Influenza

Introduction
Background
Influenza virus infection, one of the most common infectious diseases, is a highly
contagious airborne disease that causes an acute febrile illness and results in
variable degrees of systemic symptoms, ranging from mild fatigue to respiratory
failure and death. These symptoms contribute to significant loss of workdays,
human suffering, mortality, and significant morbidity. The 1918-1919 H1N1 type
influenza pandemic killed an estimated 20-50 million persons, with 549,000 deaths
in the United States alone.
Accurately diagnosing influenza A or B infection based solely on clinical criteria is
difficult because of the overlapping symptoms caused by the various viruses
associated with upper respiratory tract infection (URTI). In addition, several serious
viruses, including adenoviruses, enteroviruses, and paramyxoviruses, may initially
cause influenzalike symptoms. The early presentation of mild or moderate cases of
flavivirus infections (eg, dengue) may initially mimic influenza. For example, some
cases of West Nile fever acquired in New York in 1999 were clinically misdiagnosed
as influenza.
Patients with influenza frequently present with various symptoms shared by many
other viral infections. In the northern and southern hemispheres, these symptoms
are more common in the winter months. As a result, during the winter, clinics and
emergency department waiting rooms fill with patients who have influenza or other
URTIs.
For supplementary information, see Medscapes Influenza Resource Center.
Pathophysiology
Influenza results from infection with 1 of 3 basic types of influenza virusA, B, or C
which are classified within the family Orthomyxoviridae. These single-stranded
RNA viruses are structurally and biologically similar but vary antigenically.
The RNA core consists of 8 gene segments surrounded by a coat of 10 (influenza A)
or 11 (influenza B) proteins. Immunologically, the most significant surface proteins
include hemagglutinin and neuraminidase. The viruses are typed based on these
proteins. For example, influenza A subtype H3N2 expresses hemagglutinin 3 and
neuraminidase 2.
The most common prevailing influenza A subtypes that infect humans are H1N1 and
H3N2. Each year, the trivalent vaccine used worldwide contains A strains from H1N1
and H3N2, along with an influenza B strain.
Influenza virus infection occurs after transfer of respiratory secretions from an
infected individual to a person who is immunologically susceptible. If not neutralized

by secretory antibodies, the virus invades airway and respiratory tract cells. Once
within host cells, cellular dysfunction and degeneration occur, along with viral
replication and release of viral progeny. Systemic symptoms result from
inflammatory mediators, similar to other viruses. The incubation period of influenza
ranges from 18-72 hours.
Influenza A is generally more pathogenic than influenza B. Influenza A is a zoonotic
infection, and more than 100 types of influenza A infect most species of birds, pigs,
horses, dogs and seals. Indeed, the 1918 pandemic that resulted in millions of
human deaths worldwide is believed to have originated from a virulent strain of
H1N1 from pigs or birds. Recently, scientists obtained and sequenced the 1918
H1N1 strain from a frozen corpse found in Alaska. The virus was reconstructed at
the Centers for Disease Control and Prevention (CDC) laboratory in Atlanta and was
found to be highly lethal when tested in mice; the virus was also found to be lethal
to chicken embryos. This unique N1 neuraminidase is being studied in order to
provide better insight into the N1 found in H5N1, the type responsible for avian
influenza (also known as bird flu).
H5N1 bird flu
In 1997, an avian subtype of influenza A, H5N1, was first described in Hong Kong.
Infection was confirmed in only 18 individuals, but 6 died. Since then, sporadic
cases of H5N1 infection have continued to be described in southern China. In
January 2004, an epidemic occurred among domesticated birds in Southeast Asia,
initially in Vietnam. In nearly all cases of H5N1 bird flu in humans, the virus is
transmitted from birds. As of fall 2008, more than 390 human cases had been
documented and more than 246 persons had died following H5N1 outbreaks among
poultry and resulting bird-to-human transmission. Most human deaths due to bird
flu have occurred in Indonesia. Sporadic outbreaks among humans have continued
elsewhere, including China, Egypt, Thailand, and Cambodia.
Experts are concerned that a slight mutation could convert H5N1 to a strain that
would be easily transferred from human to human. Such a strain has the potential
to spread rapidly and precipitate a catastrophic worldwide pandemic. Because of
this concern, efforts to develop an effective vaccine are currently underway. In
addition, studies to expand the number of drugs that are effective against influenza
are underway. Ribavirin has shown activity in animal models.
Other types of avian influenza
In March 1999, infection with another avian influenza subtype, H9N2, was described
in 2 young children. Despite concern, no additional cases of H9N2 infection were
reported. As with the H5N1 influenza, experts are concerned that a virulent strain of
H9N2 influenza may mutate to allow human-to-human infection and that such a
strain may possess the triad of infectivity, lethality, and transmissibility.
H1N1 influenza (formerly called swine flu)

