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.
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 of Influenza
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. There have been 6 major influenza 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)
In 2009–2010 an H1N1 flu pandemic occurred—the virus spread to > 70 countries and to all 50 US states. The majority of the deaths occurred in Mexico. The virus was initially referred to as a swine flu virus, but it is a combination of swine, avian, and human influenza viruses. The infection is not acquired through ingestion of pork and is acquired very rarely by contact with infected pigs. Subsequently, the virus name was standardized to influenza A(H1N1)pdm09 to denote the pandemic and distinguish the virus from seasonal H1N1 strains and the 1918 pandemic H1N1 strain. Since 2009, influenza A(H1N1)pdm09 has circulated as a seasonal influenza.
Influenza viruses can be spread by
Contact with contaminated items
Airborne spread appears to be the most important mechanism.
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)
Morbidity and mortality in these patients may be due to exacerbation of underlying illness, acute respiratory distress syndrome Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is defined as severe hypoxemia (PaO2 (See also Overview of Mechanical Ventilation.) Airspace filling in acute hypoxemic respiratory failure (AHRF) may result... read more , primary influenza pneumonia, or secondary bacterial pneumonia.
Symptoms and Signs of Influenza
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 Symptoms and Signs The common cold is an acute, usually afebrile, self-limited viral infection causing upper respiratory symptoms, such as rhinorrhea, cough, and sore throat. Diagnosis is clinical. Handwashing... read more (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.
Pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more 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 Encephalitis Encephalitis is inflammation of the parenchyma of the brain, resulting from direct viral invasion or occurring as a postinfectious immunologic complication caused by a hypersensitivity reaction... read more , myocarditis Myocarditis Myocarditis is inflammation of the myocardium with necrosis of cardiac myocytes. Myocarditis may be caused by many disorders (eg, infection, cardiotoxins, drugs, and systemic disorders such... read more , and myoglobinuria, sometimes with renal failure, develop infrequently after influenza A or B infection. Reye syndrome Reye Syndrome Reye syndrome is a rare form of acute encephalopathy and fatty infiltration of the liver that tends to occur after some acute viral infections, particularly when salicylates are used. Diagnosis... read more —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 of Influenza
Sometimes rapid antigen or conventional reverse transcriptase-polymerase chain (RT-PCR) tests
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 molecular tests (antigen detection 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 Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is defined as severe hypoxemia (PaO2 (See also Overview of Mechanical Ventilation.) Airspace filling in acute hypoxemic respiratory failure (AHRF) may result... read more . Secondary bacterial pneumonia is more likely to be lobar or segmental.
Prognosis for Influenza
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 (CDC) estimates that in the US from 2010 to 2020, hospitalizations resulting from seasonal influenza ranged from 140,000 to 710,000 annually, and deaths ranged from 12,000 to 52,000 annually ( 1 Prognosis references 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... read more ). Rates of hospitalization and death are highest in patients > 65 years. During typical seasonal influenza epidemics, about 80% of deaths are estimated to occur in patients > 65 years; however, 80% of H1N1-related deaths were estimated to have occurred in people < 65 years during the first 12 months of the 2009 H1N1 pandemic. ( 2 Prognosis references 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... read more , 3 Prognosis references 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... read more ).
1. CDC: Disease Burden of Flu. Accessed 04/13/2022.
2. Dawood FS, Iuliano AD, Reed C, et al: Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: A modelling study. Lancet Infect Dis12 (9):687–695, 2012. doi: 10.1016/S1473-3099(12)70121-4
3. CDC:2009 H1N1 Pandemic (H1N1pdm09 virus). Accessed 04/13/2022.
Treatment of Influenza
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 High-risk groups 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... read more (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)
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 or at high-risk High-risk groups 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... read more of developing complications ( 1, 2 Treatment references 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... read more ).
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).
1. Hayden FG, Sugaya N, Hirotsu N, et al: Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 379:913-923, 2018. doi:10.1056/NEJMoa1716197
2. Ison MG, Portsmouth S, Yoshida Y, et al: Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis 20(10):1204-1214, 2020. doi: 10.1016/S1473-3099(20)30004-9. Epub 2020 Jun 8. PMID: 32526195.
Prevention of Influenza
Influenza infections can largely be prevented by
Sometimes chemoprophylaxis (ie, with antiviral drugs)
Current commercially available influenza vaccines Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more protect against seasonal H3N2, pandemic H1N1 influenza A, and influenza B. A vaccine for H5N1 avian influenza Avian Influenza Avian influenza is caused by strains of influenza A that normally infect only wild birds and domestic poultry. Infections due to some of these strains have been detected in humans. Human-to-human... read more 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.
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. (See also Influenza Vaccine Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more .)
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 Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more :
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. For patients ≥ 65 years, high-dose quadrivalent vaccines are also available.
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 Thimerosal and autism Despite the rigorous vaccine safety systems in place in the US, some parents remain concerned about the safety of the use and schedule of vaccines in children. These concerns have led some parents... read more 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:
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.
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).
Influenza vaccine can be given at the same time as COVID-19 vaccine COVID-19 vaccination COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively... read more .
Vaccination (both IIV and LAIV) should be avoided in people who
Previously had a severe reaction to influenza vaccine
Developed Guillain-Barré syndrome Guillain-Barré Syndrome (GBS) Guillain-Barré syndrome is an acute, usually rapidly progressive but self-limited inflammatory polyneuropathy characterized by muscular weakness and mild distal sensory loss. Cause is thought... read more (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.
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 High-risk groups 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... read more . Resistance patterns may affect drug choice, but typically oseltamivir 75 mg once a day is given.
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.