine effectiveness.25 A substantial degree of immunity
may be conferred even when the circulating and vaccine
strains differ. In a case– control study of patients 6 –59
months of age during the 2003–2004 influenza season, the
antigenic match between vaccine and circulating viruses was
suboptimal; only 25% of circulating influenza viruses were
antigenically similar to the vaccine strain.18 A total of 293
children with laboratory-confirmed influenza were matched
740
against healthy controls. Compared with unvaccinated chil-
dren, all fully vaccinated children (aged 6 –59 months) and
partially vaccinated older children (aged 24 –59 months)
showed significant reductions in medically-attended influ-
enza. In young children aged 6 –23 months, however, no
effectiveness was seen with partial vaccination, echoing ear-
lier findings.18 In the same year, a single dose of LAIV
provided 56% protection for school-aged children enrolled in
the Central Texas Field Trial.26
TREATMENT
Antiviral medications are valuable weapons for treating
and controlling influenza.27 Treatment with antiviral medica-
tions can shorten the duration and severity of symptoms and
reduce the occurrence of secondary complications.28 Two
classes of antiviral medications are available—the M2 protein
inhibitors (adamantanes) and the neuraminidase inhibitors
(NAIs). In 2005–2006, a striking increase in resistance of
influenza A(H3N2) virus strains to the adamantane drug class
(amantadine and rimantadine) was observed; in the United
States, 96.4% of A(H3N2) strains were resistant to amanta-
dine.29 In contrast, only 4% of A(H1N1) viruses isolated in
the United States during that year were resistant. Because of
this sharp increase in resistance of A(H3N2) viruses, only
NAIs (oseltamivir and zanamivir) are recommended by the
CDC for use at this time.30
The adamantanes lack activity against influenza B
strains, whereas oseltamivir and zanamivir are safe and ef-
fective for the treatment and prophylaxis of all influenza virus
infections in children. Oseltamivir is licensed for use in
persons aged ⱖ1 year and zanamivir for use in persons aged
ⱖ5 years. Therapy is recommended for children who are at
high risk of severe infection and for children with moderate-
to-severe influenza who could benefit from a decrease in the
duration of symptoms.30
The most frequent adverse event reported in pediatric
treatment trials of oseltamivir was vomiting in 15% of pa-
tients compared with 9% of placebo recipients. Other events
that were reported more often in pediatric patients, abdominal
pain, epistaxis, ear disorder (including a variety of minor
complaints—not otitis media), and conjunctivitis, generally
occurred once and resolved despite continued dosing.31 Spon-
taneous reports of neuropsychiatric behavior (self-injury and
delirium), mostly in Japanese pediatric patients, who are
treated with almost 4 times more courses of oseltamivir than
U.S. patients, have been reviewed by the Food and Drug
Administration. The relative contribution of the drug to these
events has not been determined, but patients should be mon-
itored for signs of abnormal behavior during the treatment
period.30,31 The most common adverse events in treatment of
otherwise healthy children with zanamivir are respiratory and
digestive, and similar to the frequency in placebo recipients.
However, the Food and Drug Administration has warned
about the use of zanamivir in children with reactive airways
disease, such as asthma and chronic obstructive pulmonary
disease. Caution should be exercised in use of inhaled zana-
mivir in this population. Some children find this irritating to
the airways; fast-acting bronchodilators should be available
© 2008 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
for use if a reaction is noted.30,32 The recommended duration
of treatment with oseltamivir or zanamivir is 5 days.
Early treatment, within 48 hours of symptom onset, is
essential to maximize outcomes with antiviral treatment.
Hedrick et al33 compared a 5-day course of inhaled zanamivir
twice daily against placebo in children 5 to 12 years of age.
The well-controlled trial enrolled 471 patients with influenza-
like symptoms of ⱕ36 hours in duration. Among 346 patients
with influenza-positive infection (65% type A, 35% type B),
zanamivir reduced the median time to alleviation of symp-
toms by 24% (1.25 days) compared with placebo. Those
taking zanamivir also returned to normal activities signifi-
cantly faster and took fewer relief medications.