On April 26, 2009, the US Department of Health and Human Services issued a
nationwide public health emergency regarding swine influenza A (H1N1) virus
infections in humans.1 Over the preceding several weeks, an outbreak of a new
strain of influenza virus, which contains a combination of swine, avian, and human
influenza virus genes, had been reported in Mexico and in the United States.
As of early June 2009, H1N1 influenza had infected 28,774 people in 74 countries,
and 144 deaths were confirmed to have been caused by the disease. On June 11,
2009, the World Health Organization (WHO) raised the pandemic alert level to phase
6 (indicating a global pandemic) because of widespread infection beyond North
America to Australia, the United Kingdom, Chile, Spain, and Japan. 2 For an updated
tally of affected countries and counts, see WHO's Influenza A (H1N1) Web page.
Upon suspicion of H1N1 flu, clinicians should obtain a respiratory swab for H1N1
influenza testing and place it in a refrigerator (not a freezer). Once collected, the
clinician should contact the state or local health department to facilitate transport
and timely diagnosis at a state public health laboratory. 3
The new virus is resistant to the antiviral agents amantadine and rimantadine but
sensitive to oseltamivir (Tamiflu) and zanamivir (Relenza). Initiation of antiviral
agents within 48 hours of symptom onset is imperative to provide treatment
efficacy against influenza virus. The usual vaccine for influenza administered at the
beginning of the flu season is not effective for this viral strain.
Initial symptoms of H1N1 influenza include high fever, myalgias, rhinorrhea, and
sore throat. Nausea, diarrhea, and vomiting have also been reported. Infection
control precautions (ie, handwashing, covering mouth with tissue when sneezing or
coughing) are encouraged. If suspected H1N1 flu occurs, isolation is recommended
for infected individuals and household contacts. For more information, see updated
information from the US Centers for Disease Control and Prevention.
Viral shedding
Viral shedding occurs at the onset of symptoms or just before the onset of illness (024 h). Shedding continues for 5-10 days. Young children may shed virus longer,
placing others at risk for contracting infection with the virus.
Frequency
United States
Influenza epidemics typically occur in winter months and vary in severity and attack
rates depending on the virus subtype involved. Millions of people may develop
infection during a given year. The pandemics of 1918-1919 and 1957, which
resulted in higher infection rates and profound morbidity and mortality rates,
demonstrate the impact of the disease.
In the United States, significant influenza activity occurred during the winter of
1999-2000 and 2003-2004. Influenza A/Fujian/411/2002 (H3N2) was the major strain

involved in 2003-2004. During the 2000-2003 and 2004-2005 seasons, influenza

activity was relatively low in the United States. However, the activity increased
during the 2007-2008 season to the highest levels in years.
International
In tropical areas, influenza occurs throughout the year.
Mortality/Morbidity
The CDC estimates that influenza is responsible for an average of more than 20,000
deaths annually.
Sex
Women in the third trimester of pregnancy are at higher risk for complications of
influenza A and B.
Age
Elderly people are at higher risk for complications of influenza A and B.
For more information on pediatric influenza, see the Influenza article in eMedicines
Pediatrics: General Medicine volume.
Immunosuppressed patients
Since an antibody response is not available for newly infected individuals, a T-cell
mediated cellular response may be required to limit disease severity. T-cell
impairment may result in severe disease in patients with pandemic H1N1. 4,5
Clinical
History
The presentation of influenza virus infection varies; however, it usually includes
many of the symptoms described below. Patients with influenza who have preexisting immunity or who have received vaccine may have milder symptoms.
Abrupt onset of illness is common. Many patients with influenza are able to report
the time when the illness began.
Fever may vary widely among patients, with some having low fevers (in the 100F
range) and others developing fevers as high as 104F. Some patients report feeling
feverish and a feeling of chilliness.
Sore throat may be severe and may last 3-5 days. The sore throat may be a
significant reason why patients seek medical attention.

