Influenza and Parainfluenza Viral Infections in Children

Thomas G. Fox and John C. Christenson

Pediatrics in Review 2014;35;217
DOI: 10.1542/pir.35-6-217

The online version of this article, along with updated information and services, is
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 Article infectious diseases

Influenza and Parainfluenza Viral Infections

in Children
Thomas G. Fox, MD*
Practice Gaps
John C. Christenson, MD*
1. Because influenza and parainfluenza viruses are responsible for significant morbidity
and mortality in young infants and children, especially those with chronic conditions,
Author Disclosure clinicians must learn to recognize, treat, and prevent infections caused by these
Drs Christenson and viruses.
Fox have disclosed no 2. Disease caused by influenza virus can be prevented through the vaccination of all
financial relationships persons 6 months or older. Special attention should be given to pregnant women and
relevant to this article. persons with chronic medical conditions, such as asthma, congenital heart disease,
This commentary does and neuromuscular disorders.
not contain
a discussion of an
Objectives After completing this article, readers should be able to:
unapproved/
investigative use of 1. Describe the epidemiology of influenza and parainfluenza virus infections.
a commercial product/ 2. Recognize the clinical features of influenza infections.
device. 3. Select the most appropriate vaccines for the prevention of influenza.
4. Differentiate clinically between influenza and parainfluenza virus infections.
5. Order the most appropriate test for the diagnosis of respiratory viral infections.

Introduction
Influenza and parainfluenza viruses (PIVs) are among the most common respiratory patho-
gens that affect infants and children worldwide. Infections and their complications are re-
sponsible for a significant number of hospitalizations and fatalities on a yearly basis. In
most temperate climate countries, seasonal patterns of disease are observed. In warmer cli-
mates, disease can be observed year round. The fear of an influenza pandemic looms when
new strains are discovered. Recognition and prevention become pressing priorities. In recent
years, a greater emphasis in preventing influenza through vaccination has emerged within the
United States. Many health care systems have mandatory vaccinations programs for health
care professionals. In addition, vaccination is now recommended for all persons 6 months or
older. Available antiviral agents are effective not only as therapy but also as preventive agents.
PIVs are the most common cause of laryngotracheitis or croup in children. In recent
years, these viruses have become recognized as important pathogens in the immunocom-
promised host. Unfortunately, an effective antiviral regimen or vaccine still eludes us. In
this review, we summarize the key aspects of what is known about influenza and PIVs, in-
cluding their clinical manifestations, treatment, and prevention.

Influenza Virus
Abbreviations Historical Aspects
IIV: inactivated influenza vaccine The avian origin H1N1 influenza pandemic of 1918–1919
LAIV: live attenuated influenza vaccine (Spanish flu) has been described as the single most fatal
LRI: lower respiratory tract infection event in human history, responsible for more than 50 million
PCR: polymerase chain reaction deaths worldwide. (1) Subsequent pandemics occurred in
PIV: parainfluenza virus 1957 (H2N2 Asian flu) and 1968 (H3N2 Hong Kong
URI: upper respiratory tract infection flu). The emergence of swine-origin novel H1N1 influenza
in March 2009 heralded the fourth influenza pandemic in

*Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease, Indiana University School of Medicine, Riley Hospital
for Children, Indianapolis, IN.

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infectious diseases influenza & parainfluenza