A pivotal trial of oseltamivir administered 2 mg/kg/
dose of the drug or placebo twice daily for 5 days to 452
children aged 1–12 years whose symptoms of cough or
coryza had begun less than 48 hours earlier.28 Only 3% of
children had been vaccinated against influenza. Among in-
fluenza-infected children receiving oseltamivir, the median
duration of illness was reduced by 36 hours compared with
those receiving placebo. A difference in the proportion of
oseltamivir recipients who improved was seen within 24
hours of initiating therapy. Viral shedding was also reduced
in the oseltamivir group by day 4, potentially limiting the
spread of the influenza virus. The study also showed that
antiviral treatment decreased the risk of secondary complica-
tions. Oseltamivir was associated with a 44% reduction of
new otitis media cases and reduced antibiotic usage.
Treatment with antivirals may prevent serious compli-
cations from influenza infection. A retrospective cohort study
of patients aged 1–12 years with influenza from 2000 to 2004
compared patients who received oseltamivir within 1 day of
influenza diagnosis with those who received no antiviral
therapy.34 Oseltamivir recipients had a 52% lower risk of
pneumonia compared with nonrecipients. Patients in the os-
eltamivir group also received significantly fewer antibiotic
prescriptions and had fewer emergency department and
office visits.
Animal studies indicate that antiviral treatment may
also prove effective against the highly pathogenic H5N1
influenza virus. Govorkova et al evaluated the use of oselta-
mivir as early postexposure prophylaxis and for treatment of
H5N1 infection in ferrets.35 Animals treated with oseltamivir
shortly after inoculation with H5N1 had reduced lethargy,
significant inhibition of inflammation in the upper respiratory
tract and, depending on the challenge dose of virus, either no
virus spread or significantly lower virus titers in the internal
organs. Higher daily doses were needed to see a benefit when
treatment was initiated 24 hours after inoculation compared
with initiation within 4 hours. A higher dose may be needed
for potential protection against H5N1 in humans. The same
group of investigators have suggested that combination ther-
apy with drugs that target different viral proteins may be
indicated and may reduce the risk of emergence of resistant
viruses.36,37 Ribavirin may be considered for hospitalized
patients, combined with either an M2 or NA inhibitor.38 – 41
Constant monitoring of the sensitivity of influenza viruses
to the antiviral agents is necessary. Recent reports from
© 2008 Lippincott Williams & Wilkins
Management of Influenza in Children
Japan show decreased sensitivity of influenza B viruses to
oseltamivir.42,43
Chemoprophylaxis. Antiviral therapy has a key role in the
optimal management of local outbreaks and is expected to be the
main defense during the first wave of the next pandemic.44
During influenza virus prevalence, chemoprophylaxis should
be considered for at-risk pediatric patients who receive inac-
tivated vaccine until immunity has developed (10 –14 days).
It is also recommended to limit transmission among unvac-
cinated people who may have been exposed to the influenza
virus.30 Oseltamivir and zanamivir have been shown to pre-
vent influenza illness among persons receiving these agents
as prophylaxis after a household contact was diagnosed with
influenza.45,46 The significant benefits in preventing the
spread of influenza warrant consideration of chemoprophy-
laxis in household contacts. Factors such as cost, compliance,
and potential adverse events need to be considered when
determining the timing and duration of chemoprophylaxis.
Although oseltamivir or zanamivir can be used for chemo-
prophylaxis of influenza, the CDC currently recommends
oseltamivir for chemoprophylaxis.30 Rimantadine may be
indicated for prophylaxis when the prevalent influenza A
virus is susceptible.47,48 Rimantadine in daily doses is well
tolerated by children ⱖ3 years of age for up to 5 weeks and
is less expensive than oseltamivir. Resistant viruses are less
likely to emerge when M2 inhibitors are used for prophylaxis
against susceptible viruses.27 For instance, rimantadine pro-
phylaxis would be effective when currently susceptible influ-
enza A(H1N1) viruses are predominant.