Myalgias are common and range from mild to severe.

Frontal/retro-orbital headache is common and is usually severe. Ocular symptoms
develop in some patients with influenza and include photophobia, burning
sensations, and/or pain upon motion.
Some patients with influenza develop rhinitis of varying severity, but it is generally
not the chief symptom.
Weakness and severe fatigue may prevent patients from performing their normal
activities or work. In some cases, patients with influenza may find activity difficult
and may require bedrest.
Cough and other respiratory symptoms may be initially minimal but frequently
progress as the infection evolves. Patients may report nonproductive cough, coughrelated pleuritic chest pain, and dyspnea. In children, diarrhea may be a feature.
Acute encephalopathy has recently been associated with influenza A virus. In a case
series of 21 patients, Steininger et al described clinical, CSF, MRI, and EEG findings. 6
Clinical features included altered mental status, coma, seizures, and ataxia. Of
those who underwent further testing, most had abnormal CSF, MRI, and EEG
findings.
Physical
The general appearance varies among patients who present with influenza. Some
patients may appear acutely ill, with some weakness and respiratory findings, while
others may appear only mildly ill. Upon examination, patients may have some or all
of the following findings:

Fever may range from 100-104F. The fever in elderly patients is not
generally as severe as that in young adults.
Tachycardia most likely results from hypoxia, fever, or both.

Pharyngitis may be present. Even in patients who report a severely sore

throat, findings vary from minimal infection to more severe inflammation.

Eyes may be red and watery.

Nasal discharge is absent in most patients.

Skin may be warm-to-hot, as reflected by the temperature status. Patients

who have been febrile with poor fluid intake may show signs of mild volume
depletion with dry skin.

Pulmonary findings during the physical examination may include dry cough
with clear lungs or rhonchi.

Differential Diagnoses
AdenovirusesJapanese Encephalitis

Arenaviruses Parainfluenza Virus

Cytomegalov Rhinoviruses
irus
Echoviruses Severe Acute Respiratory
Syndrome (SARS)
Other Problems to Be Considered
Acute HIV infection
Hanta pulmonary syndrome (HPS)
Workup
Laboratory Studies
Findings of standard laboratory studies such as a CBC count and electrolytes
assessment are nonspecific but helpful in the workup of influenza.
Leukopenia and relative lymphopenia are typical findings in influenza.
Thrombocytopenia may be present.
The criterion standard for diagnosing influenza A and B is a viral culture of
nasopharyngeal samples and/or throat samples. Obtain samples with Dacron swabs
and send the samples in appropriate viral transport media (eg, multimicrobe [M4]
transport media) to the laboratory to be cultured in several lines of cells. A
laboratory diagnosis of influenza is established once specific cytopathic effect is
observed or hemadsorption testing findings are positive. Staining the infected
cultured cell lines with fluorescent antibody confirms the diagnosis. The process
may require 3-7 days, long after the patient has left the clinic, office, or emergency
department and well past the time when drug therapy could be efficacious.
Some laboratories offer direct immunofluorescent tests on fresh specimens, but
these tests are labor-intensive and are less sensitive than culture methods. These
tests require specially trained laboratory personnel (people generally not available
during all shifts, even in large medical centers) for interpretation.
In order to overcome the expensive and time-consuming obstacle of culturing,
several serologic tests have become available. In reality, many of these are not
bedside tests; generally, 30-60 minutes are required to perform the test's multiple
steps. Some rapid tests are performed best in a laboratory, not in the office or
emergency department. Disadvantages to performing these rapid diagnostic tests
include the cost of the laboratory personnel, the cost of the test itself, and potential
false-negative results for influenza A and B. Test sensitivities generally range from
60-70%.