the last 100 years. Influenza epidemics can be traced back a limited number of influenza subtypes. Human infection
at least 2000 years, and the first true pandemic (intercon- and effective human-to-human transmission has been
tinental disease) occurred in 1580. achieved by only 3 hemagglutinins and 2 neuraminidases
in 3 combinations: H1N1, H2N2, and H3N2. (3) Be-
Influenza Biology cause of differences in preferred cellular binding sites, dif-
Influenza viruses are classified as orthomyxoviruses and ferent influenza strains preferentially infect birds and
contain a negative sense single-stranded RNA genome. humans. However, pigs (swine) are susceptible to infec-
There are 3 major influenza types: A, B, and C. The in- tion from both avian and human strains. Swine can serve
dividual virus is spherically shaped and studded with 2 as mixing vessels to produce novel strains that subse-
major proteins: hemagglutinin and neuraminidase. Dif- quently infect humans. In recent years, 2 influenza A
ferences in the hemagglutinin and neuraminidase anti- strains of avian origin, H5N1 and H7N9, were responsi-
gens form the basis for the nomenclature of influenza ble for several clusters of human disease in Asian coun-
A subtypes (eg, H1N1 vs H3N2). Influenza strains are tries, resulting in many hospitalizations and a high
further categorized according to type, location, and year fatality rate. (4)(5)
and are given a strain number (eg, A/California/7/2009
[H1N1]). 2009 Novel H1N1 Pandemic
Hemagglutinins facilitate attachment of the virus to In March 2009, a new strain of influenza A was identified
the columnar epithelial cell in the respiratory tract. After that caused significant disease in humans and could effi-
uptake of the virion by endocytosis, an influx of protons ciently spread from person to person, leading to the
through the virus M2 channel allows release of viral fourth influenza pandemic of the last 100 years. This virus
RNA, which is then imported to the nucleus. The virus was a novel combination of 2 individual swine viruses,
hijacks the host’s cellular machinery to produce the pro- hence the term swine-origin H1N1 or swine flu. From
teins and genetic material needed for viral progeny. Neur- April 2009 to March 2010, novel H1N1 was responsible
aminidases function in the budding of the newly formed for an estimated 60 million illnesses, 270,000 hospitaliza-
virion to aid in its release from the host cell. (2) tions, and 12,270 deaths in the United States. (6) As seen
in previous pandemics, novel H1N1 disproportionately
Influenza Genetics and the Pandemic Threat affected young adults and children, as well as pregnant
The genetic characteristics of influenza viruses facilitate and postpartum women. There were 317 confirmed pe-
the generation of novel strains with the potential to cause diatric deaths during the pandemic, significantly higher
human disease. The influenza genome is composed of 8 than prior years. The excess childhood deaths are prob-
RNA segments that can rearrange if more than one influ- ably explained by the increased attack rate in the young
enza subtype infects the same host. The virus contains its rather than enhanced virulence in this age group. (7)
own RNA polymerase, which, in contrast to DNA poly-
merase, lacks proofreading functions. Consequently, Epidemiology and Transmission
point mutations occur with regular frequency during ge- Epidemics of influenza occur annually during the winter
nome replication. The accumulation of these point mu- months in temperate regions of the world, typically peak-
tations is known as antigenic drift and is responsible ing in January or February in the Northern hemisphere.
for the seasonal variation of influenza A strains that cause There is no clear influenza season in equatorial countries,
annual epidemics. Antigenic shift occurs when an influ- where influenza can circulate year round. Children are
enza A strain with a novel hemagglutinin (and sometimes important vectors of disease because of higher attack rates
a novel neuraminidase) enters the human population. A and more prolonged viral shedding compared with
pandemic occurs if this newly generated strain causes dis- adults. The peak incidence of infection occurs earlier in
ease in humans and can efficiently spread from person to the pediatric population. An increase in missed school
person and throughout the world. To date, 17 unique days in children sick with influenza often precedes in-
hemagglutinin antigens and 10 unique neuraminidase creased work absenteeism in adults.
antigens have been identified. (2) Many of these influ- Influenza virus is transmitted primarily by large parti-
enza subtypes naturally infect the hundreds of bird spe- cle droplets, although contaminated surfaces can also
cies susceptible to influenza. Birds can be infected by spread disease. The incubation period is 1 to 4 days
multiple different strains simultaneously and serve as a ge- (mean, 2 days). Viral shedding correlates with fever in-
netic pool for the generation of new influenza strains. tensity and begins 24 hours before symptom onset, peaks
The human population has so far been susceptible to at day 3, and resolves by day 7. (8) However, young

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 infectious diseases influenza & parainfluenza

children and individuals with compromised immunity can and PIVs. Upper respiratory tract infection (URI), laryng-
shed virus for extended periods. The severity of disease otracheitis (croup), bronchiolitis, and pneumonia are all
may also correlate with duration of shedding. possible presentations of influenza in the younger child.
Hospitalization rates for influenza are highest in chil- Gastrointestinal symptoms are uncommon in adults but
dren younger than 2 years and adults older than 65 years. can be the primary symptoms in children with influenza.
Children with certain comorbidities are at increased risk
of hospitalization and influenza complications. These Complications
complications include hemoglobinopathies, diabetes Bacterial infection of the respiratory tract is the most
mellitus, neuromuscular disorders, chronic kidney disease, common complication of influenza infection and includes
and congenital heart disease. Children with underlying otitis media, sinusitis, and tracheitis. Pneumococcal pneu-
pulmonary disease, such as asthma and cystic fibrosis, are monia is a relatively common complication and should be
at risk for more severe disease. suspected in the child who develops fever and a lobar in-
filtrate during the convalescent period. Less common than
Clinical Manifestations Streptococcus pneumoniae, staphylococcal infection can com-
Classic influenza infection is characterized by the sudden plicate acute influenza and lead to a diffuse necrotizing
onset of fever, chills, and myalgias followed by prominent pneumonia with a high mortality rate, especially if caused
upper respiratory tract symptoms, such as rhinorrhea, by methicillin-resistant Staphylococcus aureus. Parapneumonic
cough, and sore throat. It is critical to recognize that effusions and empyemas are common complications.
younger children are less likely to present with this flulike Acute myositis can occur during convalescence but is
syndrome. This is especially true in infants, who can pres- almost always benign. It occurs more commonly with in-
ent with fever and irritability with minimal respiratory fluenza B. The typical presentation is a child who has sud-
findings. It is difficult in younger children to distinguish den onset of severe pain in the calves and refusal to walk.
clinically influenza infection from infections due to other The serum creatine kinase level is usually elevated. Severe
respiratory viruses (eg, respiratory syncytial virus and PIV) encephalopathy and encephalitis have been reported with
that circulate in communities during the same periods, and influenza infection. Reye syndrome is a rare form of en-
the manifestations of disease can be identical. Table 1 pro- cephalopathy that has been associated with influenza in-
vides a comparison of clinical features between influenza fection and salicylate (eg, aspirin) use.

Clinical Comparison of Influenza and Parainfluenza Viral

Table 1.