EASING THE INFLUENZA BURDEN
Influenza is one of the few viral respiratory diseases
preventable by vaccination. Alleviating the burden of influ-
enza illness in children requires maximizing every opportu-
nity to provide the influenza vaccine. Reasons suggested for
the poor record of influenza immunization include a lack of
belief among the general public that influenza causes signif-
icant illness and the inconvenience of adding annual influenza
vaccine to an already crowded pediatric immunization sched-
ule.8 Brewer and Hallman surveyed 300 people and found
that the strongest predictor of receiving vaccination was
respondents’ belief that they were at high risk of influenza.49
Clinicians are in an ideal position to challenge the common
perceptions of parents of young children. Recent reports of
laboratory-confirmed influenza deaths in children4 are chang-
ing attitudes of parents about indications for influenza vac-
cine for their children.
Most cases of influenza are unrecognized clinically.3
Use of rapid influenza tests, which can provide diagnostic
information within 30 minutes, can enable clinicians to ini-
tiate antiviral treatment and provide chemoprophylaxis to
household contacts. Antiviral treatment has been proven to
reduce the duration of symptoms by 1 day or more among
those infected and can stem the transmission of the virus
among close contacts. The use of appropriate antivirals early
in the course of illness cannot be overemphasized, given the
serious consequences of influenza virus infection.
Although mortality is an insensitive indicator of the
influenza burden in children,6 about one-half of all pediatric
741
Glezen The Pediatric Infectious Disease Journal • Volume 27, Number 8, August 2008
deaths from influenza occur in those without underlying
medical conditions.4 Because children under 6 months of age
have the highest mortality rate of any age group,4 and
influenza vaccine is not available for this group, high priority
should be placed on promoting influenza vaccination among
pregnant women and household contacts of children less than
6 months of age, as recommended by the CDC.5,9
Clinicians should remember that, if inactivated vaccine
is administered to patients after influenza viruses have started
circulating in their community, it is imperative that these
persons receive antiviral prophylaxis for 14 days to allow
time for specific antibodies to be generated.30 This prophy-
laxis is not indicated if the live attenuated vaccine is admin-
istered. LAIV gives almost immediate protection.50 In fact,
antiviral therapy is contraindicated after LAIV administration
because it may limit infection with the attenuated viruses and
reduce the immune response. However, LAIV can be admin-
istered at least 48 hours after cessation of antiviral therapy.
CONCLUSIONS
Influenza is the most important cause of acute respira-
tory illness that results in medical consultation. Clinicians
should be alert to the public health advisories of influenza
virus activity in their communities and be prepared to pre-
scribe appropriate antiviral treatment and prophylaxis. The
American Academy of Pediatrics guidelines state that “ther-
apy should be provided to children with influenza infection
who are at high risk of severe infection.”30 How do clinicians
make the decision to treat knowing that, to be effective, the
treatment must be initiated early in the course of the illness?
Many of the reported deaths have occurred within a few days
of onset of symptoms. The only effective approach is to treat
any child who is sick enough to be brought to the clinic
during the epidemic period. This should be the standard of
practice just as we currently treat group A streptococcal
infections. Early treatment of influenza virus infections will
not only reduce the risk of complications but also will limit
the spread to contacts at home, in school, or in daycare, and
will limit nosocomial spread from those hospitalized.
Clinicians’ responsibility does not end with treatment
of the presenting patient. They must be alert to the condition
of other persons in the household and be ready to recommend
treatment or short-term prophylaxis for household contacts
who are unimmunized or immunocompromised. A history of
vaccination does not eliminate the need for antiviral prophy-
laxis. In the past 7 years, 2000 –2007, at least one new
antigenic variant has appeared each season that is not opti-
mally covered by the available vaccine.25 This fact can
increase the need for short-term prophylaxis after household
or workplace exposure of vaccinated persons who are partic-
ularly vulnerable to complications of influenza.
ACKNOWLEDGMENTS
The author thanks IntraMed Educational Group for
providing editorial support on behalf of Roche.
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