Recently, the US Food and Drug Administration waived federal Clinical Laboratories
Improvement Act (CLIA) requirements and approved 3 office tests for diagnosis. Of
these, the fastest is the 10-minute QuickVue bedside test, which yields a sensitivity
of 70-80%. Because of cost, availability, and sensitivity issues, most physicians
diagnose influenza based on clinical criteria alone.
Imaging Studies
In elderly or high-risk patients with pulmonary symptoms, perform chest
radiography to exclude pneumonia. Early radiographic findings include no or
minimal bilateral symmetrical interstitial infiltrates. Later, bilateral symmetrical
patch infiltrates become visible. Focal infiltrates indicate superimposed bacterial
pneumonia.
Other Tests
Severe hypoxemia is present in severe cases of influenza. The A-a gradient may be
increased (>35 mm Hg).
Procedures
Patients with physical examination findings compatible with meningitis should
undergo lumbar puncture.
Treatment
Medical Care
As with other diseases, prevention of influenza is the most effective strategy.
Enhanced surveillance with daily temperature taking and prompt reporting with
isolation through
home medical leave and segregation of smaller subgroups decrease the spread of
influenza. In one study, symptomatic illness attributable to influenza decreased
from 12% to about 4%.7
The CDC has published recommendations for high-risk groups, including all health
care personnel, who should be vaccinated.
Amantadine and rimantadine have been approved for many years for use against
influenza A. However, since the fall of 2005 to the present, amantadine and
rimantadine are no longer recommended by the CDC because significant resistance
has evolved against these two drugs.
Oseltamivir (Tamiflu) resistance has emerged in the United States during the 20082009 influenza season.
The CDC has issued revised interim recommendations for antiviral treatment and

prophylaxis of influenza. Preliminary data from a limited number of states indicate a

high prevalence of influenza A (H1N1) virus strains resistant to oseltamivir (Tamiflu).
Because of this, zanamivir (Relenza) is recommended as the initial choice for
antiviral prophylaxis or treatment when influenza A infection or exposure is
suspected. A second-line alternative is a combination of oseltamivir plus
rimantadine rather than oseltamivir alone. Local influenza surveillance data and
laboratory testing can assist the physician regarding antiviral agent choice.
Influenza A viruses, including two subtypes (H1N1) and (H3N2), and influenza B
viruses currently circulate worldwide, but the prevalence of each can vary among
communities and within a single community over the course of an influenza season.
In the United States, 4 prescription antiviral medications (oseltamivir, zanamivir,
amantadine, rimantadine) are approved for treatment and chemoprophylaxis of
influenza. Since January 2006, the neuraminidase inhibitors (oseltamivir, zanamivir)
have been the only recommended influenza antiviral drugs because of widespread
resistance to the adamantanes (amantadine, rimantadine) among influenza A
(H3N2) virus strains. The neuraminidase inhibitors have activity against influenza A
and B viruses, while the adamantanes have activity against only influenza A viruses.
In 2007-2008, a significant increase in the prevalence of oseltamivir resistance was
reported among influenza A (H1N1) viruses worldwide. During the 2007-2008
influenza season, 10.9% of H1N1 viruses tested in the United States were resistant
to oseltamivir. Complete recommendations are available from the CDC.
Many physicians in primary care offices or the ED have not used these medications
widely.
Disadvantages of these drugs include lack of efficacy against influenza B, potential
adverse effects, and rapid development of viral resistance.
Two newer drugs have been recently marketed for treatment of influenza A and B.
These are the neuraminidase inhibitors oseltamivir and zanamivir.
Oseltamivir is taken orally (75 mg bid), and zanamivir is taken via an inhalation
apparatus (10 mg bid for 5 d).
Multiple studies have demonstrated their efficacy. These agents work by inhibiting
influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus
envelope; this spike is needed for successful cellular release of virus and
transmission within the body. To be effective, these new agents must be
administered within 40 hours of symptom onset.
For critically ill patients, evidence suggests that initiation of oseltamivir up to 6-8
days from onset of symptoms may reduce the mortality rate. 9
Studies also demonstrate the efficacy of these agents in preventing influenza A and
B, an exciting expansion in their use. The prophylactic dose is one half the acute
treatment dose.