Infections
Clinical Condition Influenza Parainfluenza Comments
Afebrile URI D DD Coryza and pharyngitis are common with PIV
infections.
Febrile URI DDD D Flulike illness
Acute otitis media DD DDD
Pneumonia D DD
Laryngotracheobronchitis (croup) D DDD Croup by influenza virus is more severe: thicker
secretions, higher temperatures, more severe
airway obstruction, and more bacterial
superinfections.
Bronchiolitis D DDD PIV is third most common cause of bronchiolitis.
Sepsis-like syndrome D Rare
Myositis D Rare Mostly observed with influenza B virus. Myositis
associated with PIV infection tends to be milder
and of shorter duration.
Myocarditis Rare Rare
Encephalopathy, aseptic meningitis, Rare Rare Necrotizing encephalitis reported with influenza
Guillain-Barré syndrome virus.
PIV¼parainfluenza virus; URI¼upper respiratory tract infection.

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infectious diseases influenza & parainfluenza

Laboratory Diagnosis influenza-like illness could be falsely negative. If that same

Laboratory testing is the mainstay in the diagnosis of in- patient presents during a period with minimal circulating
fluenza infection. Clinical findings alone are insufficiently influenza but has a positive rapid antigen test result, the
sensitive or specific, especially in younger children who test result is likely to be falsely positive. However, influenza
less often have classic findings. Accurate and rapid diag- strains can cause infections in out-of-season times of the
nosis of influenza infection can allow prompt initiation of year like in the case of an influenza A (H3N2) variant that
antiviral therapy while simultaneously limiting antibiotic initially circulated in the United States during the summer
use. A variety of testing modalities exist, and each has its months with outbreaks associated with contact with swine
merits. Serologic (antibody) testing for influenza infec- at state and county fairs in the Midwest. (11)
tion is important in the epidemiologic study of disease
but does not play a role in clinical management. Similarly, Molecular Tests
although laboratory culture of influenza virus is essential Molecular methods of detection are replacing viral cul-
for vaccine development and antiviral resistance testing, ture as the gold standard in the diagnosis of many viral
other methods have proven more clinically useful. (9) infections, including influenza. Polymerase chain reaction
Regardless of the diagnostic method used, proper (PCR)–based assays offer superior sensitivity and turn-
sampling is paramount. Nasopharyngeal specimens are around time compared with viral culture and are becoming
preferred over throat swabs. (9) The timing of specimen more widely available in many laboratories. The PCR-
collection will also affect the validity of the result. A sam- based tests for influenza are often part of multiplex assays
ple obtained in a patient with an influenza-like illness on that can concomitantly detect influenza and other impor-
days 2 to 3 of symptoms (when influenza virus shedding tant viruses, aiding in the diagnosis of noninfluenza respi-
is at its peak) will yield a more reliable result compared ratory infections. Most PCR-based influenza assays can
with one obtained later in the disease course. (9) distinguish influenza types (A from B). Some tests reliably
determine specific subtype (eg, H1N1 vs H3N2), which
Rapid Antigen Testing proved valuable in guiding antiviral therapy during the
Rapid antigen testing is the most commonly used 2009 H1N1 pandemic. None of the currently available
method in the laboratory diagnosis of influenza infection rapid antigen tests can discriminate influenza A subtypes.
and plays a vital role in high-volume patient settings, such
as emergency departments, especially during epidemics of Other Testing Choices
disease. In fact, the first case of 2009 pandemic influenza Direct and indirect fluorescent antibody testing can be
infection in the United States was diagnosed using a rapid performed on patient secretions and provide results
antigen test. These assays work by measuring the immu- within a few hours. These tests are highly specific but
nologic reaction between influenza antigens from the pa- have variable sensitivities. The reliability of the results
tient’s secretions with a specific influenza antibody. The can vary, depending on the skill of the performing tech-
advantages of rapid antigen tests include quick results nician. They are more expensive than rapid antigen tests.
(£15 minutes), bedside or point-of-care testing, and dis-
tinguishing influenza type A from B. Treatment
Rapid antigen testing can be part of treatment algo- Influenza infection is a benign self-limited disease in most
rithms in the management of patients with suspected in- children and adults, regardless of whether treatment is
fluenza. (10) Rapid antigen tests for influenza are highly provided. However, influenza infection can cause severe
specific, allowing for efficient allocation of antivirals dur- disease and death in both high-risk patients and healthy
ing peaks of activity. The major disadvantage of rapid individuals. The administration of active antiviral therapy
tests is their low and highly variable sensitivity, ranging early in the course of disease has been found to shorten
from 20% to 90%. (9) Therefore, a negative rapid test re- symptom duration and prevent the spread of virus. It may
sult in a patient presenting with sudden onset of high fe- also be beneficial in hospitalized patients and in those
ver, myalgias, and cough during peak influenza activity with severe disease, even if started later in the disease
could be falsely negative. One important aspect of rapid course. Treatment should optimally be initiated within
influenza testing—and rapid viral tests in general—is that 48 hours of symptom onset.
the accuracy of the test result is directly correlated with The decision to provide antiviral therapy as treatment
the prevalence of disease in the community. As stated or prophylaxis should be based on the duration of symp-
in the above example, during periods of peak viral activ- toms and the individual’s risk of progression to severe dis-
ity, a negative rapid test result in a patient with an ease. Hospitalized patients with suspected or confirmed

