INFLUENZA

INFLUENZA

Current diagnosis

• Influenza should be considered in any patient with respiratory symptoms between October and May in North America.

• The single most important piece of information when considering a diagnosis of influenza is the community prevalence of influenza.

• During outbreaks, sudden onset of fever and cough has a positive predictive value of about 85%.

• Rapid testing should be used when the community prevalence of influenza among patients with influenza-like illness is between 10% and 30%.

Current therapy

• The influenza vaccine is the best means of preventing influenza. The inactivated influenza vaccine is recommended for all persons age 6 months and older.

• The antivirals zanamivir (Relenza) and oseltamivir (Tamiflu) can be used for prophylaxis of influenza in unimmunized patients, in close contacts of infected patients, and during institutional outbreaks of influenza.

• Early antiviral treatment should be used for patients who are hospitalized; have severe, complicated, or progressive illness; or are at higher risk for complications.

• Antivirals may be prescribed within 48 hours of symptom onset for outpatients not at higher risk for influenza complications.

Influenza is a highly contagious viral infection that should be considered in any patient with respiratory symptoms between October and May in North America. Influenza infects 5% to 20% of the population of the United States in a typical year, and is responsible for up to 431,000 hospitalizations and 51,000 deaths per year. Influenza can range in severity from mild illness to life-threatening disease.

Those at highest risk of hospitalization, death, or complications from influenza are children younger than 5 years, adults older than 65 years, people of any age who have underlying medical conditions, those infected with HIV, and pregnant women.

Information about influenza changes rapidly. To care optimally for patients with influenza-like illness during the influenza season, clinicians need to keep abreast of updated recommendations and the current prevalence of influenza in their community. The influenza vaccine remains the best means of reducing the incidence, severity, and complications from influenza, but antiviral medications and symptomatic treatments have an important role in the prevention and treatment of influenza (Box 1).

Box 1
Influenza Vaccine Recommendations
• All persons aged ≥ 6 months should be vaccinated annually

• Vaccination efforts should prioritize people at higher risk of influenza complications:

•   6 months to 5 years old, especially 6 months to 2 years old

•   ≥ 50 years old, especially ≥ 65 years old

•   Chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, neurodevelopmental, hematologic, or metabolic (including diabetes mellitus) disorders

•   Immunosuppressed

•   Pregnant during the influenza season

•   6 months to 18 years old receiving long-term aspirin therapy and who therefore might be at risk for Reye syndrome

•   Residents of nursing homes and other chronic-care facilities

•   American Indians/Alaska Natives

•   Morbidly obese (body mass index ≥ 40)

• Vaccination efforts should also prioritize those likely to transmit influenza to higher risk people:

•   Health care personnel

•   Household contacts and caregivers of children aged < 5 years and adults aged ≥ 50 years, with particular emphasis on vaccinating contacts of children aged < 6 months

•   Household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza

Microbiology

There are two types of influenza viruses, A and B. Influenza A is separated into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N). The predominant circulating strains of influenza in recent decades have been influenza A (H1N1), influenza A (H3N2), and influenza B. Influenza A (H3N2) subtypes generally cause more severe influenza and are associated with higher mortality than other types. Influenza viruses undergo slight genetic changes from year to year, termed antigenic drift. Major changes in surface glycoproteins are termed antigenic shift and can result in severe pandemic influenza in a nonimmune population, which happened with an antigenically novel influenza A (H1N1) virus in 2009. Because of antigenic drift, and because immunity to a given type or subtype of influenza provides limited cross-immunity to other types and subtypes, the influenza vaccine needs to be reformulated and administered most years.

Patients contract influenza by being exposed to large-sized respiratory droplets from an infected person or contact with surfaces harboring influenza virus. Influenza has a latency of 1 to 4 days before the onset of symptoms. Adults are infectious from the day before symptom onset through about day 7 of illness, but immunosuppressed adults and children shed the virus for longer periods. Symptoms generally last from 7 to 14 days.

Several novel, highly-pathogenic respiratory viruses—avian influenza A (H5N1), avian influenza A (H7N9), and Middle East Respiratory Syndrome Coronavirus (MERS-CoV)—have mortality rates ranging from 30% to 60%. Collectively there have been more than 2200 cases. These pathogens, if they acquire the ability to be highly transmissible between humans, have the potential to cause pandemic respiratory disease.