Neuraminidase inhibitors have several advantages over amantadine, including less

evolution of resistance, efficacy against influenza B, fewer adverse effects, and
dramatic reduction in symptoms, even in patients who have a full course of
influenza.
In a study of 445 patients by the Management of Influenza in the Southern
Hemisphere Trialists (MIST) group 1, zanamivir was administered to one half of
patients and placebo to the others within 36 hours of symptom onset. Duration of
the flu was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk
groups. A significant decrease in the severity of illness in patients treated with
zanamivir allowed them to resume normal activities much sooner.
A study by Treanor et al compared oseltamivir with placebo. 10 This analysis included
patients with laboratory-based diagnoses of influenza and those with clinical
diagnosis based on symptoms. The 629 patients were enrolled and randomized into
1 of 3 treatment arms: (1) standard-dose oseltamivir, (2) high-dose oseltamivir, and
(3) placebo. In both oseltamivir groups, the mean illness duration was reduced from
103 to 70 hours. The symptom severity decreased in the treated group by 40%.
Additional studies analyzed the effect of neuraminidase inhibitors both in acute
disease and in prevention.
In one of these studies, 837 relatives of family members infected with influenza
were treated prophylactically with either placebo or zanamivir. 11 While 20% of the
placebo group became ill, only 4% of the drug-treated group became ill. In addition,
this study provided treatment to the index case family member, resulting in a 2.5day reduction in illness over placebo. Recombinant DNA viral sequences were
performed in this study, and no resistant influenza strains developed.
A novel study analyzed the effects of oseltamivir in experimentally induced
influenza in humans.12 In a controlled laboratory environment, volunteers were
inoculated intranasally with influenza A/Texas/36/91 (H1N1). One group was
administered oseltamivir 26 hours before virus inoculation and another group was
administered 28 hours after inoculation. In the prophylactic group, 38% of patients
developed influenza, which 67% in the placebo group developed influenza. In the
posttreatment group, the duration of illness was reduced from 95 to 53 hours and
the severity was reduced by 50% compared with placebo.
Another study by Hayden et al analyzed 1559 healthy nonimmunized patients who
were treated with either placebo or oseltamivir for 6 weeks. 13 At the end of the
period, 4.8% of the placebo group had laboratory-confirmed influenza, compared
with only 1.2% of the oseltamivir group.
In a randomized, double-blind, placebo-controlled trial of children aged 1-3 years
(n=408), Heinonen et al found that oseltamivir decreased the incidence of acute
otitis media by 85% (95% confidence interval, 25-97%) when treatment began
within 12 hours of symptom onset. When treatment began within 24 hours of
symptom onset, no significant reduction in incidence of acute otitis media was
observed. When oseltamivir treatment started within 24 hours for children with
influenza A, the median time to resolution of illness was decreased by 3.5 days (3.0

vs 6.5 d; P = 002) in all children and reduced parental work absenteeism by 3.0
days. Efficacy was not demonstrated against influenza B infections. 14
Ongoing studies are analyzing both treatment efficacy and the preventive effects of
neuraminidase inhibitors.
Whether to prescribe one of the newer neuraminidase inhibitors should depend on
the patient, the probable type of influenza involved (A or B), and the potential
benefit.
Advantages for prescribing these agents include significantly reducing illness
severity and duration. In elderly and high-risk patients who receive these agents,
the secondary complications of influenza are also decreased.
Disadvantages include potential adverse effects and costs. Some patients may be
willing to pay $100 to have a less severe episode of the flu. Adverse effects include
potential bronchospasm with inhaled zanamivir and nausea, vomiting, and
headache from oseltamivir. The bronchospasm associated with zanamivir has
received attention from national media. Until more data are available, physicians
should not prescribe zanamivir to patients prone to bronchospasm.
Although oseltamivir is approved for use up to 48 hours after the initiation of
symptoms, one study suggested that the most significant effect occurs when taken
within 6 hours of symptom onset and only limited effects when therapy is begun
more than 24 hours after symptom onset.
Ongoing clinical trials
The median time to illness alleviation in the 40-mg laninamivir octanoate is similar
to oseltamivir, as shown in a double-blind, randomized controlled trial. A single
inhalation of laninamivir octanoate is effective for the treatment of seasonal
influenza, including that caused by oseltamivir-resistant virus, in adults. 8
Consultations
Consultation with an infectious disease specialist is prudent in some cases.
Activity
Patients with influenza generally benefit from bedrest. Most patients with influenza
recover in 3 days; however, malaise may be present for weeks.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent
complications.