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 infectious diseases influenza & parainfluenza

influenza should receive therapy. Patients at high risk for months. However, according to existing safety informa-
severe disease and complications should also be provided tion, oseltamivir can be used to treat influenza in both
therapy and prophylaxis (Tables 2 and 3). (10) term and preterm infants from birth. (12) Zanamivir is
approved for use in the treatment of children 7 years
and older and as prophylaxis in children 5 years and older.
Candidates for Antiviral
Table 2. Oral oseltamivir can cause gastrointestinal distress but in
general is well tolerated. Cough and bronchospasm have
Treatment been associated with the use of inhaled zanamivir. It
should be used with caution in patients with underlying
Antiviral treatment is recommended as soon as possible
for any person with confirmed or suspected influenza pulmonary dysfunction (eg, asthma). For antiviral indica-
in any of the following categories: tions and dosages, see Tables 2 and 3. (10)(12)
• Is hospitalized
• Has severe, complicated, or progressive illness
• Is at higher risk for influenza complications Prevention
Persons at higher risk for influenza complications:
• Children younger than 2 years Yearly vaccination is the main strategy of prevention
• Adults 65 years or older against influenza. All persons 6 months and older should
• Persons with chronic pulmonary (including asthma and be vaccinated. Influenza is responsible for its greatest
cystic fibrosis), cardiovascular, renal, hepatic, morbidity in young infants, children younger than 5
hematologic, metabolic disorders, or neurologic and years, and individuals 65 years and older. In addition,
neurodevelopmental conditions (including cerebral
palsy, muscular dystrophy, or spinal cord injury) persons with chronic medical conditions, such as asthma,
• Persons with immunosuppression heart disease, cystic fibrosis, diabetes mellitus, neuromus-
• Women who are pregnant or post partum (within 2 cular disorders, cancer, and other immunodeficiencies,
weeks after delivery) are at an increased of severe disease and death. In recent
• Persons younger than 19 years who are receiving long- years, a significant number of infants and children have
term aspirin therapy
• American Indians or Alaska Natives died of the disease. Although many had underlying med-
• Persons who are morbidly obese ical conditions, close to 50% of fatalities were in previously
• Residents of nursing homes and other chronic care healthy children. Unfortunately, only approximately 50%
facilities. of children with cognitive, neurologic, and seizure disor-
ders received the vaccine. (13) Infants younger than 6
months are at risk for severe disease. Although vaccination
There are 2 classes of antivirals available for the treat- is not indicated in this age group, preliminary studies have
ment and chemoprophylaxis of influenza: the adamantanes found that influenza vaccines are safe and immunogenic in
and the neuraminidase inhibitors. The adamantanes in- infants as young as 6 to 12 weeks. (14) In an open-label
clude amantadine and rimantadine and work by interfer- study, vaccination of influenza-seronegative infants in-
ing with the viral M2 ion channel to prevent the release duced levels of antibody similar to levels in 6-month-olds.
of viral RNA into the host cell after endocytosis. The Preexisting maternal antibodies appear to blunt the im-
adamantanes do not have activity against influenza B. Fur- mune response in vaccinees. (15) One strategy that will
thermore, because of widespread resistance among influenza protect these young infants is the vaccination of mothers
A strains, their use in the treatment and chemoprophylaxis during pregnancy because maternal antibodies in the infants
of influenza A is not recommended at this time. The have been found to be protective up to 6 months. (16)(17)
neuraminidase inhibitors have activity against both influ- The vaccination of mothers was more than 90% effective in
enza A and B, and although resistant strains of influenza preventing influenza-related hospitalizations of their infants.
A have been found, most circulating influenza strains are (18) More mothers need to be vaccinated. When vaccina-
susceptible. Neuraminidase inhibitors block viral neur- tion is not proactively recommended, only 16.1% of preg-
aminidase, which prevents the budding and release of vi- nant women receive the vaccine. (19) If vaccination is
ral progeny. Oral oseltamivir and inhaled zanamivir are 2 recommended to the pregnant woman by a health care
neuraminidase inhibitors currently available for clinical practitioner, 70.5% will receive it. The vaccination of chil-
use. Intravenous formulations of zanamivir and a third dren in daycare has been found to reduce influenza-related
agent, peramivir, are being investigated. Oseltamivir is morbidity among members of the household. (20)
approved for the treatment of influenza in children older Multiple vaccines are distributed within the United
than 2 weeks and for chemoprophylaxis down to age 3 States (Table 4). Most are inactivated products, but a live

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infectious diseases influenza & parainfluenza

