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Influenza

(Flu; Grippe; Grip)

By

Brenda L. Tesini

, MD, University of Rochester School of Medicine and Dentistry

Last full review/revision Nov 2020| Content last modified Nov 2020
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Topic Resources

Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those who are institutionalized, at the extremes of age, have cardiopulmonary insufficiency, or are in late pregnancy); during pandemics, even healthy, young patients may die. Diagnosis is usually clinical and depends on local epidemiologic patterns. The influenza vaccine should be given annually to everyone aged ≥ 6 months who does not have a contraindication. Antiviral treatment reduces the duration of illness by about 1 day and should be specifically considered for high-risk patients.

Influenza refers to illness caused by the influenza viruses, but the term is commonly and incorrectly used to refer to similar illnesses caused by other viral respiratory pathogens. Influenza viruses are classified as type A, B, or C by their nucleoproteins and matrix proteins. Influenza C virus infection does not cause typical influenza illness and is not discussed here.

Influenza antigens

Hemagglutinin (H) is a glycoprotein on the influenza viral surface that allows the virus to bind to cellular sialic acid and fuse with the host cell membrane. Neuraminidase (NA), another surface glycoprotein, enzymatically removes sialic acid, promoting viral release from the infected host cell. There are 18 H types and 11 NA types, giving 198 possible combinations, but only a few are human pathogens.

Antigenic drift refers to relatively minor, progressive mutations in preexisting combinations of H and NA antigens, resulting in the frequent emergence of new viral strains. These new strains may cause seasonal epidemics because protection by antibody generated to the previous strain is decreased.

Antigenic shift refers to the relatively rare development of new combinations of H and/or NA antigens, which result from reassortment of subunits of the viral genome. Pandemics can result from antigenic shift because antibodies against other strains (resulting from vaccination or natural infection) provide little or no protection against the new strain.

Epidemiology

Influenza causes widespread sporadic illness yearly during fall and winter in temperate climates (seasonal epidemics).

Seasonal epidemics are caused by both influenza A and B viruses; since 1968, most seasonal influenza epidemics have been caused by H3N2 (an influenza A virus). Influenza B viruses may cause milder disease but often cause epidemics with moderate or severe disease, either as the predominant circulating virus or along with influenza A.

Most influenza epidemics are caused by a predominant serotype, but different influenza viruses may appear sequentially in one location or may appear simultaneously, with one virus predominating in one location and another virus predominating elsewhere.

A weekly surveillance report of seasonal influenza in the US is available at the Centers for Disease Control and Prevention's FluView.

Pandemics are much less common. As of 2020, there have been 6 major pandemics, typically named after the presumed location of origin:

  • 1889: Russian influenza (H2N2)

  • 1900: Old Hong Kong influenza (H3N8)

  • 1918: Spanish influenza (H1N1)

  • 1957: Asian influenza (H2N2)

  • 1968: Hong Kong influenza (H3N2)

  • 2009: Swine influenza (influenza A [H1N1]pdm09)

Influenza viruses can be spread by

  • Airborne droplets

  • Person-to-person contact

  • Contact with contaminated items

Airborne spread appears to be the most important mechanism.

High-risk groups

Certain patients are at high risk of complications from influenza:

  • Children < 5 years; children < 2 years are at particularly high risk

  • Adults > 65 years

  • People with chronic medical disorders (eg, cardiopulmonary disease, diabetes mellitus, renal or hepatic insufficiency, hemoglobinopathies, immuodeficiency)

  • Women in the 2nd or 3rd trimester of pregnancy

  • Patients with disorders that impair handling of respiratory secretions (eg, cognitive dysfunction, neuromuscular disorders, stroke, seizure disorders)

  • Patients 18 years taking aspirin (because Reye syndrome is a risk)

Morbidity and mortality in these patients may be due to exacerbation of underlying illness, acute respiratory distress syndrome, primary influenza pneumonia, or secondary bacterial pneumonia.

Symptoms and Signs

The incubation period for influenza ranges from 1 to 4 days with an average of about 48 hours. In mild cases, many symptoms are like those of a common cold (eg, sore throat, rhinorrhea); mild conjunctivitis may also occur.