Antiviral agents
Drugs indicated for treatment of influenza include neuraminidase inhibitors (ie,
oseltamivir and zanamivir) and amantadine and rimantadine.
Oseltamivir (Tamiflu)
Inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that
destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral
neuraminidase, decreases release of viruses from infected cells and thus, viral
spread. Effective to treat influenza A or B. Must administer within 48 h of symptom
onset. The best effect occurs the sooner it is taken after symptom onset. Reduces
the length of illness by an average of 1.5 d. (In a subgroup of high-risk patients,
illness was reduced by 2.5 d.) In addition, the severity of symptoms is also reduced.
Oseltamivir (Tamiflu) resistance has emerged in the United States during
the 2008-2009 influenza season. The CDC has issued revised interim
recommendations for antiviral treatment and prophylaxis of influenza. Preliminary
data from a limited number of states indicate a high prevalence of influenza A
(H1N1) virus strains resistant to oseltamivir (Tamiflu). Because of this, zanamivir
(Relenza) is recommended as the initial choice for antiviral prophylaxis or treatment
when influenza A infection or exposure is suspected. A second-line alternative is a
combination of oseltamivir plus rimantadine rather than oseltamivir alone. Local
influenza surveillance data and laboratory testing can assist the physician regarding
antiviral agent choice.
Dosing
Adult

Interaction
None reported

Contraindications
Documented

hypersensitivity
Acute illness: 75 mg PO bid for 5 d
Prophylaxis: 75 mg PO qd
Pediatric
Acute illness
>1 year and <15 kg: 30 mg PO bid
15-23 kg: 45 mg PO bid
23-40 kg: 60 mg PO bid
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in
humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal impairment, chronic cardiac or respiratory disease, and
breastfeeding

Zanamivir (Relenza)
Inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza
virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting
viral neuraminidase, release of viruses from infected cells and viral spread are
decreased. Effective against both influenza A and B.
To be inhaled through Diskhaler oral inhalation device. Circular foil discs that contain
5-mg blisters of drug are inserted into supplied inhalation device.
Dosing
Contraindications
Adult

Interactions
None reported

Documented

hypersensitivity,
obstructive airway disease
5-mg oral inhalation bid for 5 d
Pediatric
<7 years: Not established
>7 years: Administer as in adults
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some
studies in animals
Precautions
Monitor respiratory status; caution in breastfeeding
Vaccine
Influenza A vaccine is administered each year prior to flu season. The CDC analyzes
the vaccine subtypes each year and makes any necessary changes based on
worldwide trends.
In April 2007, the US Food and Drug Administration (FDA) approved the first vaccine
for H5N1 influenza (ie, avian influenza or bird flu). The approval was based on one
multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study in
healthy adults aged 18-64 years. The trial investigated the safety and
immunogenicity of the vaccine. A total of 103 healthy adults received a 90-mcg
dose of the vaccine via IM injection, followed by another 90-mcg dose 28 days later.
In addition, approximately another 300 healthy adults received the vaccine at doses
lower than 90 mcg, and a total of 48 received placebo by injection. Of the various
doses tested, the study showed that the 90-mcg 2-dose regimen provided the better
immune response and produced levels of antibodies expected to reduce the risk of
acquiring H5N1 influenza in 45% of those who received it.