Table 3. Antiviral Agents for Treatment and Chemoprophylaxis of Influenza

Agent Age Group Treatment Chemoprophylaxis
Oseltamivir Adults 75 mg twice daily 75 mg once daily
Children ‡12
months
£15 kg 30 mg twice daily 30 mg once daily
>15–23 kg 45 mg twice daily 45 mg once daily
>23–40 kg 60 mg twice daily 60 mg once daily
>40 kg 75 mg twice daily 75 mg once daily
Infants 9–11 3.5 mg/kg per dose 3.5 mg/kg per dose once daily
months twice daily
Term infants 3–8 3 mg/kg/dose twice daily 3 mg/kg per dose once daily
months
Term infants 0–3 3 mg/kg per dose twice daily Not recommended unless situation
monthsa is judged critical. Limited safety
and efficacy data. Consult pediatric
infectious disease specialist.
Preterm infants Dosing based on Not recommended unless situation is
postmenstrual ageb judged critical. Limited safety and
efficacy data. Consult pediatric
infectious disease specialist.
<38 weeks: 1.0 mg/kg per
dose twice daily.
38–40 weeks: 1.5 mg/kg per
dose twice daily.
>40 weeks: 3 mg/kg per
dose twice daily
Zanamivir Adults 10 mg (two 5-mg inhalations) 10 mg (two 5-mg inhalations)
twice daily once daily
Children ‡7 years: 10 mg (two 5-mg ‡5 years: 10 mg (two 5-mg inhalations)
inhalations) twice daily once daily
a
Approved by the Food and Drug Administration down to age 2 weeks. However, on the basis of existing safety information, oseltamivir can be used to treat
influenza in both term and preterm infants from birth.
b
Postmenstrual age is gestational age plus chronological age.

attenuated intranasal vaccine (LAIV) and a recombinant vaccine to young infants has also led to wheezing. Al-
vaccine are available. The antigenic composition of the var- though caution is merited, high-risk individuals with im-
ious vaccines is determined on a yearly basis based on paired immune systems do not appear to have significant
worldwide and national surveillance of current and past in- adverse events or prolonged viral shedding after the in-
fluenza seasons. The composition of the 2013–2014 trivalent advertent exposure to LAIV. Several studies have found
influenza vaccine is A/California/7/2009 (H1N1)–like superior efficacy of LAIV compared with IIA. (21) In chil-
virus, A/Victoria/361/2011 (H3N2), and B/Massa- dren 6 years or older and adolescents with asthma, the LAIV
chusetts/2/2012–like virus. The quadrivalent vaccine provided a 32% increase in protection against culture-
contains an additional influenza B strain, B/Brisbane/ proven influenza infections when compared with IIA.
60/2008–like virus, which will cover both the Victoria (22) Viral shedding from the nasopharynx occurs after
and Yamagata lineages. This year, quadrivalent vaccines vaccination, which peaks approximately 2 days after vacci-
that contain antigens for 2 strains each of influenza A nation. Postvaccination symptoms, such as runny nose,
and B are also available in addition to trivalent vaccines. headache, and sore throat, do not correlate with viral shed-
Healthy individuals 2 years or older can receive either ding. Mean duration of shedding was approximately 2.8
an inactivated influenza vaccine (IIV) or LAIV. The days. Viral shedding can be observed with LAIV recipients
LAIV is licensed for healthy persons ages 2 to 49 years. up to 6 to 8 days after vaccination. With this in mind, prac-
It is contraindicated in persons with underlying medical titioners should exercise caution when deciding who
and immunosuppressive conditions. Administration of the should receive this vaccine. Persons caring for persons with

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 infectious diseases influenza & parainfluenza

Table 4. Influenza Vaccines, 2013-2014

Vaccine Trade Name Presentation and Route of Mercury Content Age
(Manufacturer) Administration mg /0.5 mL) Indications
Inactivated, trivalent
Afluria (CSL Limited) 0.5 mL single-dose prefilled syringe 0 ‡9 yearsa
or single-dose vial, IM
0.5 mL, IM (5.0 mL multidose vial) 24.5 ‡9 years
Fluarix (GlaxoSmithKline) 0.5 mL single-dose prefilled 0 ‡3 years
syringe, IM
Flucelvax (Novartis Vaccines 0.5 mL single-dose prefilled 0 ‡18 years
and Diagnostics) syringe, IM
Flulaval (ID Biomedical 0.5 mL, IM (5.0 mL multidose vial) <25.0 ‡3 years
Corporation of Quebec)
Fluvirin (Novartis Vaccines 0.5 mL single-dose prefilled £1.0 ‡4 years
and Diagnostics) syringe, IM
0.5 mL, IM (5.0 mL multidose vial) 25.0
Fluzone (Sanofi Pasteur) 0.25 mL, single-dose prefilled 0 6–35 months
syringe, IM
0.5 mL single-dose prefilled 0 ‡36 months
syringe or single-dose vial, IM
0.5 mL, IM (5.0 mL multidose vial) 25 ‡6 months
Fluzone Intradermal 0.1 mL prefilled microinjection 0 18–64 years
(Sanofi Pasteur) system, ID
Inactivated quadrivalent
Fluarix Quadrivalent 0.5 mL single-dose prefilled 0 ‡3 years
(GlaxoSmithKline) syringe, IM
Fluzone Quadrivalent 0.25 mL, single-dose prefilled 0 6–35 months
(Sanofi Pasteur) syringe, IM
0.5 mL single-dose prefilled syringe 0 ‡36 months
or single-dose vial, IM
Flulaval Quadrivalent (ID 0.5 mL, IM (5.0 mL multidose vial) <25.0 ‡3 years
Biomedical Corporation
of Quebec)
Inactivated, trivalent, high dose
Fluzone High-Dose 0.5 mL single-dose prefilled 0 ‡65 years
(Sanofi Pasteur) syringe, IM
Recombinant, trivalent
FluBlok (Protein Sciences) 0.5 mL, single-dose vial, IM 0 18–49 years
Live attenuated, quadrivalent,
intranasal
FluMist Quadrivalent 0.2 mL intranasal sprayer 0 2–49 yearsb
(MedImmune)
ID¼intradermal; IM¼intramuscular.
a
The Advisory Committee on Immunization Practices recommends that this vaccine not be given to infants and children ages 6 months through 8 years
because of an increased risk of febrile reactions. If no other influenza vaccine is available for children ages 5 to 8 years, the vaccine could be used only after
discussing with parents or caregivers the risks and benefits of vaccination.
b
Healthy, nonpregnant individuals.
Table modified from Centers for Disease Control and Prevention. (23)

