eMedicine Specialties > Infectious Diseases > Viral Infections

Influenza

Robert W Derlet, MD, Professor of Emergency Medicine, University of California at Davis School of Medicine; Chief Emeritus, Emergency Department, University of California at Davis Health System
Christian E Sandrock, MD, MPH, FCCP, Assistant Professor of Clinical Medicine, Division of Pulmonary/Critical Care Medicine, Division of Infectious Diseases, Department of Internal Medicine, University of California, Davis Medical Center; Hien H Nguyen, MD, Assistant Clinical Professor, Division of Infectious Diseases and Pulmonary/Critical Care Medicine, University of California at Davis School of Medicine; Medical Director, Acute Infections Management Service, UC Davis Health System; Ruth Lawrence, MD, Chief, Division of Infectious and Immunologic Diseases, Director of Medical Student Education, Department of Internal Medicine, UC Davis Health System

Updated: Aug 12, 2009

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 Medscape’s Influenza Resource Center.

Pathophysiology

Influenza results from infection with 1 of 3 basic types of influenza virus—A, 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 (0-24 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 eMedicine’s Pediatrics: General Medicine volume.

Clinical

History

The presentation of influenza virus infection varies; however, it usually includes many of the symptoms described below. Patients with influenza who have pre-existing 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 100°F range) and others developing fevers as high as 104°F. 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 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, cough-related 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.⁴ 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 100-104°F. 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

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.
• Viral culture
  • 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.
• Direct immunofluorescent tests
  • 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.
• Serologic studies
  • 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%.
• Office tests
  • 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

• Chest radiography: 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

• Arterial blood gas
  • 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.
  • 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 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.
    • 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.
  • Recent 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.⁵ 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.⁶ 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 2.5-day 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.⁷ 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.⁸ 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.
    • 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.

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

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
>40 kg: Administer as in adults
Prophylaxis
>13 years: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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

Adult

5-mg oral inhalation bid for 5 d

Pediatric

<7 years: Not established
>7 years: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; obstructive airway disease

Precautions

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.

Influenza virus vaccine (Fluarix, Fluvirin, Fluzone)

Indicated for active immunization to prevent influenza A and B viruses. Induces antibodies specific to virus strains contained in vaccine following administration. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. Fluzone is approved for children as young as age 6 mo, whereas Fluvirin is approved for children aged 4 years or older.

Dosing

Adult

0.5 mL IM for 1 dose each year prior to flu season

Pediatric

<6 months: Not established
6-35 months (Fluzone): 0.25 mL IM once; administer 2nd dose 4 wk after first dose for vaccine-naïve children
3-8 years: 0.5 mL IM once; administer 2nd dose 4 wk after first dose for vaccine-naïve children
>8 years: 0.5 mL IM for 1 dose each year prior to flu season
Fluviron: <4 years: Not established
Fluarix: <18 years: Not established

Interactions

Immunosuppressive therapy (eg, high-dose corticosteroids, chemotherapy) may reduce antibody response

Contraindications

Documented hypersensitivity to vaccine contents including thimerosal, eggs, egg products, or chicken protein; history of Guillain-Barré syndrome; history of neurologic symptoms following vaccination

Precautions

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

Defer vaccination with acute febrile illnesses or neurological findings until symptoms have abated; may cause soreness at injection site, fever, malaise, and myalgia

Influenza virus vaccine, intranasal (FluMist)

Indicated for active immunization to prevent influenza A and B viruses in healthy children, adolescents, and adults. Induces antibodies specific to virus strains contained in vaccine following administration. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year.

Dosing

Adult

0.2 mL intranasally (ie, 1 mL in each nostril) once per season
>49 years: Not established

Pediatric

<2 years: Not established
2-8 years NOT previously vaccinated with intranasal influenza vaccine: 0.2 mL intranasally (ie, 1 mL in each nostril), then repeat dose in 46-74 d
2-8 years previously vaccinated with intranasal influenza vaccine: 0.2 mL intranasally (ie, 1 mL in each nostril) once per season
>8 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-Barré history; known or suspected immune deficiency conditions, including those secondary to immunosuppressive therapies; asthma or reactive airway diseases

Precautions

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

Precautions

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

• Hospitalization
  • 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/60/2008–like antigens (changed from B/Florida/4/2006–like virus in the 2008-2009 Northern Hemisphere influenza vaccine).⁹
• 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 95°F.
• 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 high-dose 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.¹⁰
• A vaccine designed to be effective against H5N1 is approved.

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.

References

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Keywords

influenza, flu, influenza virus, flu virus, influenzavirus, influenza A, influenza B, influenza C, influenza A subtype H3N2, H1N1, H5N1, H9N2, avian influenza, avian flu, bird flu, upper respiratory tract infection, URTI, severe acute respiratory syndrome, SARS, flu pandemic, Orthomyxoviridae, respiratory syncytial virus, RSV, West Nile virus

Contributor Information and Disclosures

Author

Robert W Derlet, MD, Professor of Emergency Medicine, University of California at Davis School of Medicine; Chief Emeritus, Emergency Department, University of California at Davis Health System
Robert W Derlet, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Association for the Advancement of Science, Infectious Diseases Society of America, Society for Academic Emergency Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Christian E Sandrock, MD, MPH, FCCP, Assistant Professor of Clinical Medicine, Division of Pulmonary/Critical Care Medicine, Division of Infectious Diseases, Department of Internal Medicine, University of California, Davis Medical Center
Christian E Sandrock, MD, MPH, FCCP is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Hien H Nguyen, MD, Assistant Clinical Professor, Division of Infectious Diseases and Pulmonary/Critical Care Medicine, University of California at Davis School of Medicine; Medical Director, Acute Infections Management Service, UC Davis Health System
Hien H Nguyen, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Ruth Lawrence, MD, Chief, Division of Infectious and Immunologic Diseases, Director of Medical Student Education, Department of Internal Medicine, UC Davis Health System
Ruth Lawrence, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Artificial Internal Organs, American Thoracic Society, Physicians for Social Responsibility, and Society of Critical Care Medicine
Disclosure: sepracor Ownership interest None

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: BioMerieux Honoraria Review panel membership; Cubist Honoraria Review panel membership; Pfizer Honoraria Speaking and teaching; Merck Stock dividends stock holdings

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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