Typical influenza in adults is characterized by sudden onset of chills, fever, prostration, cough, and generalized aches and pains (especially in the back and legs). Headache is prominent, often with photophobia and retrobulbar aching. Respiratory symptoms may be mild at first, with scratchy sore throat, substernal burning, nonproductive cough, and sometimes coryza. Later, lower respiratory tract illness becomes dominant; cough can be persistent, raspy, and productive.

Gastrointestinal symptoms may occur and appear to be more common with the 2009 pandemic H1N1 strain. Children may have prominent nausea, vomiting, or abdominal pain, and infants may present with a sepsis-like syndrome.

After 2 to 3 days, acute symptoms rapidly subside, although fever may last up to 5 days. Cough, weakness, sweating, and fatigue may persist for several days or occasionally for weeks.

Complications

Pneumonia is suggested by a worsening cough, bloody sputum, dyspnea, and rales. Secondary bacterial pneumonia is suggested by persistence or recurrence of fever and cough after the primary illness appears to be resolving.

Encephalitis, myocarditis, and myoglobinuria, sometimes with renal failure, develop infrequently after influenza A or B infection. Reye syndrome—characterized by encephalopathy; fatty liver; elevation of liver enzymes, ammonia, or both; hypoglycemia; and lipidemia—often occurs during epidemics of influenza B, particularly in children who have ingested aspirin.

Diagnosis

  • Clinical evaluation

  • Sometimes rapid diagnostic testing or molecular testing

  • Pulse oximetry and chest x-ray for patients with severe respiratory symptoms

The diagnosis of influenza is generally made clinically in patients with a typical syndrome when influenza is known to be present in the community.

Although many rapid diagnostic tests are available and most have good specificity, their sensitivities vary widely, and they usually add little to patient management. Diagnostic tests should be done when results will affect clinical decisions.

Reverse transcriptase–polymerase chain reaction (RT-PCR) tests are sensitive and specific and can differentiate influenza types and subtypes. If this test is quickly available, results may be used to select appropriate antiviral therapy; it should also be done when influenza is suspected in hospitalized patients because antiviral treatment is usually indicated. Also, these tests can prevent the unnecessary use of antibacterial drugs, and identification of the specific influenza virus can be important for infection control. These tests are also useful to determine whether outbreaks of respiratory disease are due to influenza.

Cell culture of nasopharyngeal swabs or aspirates takes several days and is not useful for patient management decisions.

If patients have lower respiratory tract symptoms and signs (eg, dyspnea, rales noted during lung examination), pulse oximetry to detect hypoxemia and a chest x-ray to detect pneumonia should be done. Primary influenza pneumonia appears as focal or diffuse interstitial infiltrates or as acute respiratory distress syndrome. Secondary bacterial pneumonia is more likely to be lobar or segmental.

Prognosis

Most patients recover fully, although full recovery often takes 1 to 2 weeks. However, influenza and influenza-related pneumonia are important causes of morbidity or mortality in high-risk patients. Prompt antiviral treatment in these patients can reduce the incidence of lower respiratory disease and hospitalization. Appropriate antibacterial therapy decreases the mortality rate due to secondary bacterial pneumonia.

Overall, the case fatality rate is low (eg, < 1%), but because incidence of disease is high, the total number of deaths can be significant. The Centers for Disease Control and Prevention estimates that in the US, > 700,000 hospitalizations and 50,000 deaths result from seasonal influenza annually; rates are highest in patients > 65 years. Worldwide, deaths during the first 12 months of the 2009 H1N1 pandemic are estimated to be up to 575,000; > 80% of these deaths occurred in patients < 65 years (1, 2).

Prognosis references

Treatment

  • Symptomatic treatment

  • Sometimes antiviral drugs

Treatment for most patients with influenza is symptomatic; it includes rest, hydration, and antipyretics as needed, but aspirin is avoided in patients 18 years. Complicating bacterial infections require appropriate antibiotics.

Drugs for influenza

Antiviral drugs given within 1 to 2 days of symptom onset decrease the duration of fever, severity of symptoms, and time to return to normal activity. Treatment with antiviral drugs is recommended for high-risk patients (including all hospitalized patients) who develop influenza-like symptoms; this recommendation is based on data suggesting that early treatment may prevent complications in these patients.

Drugs for influenza include the following:

  • Oseltamivir, zanamivir, and peramivir (neuraminidase inhibitors)

  • Baloxavir (endonuclease inhibitor, new)

Neuraminidase inhibitors interfere with release of influenza virus from infected cells and thus halt spread of infection.