immunosuppression need to practice caution to minimize vaccine. Vaccine effectiveness varies significantly among
the spread of attenuated virus. If caring for severely immu- age groups and persons with various medical conditions.
nosuppressed persons who require protective environ- Because of this variability, it is critical that more persons
ment, the caregiver should not receive this vaccine. (23) receive their yearly vaccine. The higher the number of
Injectable IIVs are used in individuals who are not vaccinated individuals, the better protected the at-risk
candidates for LAIV. Health care workers who work community is. This is critical in groups with a large num-
with immunocompromised persons should receive this ber of infants younger than 6 months.

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infectious diseases influenza & parainfluenza

Antibodies against influenza viruses are type specific. retrospective medical record review study of egg-allergic
Eighty percent to 95% of children 6 months or older de- children concluded that patients without a history of ana-
velop protective antibody levels after 2 doses of vaccine. phylaxis to egg can receive the influenza vaccine without
(24) In children ages 6 to 35 months, 50% will develop the need for skin testing. (25) Current recommendations
protective antibody levels, and in those ages 3 to 9 years, of the Centers for Disease Control and Prevention and
75% will develop protective antibody levels. Vaccine effi- the American Academy of Pediatrics recommend the use
cacy varies according to season, patient age, type of vaccine, of the newer recombinant vaccine for individuals ages 18
and study design. Using culture-confirmed studies, vaccine to 49 years with a history of anaphylaxis or hives to egg.
efficacy varies between 56% and 100%. Influenza vaccines (12)(23) For individuals with a history of only hives, vac-
have been found to be immunogenic and safe when given cination with an IIV can be performed safely.
simultaneously with other vaccines. All infants and children For infants and children ages 6 to 36 months, a dose of
younger than 9 years will require 2 doses of vaccine sepa- 0.25 mL of the IIV is administered by the intramuscular
rated by 4 weeks if receiving the vaccine for the first time. route. Past age 3 years, 0.5 mL is administered. The intra-
Most influenza vaccines have been derived from chicken nasal vaccine delivers a dose of 0.1 mL into each nostril.
embryo tissue cultures. In persons with documented aller- Recently, an intradermal vaccine became available, re-
gies to egg, the administration of vaccines may be consid- sulting in a less painful injection. This vaccine was found
ered to be contraindicated. However, recently, cell culture to be more immunogenic than vaccines administered via
and recombinant vaccines have become available, allowing the intramuscular route. There is currently limited expe-
for the vaccination of patients with allergies to eggs. Pa- rience with this vaccine in young children.
tients with a history of anaphylaxis to egg products should Large postlicensure population-based studies have failed
not be vaccinated with chick embryo–derived vaccines (Ta- to demonstrate any increase in clinically important medi-
ble 5). Skin testing by an allergist-immunologist is no lon- cally attended events in the 2 weeks after vaccination. Acute
ger recommended for children with a history of urticaria respiratory infections, acute otitis media, and asthma epi-
after the consumption of egg products. (12)(23) A recent sodes are less common in the weeks after vaccination. Fever,
malaise, pain at the site of injection, myalgias, and head-
aches have been reported after the receipt of influenza vac-
cines. Wheezing and rhinorrhea have been reported after
Influenza Vaccination: Egg
Table 5.
LAIV. Febrile seizures can occur after vaccination. How-
Allergy (12)(23) ever, its risk appears to be related to a specific vaccine pro-
duced by CSL Biotherapies (Afluria). Because of the risk,
Symptom Treatment
this vaccine is not recommended for children younger than
If tolerates lightly cooked Vaccinate with LAIV, TIIV, 9 years. In transplantation patients, vaccination did not alter
eggs (scrambled eggs) or QIIV allograft function or cause rejection episodes. Oculorespi-
without reaction
ratory syndrome, an acute, self-limited reaction to IIVs that
Develops ONLY hives after If 18–21 years: administer
eating eggs or egg- RIV3 OR TIIV or QIIV consists of red eyes, cough, wheeze, chest tightness, diffi-
containing foods (observe for reaction for culty breathing, sore throat, or facial swelling, has been
at least 30 minutes reported 2 to 24 hours after vaccination. It resolves spon-
after vaccination)a taneously within 48 hours. This syndrome may represent
After eating eggs or If 18–21 years: administer
a type of hypersensitivity reaction. Guillain-Barré syndrome
egg-containing foods, RIV3 OR refer to
the child experiences allergist-immunologist has been described after influenza vaccination. The risk is
hypotension, respiratory considered low. After vaccination, 1 additional Guillain-
distress (wheezing or Barré syndrome case per 1 million was observed.
throat swelling), nausea
or vomiting, and
reactions requiring
epinephrine and/or Parainfluenza Virus
medical attention Biology and Epidemiology
PIVs are members of the Paramyxoviridae family. They
LAIV¼live attenuated influenza vaccine (intranasal);
QIIV¼quadrivalent inactivated influenza vaccine; RIV3¼recombinant are RNA viruses with a viral envelope covered with gly-
influenza vaccine, trivalent; TIIV¼trivalent inactivated influenza coproteins, such as hemagglutinins-neuraminidases and
vaccine.
a
RIV3 is licensed for persons ages 18–49 years. fusion proteins, that are responsible for the entry into re-
spiratory epithelial cells, where they replicate exclusively.