Prevention

Influenza vaccination is between 20% and 90% effective in preventing influenza or complications of influenza. Influenza vaccination is highly cost-effective and can even be cost-saving in high-risk groups. Influenza vaccination is less effective in younger children, in adults older than 65 years, in adults with comorbid conditions, and when there is a poor match between the influenza vaccine and circulating influenza. The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) puts out annual recommendations and supplementary updates on the prevention and treatment of influenza (www.cdc.gov/flu). Beginning in the 2010 to 2011 influenza season, the ACIP recommended vaccinating all persons 6 months old and older.

At present there are three commonly-administered types of influenza vaccine: trivalent inactivated influenza vaccine (IIV3), quadrivalent inactivated influenza vaccine (IIV4), and quadrivalent live attenuated influenza vaccine (LAIV4).

The IIV4 (Fluarix Quadrivalent, FluLaval Quadrivalent, Fluzone Quadrivalent) and IIV3 (Afluria, Fluarix, Flucelvax, FluLaval, Fluvirin, Fluzone) are administered as an intramuscular injection. Different products are approved for administration in different lower age limits. In particular, Afluria should not be administered to children younger than 9 years old because of an increased risk of febrile seizures. A high-dose IIV3 (Fluzone High-Dose) is available for patients aged 65 years and older, who are less likely to respond immunologically to the traditional dose of inactivated influenza vaccine (IIV). An intradermal IIV3 (Fluzone Intradermal) is available for use in patients 18 to 64 years old. The main adverse effect of the IIV is soreness at the injection site. Patients often report a mild immune response of fever, malaise, myalgia, and headache that can last for 1 to 2 days, but rates of most of these symptoms are no different from those in patients who receive placebo injection. Allergic reactions to egg proteins or other vaccine components (e.g., antibiotics and inactivating compounds) include hives, angioedema, asthma, and anaphylaxis. For patients with egg allergy who have only hives, IIV can be administered, but patients should be observed for 30 minutes by providers familiar with manifestations of egg allergy. Patients aged 18 to 49 years with more severe reactions to egg can receive the recombinant influenza vaccine (RIV3; FluBlok), or cell culture-based IIV (ccIIV3; Flucelvax), which are manufactured without the use of eggs. Vaccination should be deferred in patients with acute febrile illness, but patients with more moderate illness can be vaccinated.

Guillain-Barré syndrome was associated with the 1976 swine flu vaccine, but there is no consistent evidence that modern influenza vaccines are associated with Guillain-Barré syndrome.

The LAIV4 (FluMist Quadrivalent) is administered as a nasal spray, is approved for patients ages 2 to 49 years, and preferred to the IIV for use in children aged 2 to 8 years. The LAIV4 is contraindicated in children aged 2 to 4 years with recurrent wheezing or asthma; children who are receiving aspirin or aspirin-containing products; in patients with comorbid conditions or egg allergy; in pregnant women; and in family members or close contacts of severely immunosuppressed patients, who require a protected environment (e.g., hematopoietic stem cell transplant recipients). The LAIV4 should not be administered to those with severe nasal congestion. Adverse effects of the LAIV4 include runny nose, nasal congestion, headache, sore throat, chills, and tiredness, although these are only slightly more common than in patients receiving placebo. Those receiving the LAIV4 should avoid contact with severely immunosuppressed persons for 7 days.

Patients should be vaccinated in the fall when the seasonal vaccine becomes available, even as early as August. In the event of vaccine shortages, higher-risk patients should receive priority. Patients should continue to be vaccinated until February and beyond because in the majority of recent influenza seasons the peak has been February or later. Children 6 months to 8 years of age, who have not been previously immunized against influenza, should be given two doses separated by at least 4 weeks.

Evaluation

Community Prevalence of Influenza

In caring for a patient with suspected influenza, the single most important piece of data is the community prevalence of influenza among patients with influenza-like illness. This ranges from near 0% during summer months to about 30% during a typical influenza seasonal peak. The prevalence may be higher during a particularly severe outbreak. Clinicians can check the local prevalence of influenza among patients with influenza-like illness through the CDC (www.cdc.gov/flu) and their state department of public health.

History and Physical Examination

Beyond the local prevalence of influenza, the diagnosis of influenza rests on the patient’s history. All methods of diagnosing influenza— symptom complexes, clinician judgment, and testing—generally are highly specific, but have poor sensitivity. Thus it is important to consider a diagnosis of influenza in any patient with respiratory symptoms during influenza season. Influenza is classically described as the very sudden onset of fever, headache, sore throat, myalgias, cough, and nasal symptoms. Children can also have otitis media, nausea, and vomiting. In differentiating influenza from nonspecific upper respiratory tract infections, it is most useful to consider the circulating prevalence of influenza, the abruptness of onset, and the severity of symptoms.