Dosing
Adult
0.5 mL IM for 1 dose each year prior to flu season
Pediatric
<6 months: Not established
Fluzone:
6-35 months: 0.25 mL IM once; administer 2nd dose 4 wk after first dose for
vaccine-nave children
3-9 years: 0.5 mL IM (deltoid) once; administer 2nd dose 4 wk after first dose for
vaccine-nave children
>9 years: 0.5 mL IM for 1 dose each year prior to flu season
Fluviron:
<4 years: Not established
4-9 years: 0.5 mL IM (deltoid) once; administer 2nd dose 4 wk after first dose for
vaccine-nave children
>9 years: Administer as in adults
Fluarix:
<3 years: Not established
3-9 years: 0.5 mL IM (deltoid) once; administer 2nd dose 4 wk after first dose for
vaccine-nave children
>9 years: Administer as in adults
Interactions
Do not administer to children or adolescents receiving aspirin (may increase Reye
Syndrome); do not administer until 48 h following discontinuing antiviral agents,
and do not initiate antiviral agents for 2 wk following vaccine administration; no
data regarding coadministration with other intranasal drugs
Contraindications
Documented hypersensitivity to vaccine contents, including egg or egg protein;
children or adolescents receiving aspirin therapy; Guillain-Barr history; known or
suspected immune deficiency conditions, including those secondary to
immunosuppressive therapies; asthma or reactive airway diseases
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in
humans; may use if benefits outweigh risk to fetus

Precautions
For nasal use only; thaw prior to use; may increase cough, rhinorrhea, and nasal
congestion following second dose in children; may cause cough, runny nose, or sore
throat in adults
Influenza virus vaccine, H5N1
Inactivated virus vaccine. Induces antibodies against viral hemagglutinin in vaccine,
thereby blocking viral attachment to human respiratory tract epithelial cells.
Estimated to reduce risk of contracting avian influenza by 45%. Indicated for active
immunization of adults at increased risk of exposure to H5N1 influenza virus
subtype.
Dosing
Adult
18-64 years: Administered as 2-dose regimen; 1 mL (90 mcg) IM on day 1, then
repeat dose once on day 28
Pediatric
<18 years: Not established
>18 years: Administer as in adults
Interactions
Immunosuppressive therapies (eg, high-dose corticosteroids, transplant
antirejection medication, antineoplastic agents) may reduce immune response to
vaccine
Contraindications
None known
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in
humans; may use if benefits outweigh risk to fetus
Precautions
Data limited; common adverse effects include pain and tenderness at injection site,
headache, malaise, and myalgia; do not mix with other vaccines in same syringe;
avoid in pregnant or breastfeeding women because of insufficient data in these
populations

Follow-up
Further Inpatient Care
Most frequently, hospitalization is necessary when influenza exacerbates underlying
chronic diseases. Some patients, especially elderly individuals, may be too weak to
care for themselves alone at home.
On occasion, the direct pathologic effects of influenza may require hospitalization.
Most commonly, this is influenza pneumonia.
Further Outpatient Care
Patients with influenza who do not improve should return for further evaluation.
Patients diagnosed with influenza should be educated about potential complications
and encouraged to return for evaluation if concerned. This is especially true of
patients with underlying chronic disease or those who are immunocompromised.
Deterrence/Prevention
Influenza vaccine provides good protection against immunized strains. The
vaccination becomes effective 10-14 days after administration.
Each year in the United States, a vaccine that contains antigens from the strains
most likely to cause infection during the winter flu season is produced. As an
historic example, during 2001-2003, 2 strains of influenza A virus
(A/Panama/2007/99 [H3N2] and A/New Caledonia/20/99 [H1N1]) and 1 strain of
influenza B (B/Hong Kong 330/01) comprised the vaccine. For the 2009-2010
season, the trivalent vaccine contains the following antigenic strains:
A/Brisbane/59/2007 (H1N1)like virus, A/Brisbane/10/2007 (H3N2)like virus, and
B/Brisbane/60/2008like antigens (changed from B/Florida/4/2006like virus in the
2008-2009 Northern Hemisphere influenza vaccine). 15
Influenza vaccine is also available as a nasal spray (FluMist) for healthy children
aged 5 years or older, adolescents, and adults aged younger than 50 years. Clinical
trials are limited in scope regarding the protective effects of live vaccine. The live
virus is attenuated by cold; therefore, only very limited viral replication occurs at
temperatures of more than 95F.
Specific recommendations for individuals who should be immunized can be obtained
from the CDC (see Prevention and Control of Influenza). People recommended for
immunization include elderly individuals, those with certain chronic diseases, and
health care workers.
In order to improve the immunogenicity of influenza virus vaccine in elderly adults,
a high-dose trivalent inactivated influenza vaccine has been developed. In a
multicenter, randomized, double-blind controlled trial, seroconversion of the highdose vaccine was compared with seroconversion of the standard-dose vaccine in
elderly adults (65 y). A statistically significant increase in seroconversion rate was