The endonuclease inhibitor baloxavir interferes with viral replication by blocking viral RNA transcription. It is active against influenza A and B and may be an important new treatment option should resistance to neuraminidase inhibitors develop.

Zanamivir is given by an inhaler, 2 puffs (10 mg) 2 times a day; it can be used in adults and children 7 years. Zanamivir sometimes causes bronchospasm and should not be given to patients with reactive airway disease; some people cannot use the inhalation device.

Oseltamivir 75 mg orally 2 times a day is given to patients > 12 years; lower doses may be used in children as young as 1 year. Oseltamivir may cause occasional nausea and vomiting. In children, oseltamivir may decrease the incidence of otitis media; however, no other data clearly show that treatment of influenza prevents complications.

Peramivir is given IV as a single dose and can be used in patients > 2 years who cannot tolerate oral or inhaled drugs. Studies of its use for influenza B are limited.

Baloxavir is given as a single 40 mg dose orally to patients ≥ 12 years and 40 to 80 kg or a single 80 mg dose for patients >80 kg. It can be used in patients ≥ 12 years with uncomplicated influenza who have been symptomatic for ≤ 48 hours and who are otherwise healthy and not at high-risk. It has not been studied in patients who are hospitalized, immunocompromised, or pregnant. or have severe pneumonia (1).

Adamantanes (amantadine and rimantadine) were previously used; however, more than 99% of current and recent circulating influenza viruses are resistant to adamantanes, so these drugs are currently not recommended for treatment. Adamantanes block the M2 ion channel and thus interfere with viral uncoating inside the cell. They were effective only against influenza A viruses (influenza B viruses lack the M2 protein).

Treatment reference

Prevention

Influenza infections can largely be prevented by

  • Annual vaccination

  • Sometimes chemoprophylaxis (ie, with antiviral drugs)

Current commercially available influenza vaccines protect against seasonal H3N2, pandemic H1N1 influenza A, and influenza B. A vaccine for H5N1 avian influenza has been approved for people > 18 years at high risk of H5N1 exposure but is available only through public health officials. No vaccines are currently available for the other avian influenza viruses rarely associated with human disease (H7N7, H9N2, H7N3, and H7N9).

Prevention is indicated for all patients but is especially important for high-risk patients and health care practitioners.

Influenza vaccines

Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention, influenza vaccines are modified annually to include the most prevalent strains (usually 2 strains of influenza A and 1 or 2 strains of influenza B). Sometimes slightly different vaccines are used in the northern and southern hemisphere.

When the vaccine contains the same HA and NA as the strains in the community, vaccination decreases infections by 70 to 90% in healthy adults. In institutionalized older patients, vaccines are less effective for prevention but decrease the rate of pneumonia and death by 60 to 80%. A higher-dose formulation of the vaccine is recommended for adults > 65 years.

Vaccine-induced immunity is decreased by antigenic drift and is absent if there is antigenic shift.

There are 2 basic types of influenza vaccine:

  • Inactivated influenza vaccine (IIV)

  • Live-attenuated influenza vaccine (LAIV)

IIV is given by IM injection. Trivalent vaccines have been superseded in the US by quadrivalent vaccines that cover an additional B virus strain. A high-dose trivalent vaccine is available for patients ≥ 65 years, and a high-dose quadrivalent was recently FDA-approved and expected to be available for the 2020-2021 influenza season.

For all IIVs, patients aged 3 years are given 0.5 mL. Children age 6 to 35 months may be given 0.25 mL or 0.5 mL doses depending upon the specific vaccine; clinicians should follow manufacturer's instructions. Children age 6 months to 8 years who have received fewer than 2 influenza vaccine doses or whose influenza vaccination history is unknown should receive 2 doses, separated by at least 4 weeks (1).

Adverse effects are usually limited to mild pain at the injection site; the pain lasts no more than a few days. Fever, myalgia, and other systemic effects are uncommon. Multidose vials contain thimerosal, a mercury-based preservative. Public concerns about a possible link between thimerosal and autism have proved unfounded; however single-dose vials, which are thimerosal-free, are available.