Certain symptom complexes have been shown in trials of antiviral treatment to strongly suggest influenza. For example, in an area with circulating influenza, the acute onset of cough and fever can have a positive predictive value as high as 85%. One rule assigned 2 points for fever plus cough, 2 points for myalgias, 1 point for duration less than 48 hours, and 1 point for chills or sweats. The prevalence of influenza for patients with 0 to 2 points, 3 points, or 4 to 6 points was 8%, 30%, and 59%, respectively. Other studies have shown that clinician judgment performed as well as or better than hard-and-fast symptom complexes or rapid testing.

The physical examination in influenza primarily serves to identify the severity of influenza, complications, and worsening of underlying medical conditions. Clinicians should record vital signs and perform examinations of the ears, nose, sinuses, throat, neck, lungs, and heart for all patients suspected of having influenza.

Testing

Rapid influenza diagnostic test kits, some of which can distinguish influenza A from influenza B, can provide a point-of-care result in about 15 minutes. Specimens (nasopharyngeal swab, nasal swab, nasal wash, or nasal aspirate, depending on the particular test) should ideally be collected within 3 days of symptom onset. Rapid tests have sensitivities that range from 50% to 70%, but are more than 90% specific. Testing is most useful when there is an intermediate probability of influenza (e.g., a community prevalence of influenza among patients with influenza-like illness of 10% to 30%), and patients have an intermediate probability of complications from influenza. If circulating prevalence of influenza is low (e.g., < 10%), testing is unlikely to be positive and is not necessary. If the circulating prevalence of influenza is high (e.g., > 30%), the relatively low sensitivity of rapid tests makes the risk of a false-negative test unacceptably high. In the event of a high prevalence of influenza or a high risk of complications from influenza, empiric antiviral treatment is indicated. Testing may be particularly helpful for hospitalized patients to rule out a need for antibiotics, but given the low sensitivities anti-influenza treatment should not be withheld based solely on a negative rapid influenza detection test.

Reverse transcriptase polymerase chain reaction (RT-PCR) testing and viral culture have higher sensitivities than rapid influenza diagnostic tests. RT-PCR should be considered for hospitalized patients, institutional outbreaks, or other situations when clinicians are concerned about false-negative rapid test results. RT-PCR assays return results in under 8 hours. Availability of RT-PCR in recent years has expanded. Some RT-PCR assays can detect influenza type and subtypes. Other nucleic acid amplification tests, which can differentiate influenza from other respiratory pathogens, are becoming more available.

Chest radiography, cultures, and blood tests are not routinely indicated, but they should be obtained for patients with suspected pneumonia or to identify other suspected complications.

Complications

Complications of influenza include primary complications, suppurative complications, and worsening of comorbid conditions. Primary complications of influenza include viral pneumonia, which is a feared complication and is likely a main cause of mortality in pandemic influenza. Other, less common primary complications of influenza include myositis and rhabdomyolysis, Reye syndrome, myocarditis, pericarditis, toxic shock syndrome, and central nervous system disease (e.g., encephalitis, transverse myelitis, and aseptic meningitis). Children can have a severe course with influenza, including signs and symptoms of sepsis along with febrile seizures.

Suppurative complications of influenza include bacterial pneumonia, otitis media, and sinusitis. Influenza can cause worsening of comorbid conditions such as asthma, chronic obstructive pulmonary disease, congestive heart failure, and chronic kidney disease.

Chemoprophylaxis

Antiviral medications can be used to prevent influenza in patients who did not receive the influenza vaccine, cannot receive the influenza vaccine, received the vaccine in the prior 2 weeks (before reliable immunity develops), or in the event of poor matching between vaccine and circulating influenza strains (Table 1).

Chemoprophylaxis should also be considered for close contacts of patients with confirmed influenza or for patients with immune deficiency who are unlikely to respond to the influenza vaccine but who are at high risk for having complications from influenza.

Table 1

Antiviral Agents for the Treatment and Prophylaxis of Influenza

Adapted from Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Available at http://www.cdc.gov/flu/professionals/antivirals/ [accessed February 4, 2015].

* Suspected or confirmed influenza among persons with severe influenza or for persons at higher risk for influenza complications up to 5 days after symptom onset. For outpatients not at higher risk for influenza complications, treatment should be started within 48 hours of symptom onset.