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 infectious diseases influenza & parainfluenza

Other members of this family include respiratory syncytial pharyngitis, and low-grade fever are common features of
virus, mumps, measles, and human metapneumovirus. URI caused by PIV. Cervical lymphadenopathy is gener-
There are 4 antigenically distinct types of PIV (PIV-1, ally absent.
-2, -3, and -4). There are also 2 antigenic subtypes In contrast to influenza viruses, in most communities
(PIV-4A and PIV-4B). Most of the disease caused by PIVs circulate all year. Cases of croup observed in the
PIV occurs in children younger than 5 years and is respon- summertime are generally caused by PIVs. The clinical
sible for 6% to 11% of hospitalizations due to respiratory presentation of croup is distinctive. A sudden onset of
infections. (26)(27) Most hospitalizations are in infants a hoarse, barkinglike cough accompanied by laryngeal
younger than 1 year. Parainfluenza viruses are responsible obstruction, dyspnea, and inspiratory stridor is common.
for approximately 4% of all respiratory tract infections. (28) Symptoms usually last 3 to 5 days. The presence of fever
Coinfections with other respiratory viruses are a common and recurrence helps differentiate it from spasmodic
occurrence, with percentages as high as 40%. (29) Coin- croup. In some young children, drooling, difficulty swal-
fected children tend to have a longer duration of symptoms lowing, and decreased appetite can be observed. How-
and prolonged viral shedding. By age 5 years, all children ever, excessive drooling, severe respiratory distress, and
have been infected by all types of PIV. (30)(31) a child sitting quietly and still at the edge of a chair are
PIVs are a frequent cause of childhood disease, such as highly suggestive of epiglottitis, an infection usually asso-
laryngotracheobronchitis (croup) and pneumonia. PIV-1 ciated with Haemophilus influenzae type b, which now is
and -2 are the most common causes of croup, especially rare thanks to routine vaccination. Children with croup
during the fall season, whereas PIV-3 is mostly responsi- generally do not require intubation. Children with croup
ble for lower respiratory tract infections (LRIs), such as caused by influenza virus tend to be more febrile, have
bronchiolitis and pneumonia, occurring mostly in the tenacious thick secretions, and have more severe laryn-
spring and summer months. The epidemiology of PIV- geal obstruction. Subglottic stenosis is a common com-
4 has been less known, but it appears to be responsible plication of croup. Subglottic stenosis may lead to
for URIs and LRIs in infants younger than 6 months. prolonged intubation and/or symptoms of coughing
In a recently published retrospective study, PIV-4 had and respiratory distress. A steeple sign is frequently ob-
a year-round prevalence with clinical features similar to served on an anteroposterior radiograph of the neck
those of PIV-3. (32) No patients with PIV-4 had croup. and chest. The epiglottis appears normal on a lateral neck
PIV infections mostly involve the large airways of the radiograph. PIV-1 is isolated in most children with croup.
lower respiratory tract of children. Tropism for this re- Laryngitis in children is frequently caused by a PIV.
gion is influenced by the large number of ciliated epithe- All types of PIV, but especially PIV-1 and PIV-3,
lial cells in the area. Many of the clinical features of PIV cause bronchiolitis, which is indistinguishable from dis-
infections are indistinguishable from those observed with ease caused by respiratory syncytial virus and human
other viruses, such as influenza virus (Table 1). PIV-1, -2, metapneumovirus. Five percent to 15% of bronchiolitis
and -3 are responsible for most pediatric disease, with cases are caused by PIV. (36)(37) Fever, tachypnea, re-
PIV-3 being responsible for 50% of all PIV infections. tractions, expiratory wheezing, rales, and air trapping
(30)(31) In a study of children in China, PIV-3 was are common features. Approximately 10% of outpatient
the most common PIV isolated (61% of children), fol- LRIs are caused by PIV-1, -2, and -3. Young infants, es-
lowed by PIV-1 (21% of children). PIV-4 was detected pecially those born prematurely, can experience apnea in
in 10% of children with PIV infection. (33) the presence of an LRI. Most hospitalizations will occur
in the first year of life. Conjunctivitis is observed in more
Clinical Aspects than 35% of infected children. The most severe LRI will
The virus is transmitted through exposure to contami- occur in chronically ill or immunocompromised children.
nated nasopharyngeal secretions by droplets or contact Patients with weakened immune systems, such as those
with contaminated surfaces. The usual incubation period with T-cell deficiencies or who have undergone hemato-
is 2 to 4 days, with viral shedding that may last up to 1 poietic stem cell transplantation, are at risk of more severe
week after onset of symptoms. Infected persons may shed disease, such as pneumonia. Pneumonia in this popula-
virus up to 1 week before onset of symptoms. The dura- tion can be life-threatening, with a fatality rate of approx-
tion of shedding may be serotype specific, with PIV-3 imately 30%. (38)(39) Patients undergoing HSCT have
lasting 3 to 4 weeks. Acute otitis media is frequently pre- the highest mortality, especially in the first 100 days of
ceded by infections caused by PIV. PIVs are responsible the transplantation, when lymphopenia is common. Pro-
for 18% to 45% of all URIs. (34)(35) Coryza, rhinorrhea, longed viral shedding is a common feature of children