LAIV is given intranasally at a dose of 0.1 mL in each nostril (total dose is 0.2 mL). It may be used for healthy people aged 2 to 49 years. This vaccine is not recommended for the following:

  • High-risk patients

  • Pregnant women

  • Household contacts of patients with severe immunodeficiency (eg, with hematopoietic stem cell transplants)

  • Children who are receiving long-term aspirin therapy

Also, it should not be given until 48 hours after stopping drug treatment of influenza.

Adverse effects associated with the vaccine are mild; rhinorrhea is the most common, and mild wheezing may occur. LAIV should not be given to children who are < 5 years and have reactive airway disease (eg, known asthma, recurrent or recent wheezing episodes).

LAIV was not recommended for any population in the 2016–2017 and 2017–2018 flu seasons because the vaccine's H1N1 component was not adequately effective. However, the LAIV vaccine has been reformulated, and both the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) have reinstated it as an acceptable vaccine.

For both types of vaccines, children who are < 8 years and have not been vaccinated should be given a primary dose and a booster dose 1 month apart.

A complete list of influenza vaccines for the current season is available from the Centers for Disease Control and Prevention.

Vaccination recommendations

Annual vaccination is recommended for everyone ≥ 6 months who do not have a contraindication.

Influenza vaccine is given annually to maintain antibody titers and allow vaccine modification to compensate for antigenic drift. Vaccine is best given in the fall, so that antibody titers will be high during the winter influenza season (between November and March in the US).

Vaccination (both IIV and LAIV) should be avoided in people who

  • Previously had a severe reaction to influenza vaccine

  • Developed Guillain-Barré syndrome (GBS) within 6 weeks of a previous influenza vaccination (it is not known whether influenza vaccination increases risk of recurrent GBS in patients who have previously had GBS that was not related to influenza vaccination)

  • Have had GBS in the previous 6 weeks, regardless of cause

  • Are < 6 months old

Any of the influenza vaccines can be given to patients with a history of egg allergy, except to patients who have had a severe allergic reaction to a previous influenza vaccination, which is a contraindication to receiving the vaccine. If patients have had an allergic reaction more severe than just hives (eg, angioedema, respiratory distress, recurrent emesis), they may be given the vaccine, provided that it is given in an inpatient or outpatient medical setting and supervised by a clinician who is able to recognize and manage severe allergic reactions. Also, egg-free vaccines—a recombinant IIV for adults and a cell-culture produced IIV for people > 4 years—are available.

Antiviral drugs

Although vaccination is the preferred method of prevention, antiviral drugs are also effective.

Preexposure prophylactic antiviral drugs can be considered during an epidemic for patients

  • Who have been vaccinated only within the previous 2 weeks

  • For whom vaccination is contraindicated

  • Who are immunocompromised and thus may not respond to vaccination

Antiviral drugs do not impair development of immunity from inactivated vaccine. They can be stopped 2 weeks after vaccination. If vaccine cannot be given, antiviral drugs are continued for the duration of the epidemic.

Postexposure prophylactic antiviral drugs are typically indicated for potentially exposed people when clusters of cases occur in a closed environment (eg, nursing home, hospital unit). These drugs may also be given to household contacts or other exposed people at high risk of developing complications of influenza. Resistance patterns may affect drug choice, but typically oseltamivir 75 mg once a day is given.

Prevention reference

Key Points

  • Minor antigenic drift in H and/or NA antigens produces strains that cause seasonal epidemics; rare antigenic shifts resulting in new combinations of H and NA antigens can cause a pandemic with significant mortality.

  • Influenza itself may cause pneumonia, or patients with influenza may develop secondary bacterial pneumonia.

  • Diagnosis is usually clinical, but sensitve and specific RT-PCR assays can differentiate influenza types and subtypes and thus help select antiviral therapy and determine whether outbreaks of respiratory disease are due to influenza.

  • Treat most patients symptomatically.

  • Antiviral drugs given early can slightly decrease duration and severity of symptoms but are typically used only in high-risk patients; different influenza types and subtypes are resistant to different drugs.

  • Vaccinate annually everyone aged ≥ 6 months who does not have a contraindication; antiviral drugs can be used for prevention in immunocompromised patients (who may not respond to vaccination) and patients with contraindications to vaccination.

Drugs Mentioned In This Article

Drug Name Select Trade
FLUMADINE
TAMIFLU
No US brand name
Peramivir
RELENZA
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