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Influenza

(Flu; Grippe; Grip)

by Craig R. Pringle, BSc, PhD

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. Everyone aged ≥ 6 mo should receive annual influenza vaccination. 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 native 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 and often occur in 2 waves—the first in schoolchildren and their household contacts (generally younger people) and the 2nd mostly in housebound or institutionalized people, particularly the elderly. Influenza B viruses may cause milder disease but often cause epidemics with moderate or severe disease, usually in 3- to 5-yr cycles. 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.

Pandemics are much less common. As of 2013, 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, or contact with contaminated items. Airborne spread appears to be the most important mechanism.

At-risk groups

Certain patients are at high risk of complications from influenza:

  • Children < 4 yr

  • Adults > 65 yr

  • 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 yr 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 ranges from 1 to 4 days with an average of about 48 h. 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. GI 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 (see 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

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

The diagnosis 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–PCR (RT-PCR) assays are sensitive and specific and can differentiate influenza types and subtypes. If this assay is quickly available, results may be used to select appropriate antiviral therapy. 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 wk. However, influenza and influenza-related pneumonia are important causes of increased morbidity or mortality in high-risk patients. Use of antiviral treatment in these patients appears to reduce the incidence of lower respiratory disease and hospitalization. Appropriate antibacterial therapy decreases the mortality rate due to secondary bacterial pneumonia.

Treatment

  • Symptomatic treatment

  • Sometimes antiviral drugs

Treatment for most patients is symptomatic, including rest, hydration, and antipyretics as needed, but aspirin is avoided in patients 18 yr. 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 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 and zanamivir (neuraminidase inhibitors)

  • Amantadine and rimantadine (adamantanes)

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

Adamantanes block the M2 ion channel and thus interfere with viral uncoating inside the cell. They are effective only against influenza A viruses (influenza B viruses lack the M2 protein).

Choice of antiviral drug is complicated by resistance of different influenza types and subtypes to different drugs (see Table: Drug Sensitivities of Various Influenza Strains). If RT-PCR testing is rapidly available, results can be used to direct treatment. If RT-PCR is not available, patients may be treated with zanamivir alone or with rimantadine plus oseltamivir.

Drug Sensitivities of Various Influenza Strains

Virus

Amantadine or Rimantadine

Oseltamivir

Zanamivir

Influenza A viruses

Seasonal H3N2

Resistant

Sensitive

Sensitive

Seasonal H1N1

Sensitive

Resistant

Sensitive

Pandemic H1N1

Resistant

Sensitive

Sensitive

Avian H5N1

Resistant

Sensitive

Sensitive

Influenza B viruses

All

Resistant

Sensitive

Sensitive

Zanamivir is given by an inhaler, 2 puffs (10 mg) bid; it can be used in adults and children 7 yr. 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 po bid is given to patients > 12 yr; lower doses may be used in children as young as 1 yr. 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.

Rimantadine is the preferred adamantane because it has fewer side effects and is better tolerated. Treatment is stopped 1 to 2 days after symptoms resolve or after 3 to 5 days. For rimantadine or amantadine, 100 mg po bid can be used in adults ≤ 65, and 100 mg po once/day can be used in those > 65. To avoid adverse effects due to drug accumulation, clinicians reduce the dose for children (2.5 mg/kg bid to a maximum of 150 mg/day for children < 10 yr or 200 mg/day for children 10 yr). In patients with impaired renal function, dose is adjusted according to creatinine clearance. The dose of rimantadine should not exceed 100 mg/day if patients have hepatic dysfunction. Dose-related nervousness, insomnia, or other CNS effects occur in about 10% of people receiving amantadine and in about 2% of people receiving rimantadine. These effects usually occur within 48 h after starting the drug, are more prominent in the elderly and in patients with CNS diseases or impaired renal function, and often resolve during continued use. Anorexia, nausea, and constipation may also occur.

Prevention

Influenza infections can largely be prevented by

  • Annual vaccination

  • Sometimes chemoprophylaxis (ie, with antiviral drugs)

Current commercially available vaccines protect only against seasonal influenza. A vaccine for H5N1 avian influenza has been approved for people > 18 yr 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.

Vaccines

Based on recommendations by the WHO and US Centers for Disease Control and Prevention (CDC), 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 the institutionalized elderly, vaccines are less effective for prevention but decrease the rate of pneumonia and death by 60 to 80%. Vaccine-induced immunity is decreased by antigenic drift and is absent if there is antigenic shift.

There are 2 basic types of vaccine:

  • Multivalent inactivated influenza vaccine (MIV)

  • Live-attenuated influenza vaccine (LAIV)

MIV is given by IM injection. Trivalent vaccines are gradually being superseded by quadrivalent vaccines that cover an additional B virus strain. An egg protein–free vaccine (RIV3) is available for patients who are aged 18 through 49 yr and have any degree of egg allergy. A high-dose trivalent vaccine is available for patients ≥ 65 yr, but efficacy is still being studied. For all MIVs, patients aged 6 mo to 35 mo are given 0.25 mL, and those 3 yr are given 0.5 mL. Adverse effects are usually limited to mild pain at the injection site; it 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 (see Thimerosal and autism); however single-dose vials, which are thimerosal-free, are available.

LAIV is given intranasally at a dose of 0.25 mL in each nostril. It may be used for healthy people aged 2 to 49 yr. This vaccine is not recommended for high-risk patients, pregnant women, household contacts of patients with severe immunodeficiency (eg, with hematopoietic stem cell transplants), or children who are receiving long-term aspirin therapy. Also, it should not be given until 48 h 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 yr and have reactive airway disease (eg, known asthma, recurrent or recent wheezing episodes).

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

A complete list of vaccines for the 2013-2014 season, is available from the CDC (see CDC Influenza Vaccines ).

Vaccination recommendations

Annual vaccination is recommended for everyone ≥ 6 mo.

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 MIV and LAIV) should be avoided in people who

  • Have a severe egg allergy (if the only allergic manifestation is urticaria, an egg-protein free vaccine can be used in patients aged 18 through 49 yr, or a standard vaccine can be used if appropriate precautions are taken to manage a possible allergic reaction)

  • Previously had a severe reaction to influenza vaccine

  • Developed Guillain-Barré syndrome (GBS) within 6 wk 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 wk, regardless of cause

  • Are < 6 mo old

Antiviral drugs

Although vaccination is the preferred method of prevention, antiviral drugs are also effective. Prophylactic antiviral drugs are indicated when influenza is circulating in the community for patients

  • Who have been vaccinated only within the previous 2 wk

  • 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 wk after vaccination. If vaccine cannot be given, antiviral drugs are continued for the duration of the epidemic.

If the circulating influenza types or subtypes are unknown, patients may be treated with either zanamivir alone (in patients for whom it is not contraindicated) or with a combination of rimantadine and oseltamivir.

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 everyone ≥ 6 mo annually; antiviral drugs can be used for prevention in immunocompromised patients (who may not respond to vaccination) and patients with contraindications to vaccination.

Resources In This Article

Drugs Mentioned In This Article

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

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