found in those who received the high-dose vaccine (n=2575) compared with the
standard-dose vaccine (n=1262). The high-dose vaccine met superiority criteria for
both strains of influenza A, and noninferiority criteria were met for influenza B
strains. Seroprotection rates were higher for the high-dose vaccine compared with
the standard-dose vaccine. The authors suggest that the high-dose vaccine may
provide improved immunity for elderly adults.16
Dual vaccination with pneumococcal and influenza vaccine is effective in protecting
elderly persons with chronic illness from developing complications due to
respiratory, cardiovascular, and cerebrovascular diseases, thereby reducing
hospitalization, coronary or intensive care admissions, and death. 17
A vaccine designed to be effective against H5N1 is approved.
Woods et al found that, in sedentary older adults, cardiovascular exercise extends
influenza vaccine seroprotection. A randomized controlled trial in 144 sedentary but
healthy older (age 69.9 +/- 0.4 y) adults who underwent either cardiovascular
exercise or flexibility and balance training showed that peak (3 and 6 weeks)
postvaccine anti-influenza hemagglutination inhibition (HI) titers were similar in
both groups, but participants randomized to cardiovascular exercise were
significantly more likely to have seroprotective HI titers at 24 weeks, suggesting
enhanced influenza seroprotection throughout the entire influenza season. 18
Complications
Primary influenza pneumonia is characterized by progressive cough, dyspnea, and
cyanosis following the initial presentation on the infection. Chest radiographs show
diffuse infiltrative patterns bilaterally, without consolidation, which can progress to a
presentation similar to acute respiratory distress syndrome. Risks for viral
pneumonia involve numerous complex host immune responses and viral virulence.
Although elderly individuals, especially nursing home patients, and those with
cardiovascular disease constitute the highest risk groups, do not forget that, in the
1918-1919 epidemic, many young adults died of a pneumonia that some experts
believe was caused directly by the virus.
Secondary bacterial pneumonia can occur from numerous bacteria (eg,
Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae ).
The most dreaded complication is staphylococcal pneumonia, which develops 2-3
days following the initial presentation of viral pneumonia. Patients appear severely
ill, with hypoxemia, an elevated WBC count, productive bloody cough, and a chest
radiograph showing multiple cavitary infiltrates. Methicillin-susceptible S aureus
( MSSA) and methicillin-resistant S aureus (MRSA) pneumonias have occurred
following influenza pneumonia. MRSA pneumonia may be severe and difficult to
treat, and deaths have occurred within 24 hours of presentation of pneumonia
symptoms.
S pneumoniae or H influenzae pneumonia, if occurring as a complication, usually
develops 2-3 weeks after the initial symptoms of influenza and can be managed as

a community-acquired pneumonia, following standard antibiotic and

admission/discharge guidelines. Myositis is a rare complication. This group of
patients may develop frank rhabdomyolysis, with elevated creatine kinase levels
and myoglobinuria.
Myocarditis and pericarditis have been associated with influenza infections.
Prognosis
In patients without comorbid disease, the prognosis is very good, although some
patients have a prolonged recovery time and remain weak and fatigued for weeks.
Patient Education
For excellent patient education resources, visit eMedicine's Cold and Flu Center.
Also, see eMedicine's patient education article Flu in Adults.
Miscellaneous
Medicolegal Pitfalls
Early presentations of more serious infections may initially be misdiagnosed as
influenza.
Physicians who diagnose influenza in residents of nursing homes should notify the
nursing home medical director so that preventive measures can be taken to protect
other residents.
Postinfluenza pneumonia is a serious complication and needs to be treated
aggressively.