† Prophylaxis should be given 10 days for household exposure, 7 days for other exposures and for outbreaks, at least 2 weeks or until 1 week after the end of the  outbreak.

‡ Oseltamivir is approved by the FDA for treatment in children 14 days and older and prophylaxis in children 1 year and older. Treatment in children < 14 days old and prophylaxis in children < 1 year old is recommended by the Centers for Disease Control and Prevention and the American Academy of  Pediatrics.

§  NA = not approved.

Amantadine (Symmetrel) and rimantadine (Flumadine) are not recommended for chemoprophylaxis or treatment because of a high prevalence of resistant influenza A strains. The neuraminidase inhibitors oseltamivir (Tamiflu), and zanamivir (Relenza) are about 80% effective in preventing influenza in household contacts of persons with influenza, and more than 90% effective in preventing influenza in institutional settings. Chemoprophylaxis should be taken for 10 days after a household exposure, 7 days after a nonhousehold exposure, and for a minimum of 2 weeks or until 1 week after the end of long-term care facility or hospital outbreak. For patients allergic to or unable to respond to the vaccine, chemoprophylaxis should be used for the duration of circulating influenza. The IIV can be given to patients receiving chemoprophylaxis. The LAIV should not be given from 2 days before to 14 days after taking an antiviral medication.

Patients who receive the LAIV in this window should be revaccinated at a later date.

Treatment

The influenza vaccine is the best means of reducing influenza-related morbidity and mortality, but its limitations include production problems, low vaccination rates, and the variable effectiveness of the vaccine itself. Given these limitations, there is an important role in management for influenza-specific antiviral medications (see Table 1). Antiviral medications reduce the duration of influenza symptoms by about 1 day, reduce complications requiring antibiotics by 30% to 50%, might decrease hospitalizations and mortality, and are cost-effective. Early antiviral treatment starting up to 5 days after symptom onset can reduce complications for patients who are hospitalized; have severe, complicated, or progressive illness; or are at higher risk for complications (see Box 1). For outpatients not at higher risk for complications, antiviral treatment must be started within 48 hours of symptom onset.

Amantadine and rimantadine are not recommended for the treatment of influenza because of a high prevalence of resistant influenza A strains. Zanamivir is taken as an oral inhaled powder and is not recommended for patients with underlying lung or heart disease. Adverse effects of zanamivir include worsening of underlying lung disease and allergic reactions. Oseltamivir is taken as a capsule or oral suspension. The dose of oseltamivir should be reduced in patients with renal disease. Adverse effects of oseltamivir include nausea, vomiting, and, perhaps behavioral changes.

Peramivir (Rapivab), an intravenous neuraminidase inhibitor, was approved in the United State in December 2014 for patients within 48 hours of symptom onset. Peramivir has been associated with diarrhea, rashes including Stevens-Johnson syndrome, and neuropsychiatric changes.

Antibiotics are generally not necessary, but they should be prescribed to treat suppurative complications of influenza.

Antitussives such as guaifenesin with codeine (Robitussin AC) help coughing patients sleep at night. Beta-agonists, such as albuterol (Proventil),1 can help patients with cough, especially if there is wheezing on examination. Analgesics and antipyretics like acetaminophen (Tylenol) and ibuprofen (Motrin) reduce fever and generally help patients feel better. Patients should be encouraged to rest and drink plenty of fluids.

Patients with suspected influenza should minimize contact with others to avoid spreading the infection. Use of face masks and hand hygiene can reduce the transmission of influenza.

References

1.     Centers for Disease Control and Prevention. Influenza (Flu): information for health professionals. http://www.cdc.gov/flu/professionals/index.htm [accessed 20.11.14].

2.    Ebell M.H., Afonso A.M., Gonzales R., et al. Development and validation of a clinical decision rule for the diagnosis of influenza. J Am Board Fam Med. 2012;25:55–62.

3.     Falsey A.R., Murata Y., Walsh E.E. Impact of rapid diagnosis on management of adults hospitalized with influenza. Arch Intern Med. 2007;167:354–360.

4.    Grohskopf L.A., Olsen S.J., Sokolow L.Z., Bresee J.S., et al.  Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) —United States, 2014–2015 influenza season. MMWR Morb Mortal Wkly Rep. 2014;63:691–697.

5.     Rothberg M.B., Bellantonio S., Rose D.N. Management of influenza in adults older than 65 years of age: Cost- effectiveness of rapid testing and antiviral therapy. Ann Intern Med. 2003;139:321–329.

1  Not FDA approved for this  indication.

KNOWLEDGE BASE
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