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infectious diseases influenza & parainfluenza

with primary immunodeficiency. Reinfections are com-

mon but tend to be milder or asymptomatic in the other- Summary
wise immunocompetent host.
• On the basis of strong epidemiologic evidence,
Diagnosis influenza and parainfluenza viruses are responsible for
With the exception of direct fluorescent and PCR as- significant morbidity and mortality in young infants
and children and in persons with chronic medical
says, there are no rapid diagnostic assays, especially conditions. (1)(4)(26)(27)(35)
for point-of-care testing. Diagnosing PIV infection • On the basis of research evidence, influenza vaccines
can be important because it may obviate the use of an- are effective in preventing disease in high-risk
tibacterial therapy. Most laboratories consider nasopha- individuals. (8)(17)(18)
ryngeal aspirates and washes to be the most optimal • On the basis of strong research evidence, influenza
vaccines are safe in young infants and children 6
specimens for the detection of respiratory viruses by re- months or older. (8)(15)
verse-transcription PCR and direct immunofluores- • On the basis of research evidence, the use of
cence. However, nasopharyngeal flocked swabs are corticosteroids and epinephrine is beneficial in the
easier to perform and are better tolerated by patients. treatment of laryngotracheitis caused by
The sensitivity of both methods was excellent (100%) parainfluenza viruses. (44)(45)(46)(47)
• Strong evidence supports the use of influenza vaccines
for respiratory viruses other than adenovirus. (40) in pregnant mothers as a strategy to prevent disease in
PCR-based testing from bronchoalveolar lavage has infants younger than 6 months. (17)(18)(19)
high sensitivity and specificity.

Treatment
There is no available licensed antiviral therapy for the References
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infectious diseases influenza & parainfluenza

PIR Quiz Requirements

To successfully complete 2014 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance
level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. If you score
less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.
NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only at: http://pedsinreview.org.

1. A previously healthy 5-year-old boy has a 3-day history of high temperatures, sore throat, coughing, and malaise.
He is diagnosed as having influenza A. Which of the following statements is correct about his condition?
A. He is likely to benefit from oseltamivir.
B. Oseltamivir is not likely to be beneficial.
C. A prophylactic antibiotic would be beneficial.
D. A chest radiograph is always indicated.
E. Hospitalization is required.

2. Which of the following vaccine strategies would be most protective of an infant boy younger than 6 months?
A. Vaccination of the infant in the first 6 months of life.
B. Vaccination of the teachers of his siblings.
C. Use of oseltamivir chemoprophylaxis during influenza season.
D. Avoidance of state fairs.
E. Vaccination of mother during pregnancy, caregivers, and school-age siblings.

3. A healthy 5-year-old girl gets an upset stomach when she eats eggs. The parents deny hives or respiratory distress.
Which of the following statements would best describe her ability to receive the yearly influenza vaccine?
A. She has a serious egg allergy and should not receive the vaccine.
B. She can receive the live attenuated intranasal vaccine but not the inactivated type.
C. She does not have a significant egg allergy and can receive the vaccine safely.
D. Do not vaccinate. Use chemoprophylaxis instead.
E. Give vaccine preceded by injection of epinephrine.

4. A 2-year-old boy has a croup-like illness. Which of the following statements is FALSE?
A. Parainfluenza types 1 and 2 are common causes of croup.
B. Previously healthy children should receive ribavirin as antiviral therapy.
C. Child may benefit from receiving dexamethasone and epinephrine.
D. Crouplike symptoms accompanied by high temperatures most likely represent an infection by influenza virus.
E. Subglottic stenosis is a known complication.

5. Influenza vaccines are effective in preventing disease in high-risk children. Which of the following statements
is/are CORRECT?
A. Patients with asthma can receive live-attenuated intranasal vaccine.
B. Recombinant influenza vaccine can be administered to a 5-year-old egg-allergic child.
C. Yearly influenza vaccination of household contacts will diminish risk of acquiring infection.
D. Intranasal quadrivalent vaccine is protective against 4 strains of influenza A.
E. B and D

Cystic Fibrosis CME Quiz Correction

In the May 2014 article “Cystic Fibrosis” (Paranjape SM and Mogayzel PJ. Pediatrics in Review. 2014:35(5):194. DOI: 10.1542/
pir.35-5–194), there was an error in Question 2 of the CME quiz. The query sentence before the answer options should read:
“The most likely explanation for the normal newborn screen finding is that: . .” The correct answer option – E – remains
unchanged. The online versions of the article and quiz have been corrected. The journal regrets the error.

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 Influenza and Parainfluenza Viral Infections in Children
Thomas G. Fox and John C. Christenson
Pediatrics in Review 2014;35;217
DOI: 10.1542/pir.35-6-217

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References This article cites 42 articles, 13 of which you can access for free at:
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