Influenza

Infectious Agent

Influenza is caused by infection of the respiratory tract with influenza viruses, RNA viruses of the Orthomyxovirus genus. Influenza viruses are classified into 3 types: A, B, and C. Only virus types A and B commonly cause illness in humans. Influenza A viruses are further classified into subtypes based on 2 surface proteins, hemagglutinin (HA) and neuraminidase (NA). Although 3 types and subtypes of influenza virus cocirculate in humans worldwide (influenza A [H1N1], A [H3N2], and influenza B viruses), the distribution of these viruses varies from year to year and between geographic areas and time of year. Information about circulating viruses in various regions can be found via CDC (www.cdc.gov/flu/weekly) or the World Health Organization (www.who.int/topics/influenza/en). Avian and swine influenza viruses can occasionally infect and cause disease in humans, usually associated with close exposure to infected animal populations. Notably, avian influenza A (H5N1) and A (H7N9) have led to sporadic human cases in recent years, and swine-origin A (H3N2) variant viruses have been associated with disease in humans in the United States.

Transmission

Influenza viruses spread from person to person, primarily through respiratory droplet transmission (such as when an infected person coughs or sneezes near a susceptible person). Transmission via large-particle droplets requires close proximity between the source and the recipient, because droplets generally travel only short distances (approximately 6 feet or less) through the air, before settling onto surfaces. Indirect (fomite) transmission can also occur, such as when a person touches a virus-contaminated surface and then touches his or her face. Airborne transmission via small-particle aerosols in the vicinity of the infectious person also occurs.

Most adults who are ill with influenza shed the virus in the upper respiratory tract and are infectious from the day before symptom onset to approximately 5–7 days after symptom onset. Infectiousness is highest within 3 days of illness onset and is correlated with fever. Children and those who are immunocompromised or severely ill may shed influenza virus for 10 days or more after the onset of symptoms. Seasonal influenza viruses have rarely been detected from nonrespiratory sources such as stool or blood.

Epidemiology

Seasonal Influenza

Influenza circulation varies geographically. The risk of exposure to influenza during travel depends on the time of year and destination. In temperate regions, influenza typically circulates at higher levels during colder winter months: October to May in the Northern Hemisphere and April to September in the Southern Hemisphere. In many tropical or subtropical regions, influenza can occur throughout the year.

Influenza is typically most common in children, especially in school-aged children. Rates of severe illness and death are typically highest among people aged ≥65, children <2 years, and people of any age who have underlying medical conditions that place them at increased risk for complications of influenza. Children aged <2 years have rates of influenza-associated hospitalizations that are as high as those in the elderly, although with much lower death rates. CDC estimates that from 1976 through 2006, annual influenza-associated deaths in the United States ranged from a low of approximately 3,000 people to a high of approximately 49,000 people; approximately 80%–90% of these deaths occurred among people aged ≥65 years.

Zoonotic Influenza

Influenza B viruses circulate widely only among humans, although influenza A viruses circulate among many animal populations. The primary reservoir for influenza A viruses is wild waterfowl and other wild birds, but viruses are common in swine populations as well. Influenza A viruses can also infect other animal species, such as poultry, cats, dogs, horses, sea lions, and bats.

Human infections with animal-origin influenza A viruses are uncommon. In the United States, human influenza illnesses caused by swine-origin influenza A viruses (called “variant” influenza virus infections and denoted with the letter “v”) have been sporadically identified. In 2012, 309 cases (and 1 death) of human illnesses caused by influenza A (H3N2v) viruses were identified. In the summer of 2013, 19 human cases were identified in 5 states. Most illnesses caused by H3N2v have occurred after direct or indirect contact with an infected pig, often among exhibitors or visitors to agricultural fairs. Limited person-to-person transmission has occurred with this virus. The severity of illness has been similar to that seen with seasonal influenza.

Although avian influenza viruses do not commonly infect humans, disease resulting from these viruses has been reported. From 1997 through March 2016, 850 human illnesses caused by avian influenza A (H5N1) virus were reported globally, approximately 53% of which were fatal. Most disease from H5N1 has occurred after direct or close contact with sick or dead infected poultry. H5N1 is widespread among poultry in some countries in Asia and the Middle East and is considered to be endemic among poultry in 6 countries: Bangladesh, China, Egypt, India (West Bengal), Indonesia, and Vietnam (Map 3-7). Egypt, Indonesia, and Cambodia have accounted for 71% of reported infections in humans globally. Instances of limited, nonsustained human-to-human transmission of H5N1 virus have been reported. In the United States, since December 2014, highly pathogenic avian influenza (HPAI) H5 infections have been detected in backyard and commercial poultry from 21 states. Although no human HPAI H5 infections have been reported in the United States, surveillance in domestic birds is ongoing given the low but continued risk of transmission to humans.

Map 3-7. Distribution of highly pathogenic avian influenza A (H5N1) virus
Descriptive text is not available for this image

Avian influenza A (H7N9) virus emerged in China in 2013, and as of March 2016, has caused 767 confirmed human illnesses. Most cases have been identified in mainland China, but several cases associated with exposure in mainland China and subsequent travel have been identified in Malaysia, Taiwan, and Hong Kong. In 2014, Canada reported the first imported H7N9 case in North America. Most of the people with illness caused by H7N9 had exposure to infected poultry or contaminated environments, and the virus has been found in poultry and environmental samples collected in China. A small proportion of human H7N9 illnesses has been mild, but most patients have developed severe respiratory illness, and 38% have died.

Although rare, human infections with other avian influenza A viruses, including H7N2, H7N3, H7N7, H9N2, and H10N8, have been reported in recent years. In the United States, 2 infections with H7N2 virus were reported in humans in 2002 and 2003, both of whom recovered.

Clinical Presentation

Uncomplicated influenza illness is characterized by the abrupt onset of signs and symptoms that include fever, muscle aches, headache, malaise, nonproductive cough, sore throat, vomiting, and rhinitis. Less commonly, rashes have been associated with influenza infection. Illness without fever can occur, especially in the elderly. Children are more likely than adults to also experience nausea, vomiting, or diarrhea when ill with influenza. Physical findings are predominantly localized to the respiratory tract and include nasal discharge, pharyngeal inflammation without exudates, and occasionally rales on chest auscultation. The incubation period is usually 1–4 days after exposure. Influenza illness typically resolves within 1 week for most previously healthy children and adults who do not receive antiviral medication, although cough and malaise can persist for >2 weeks, especially in the elderly. Complications of influenza virus infection include primary influenza viral pneumonia, secondary bacterial pneumonia, parotitis, exacerbation of underlying medical conditions (such as pulmonary and cardiac disease), encephalopathy, myocarditis, myositis, and coinfections with other viral or bacterial pathogens.

Diagnosis

Influenza can be difficult to distinguish from respiratory illnesses caused by other pathogens on the basis of signs and symptoms alone. The positive predictive value of clinical signs and symptoms for influenzalike illness (fever with either cough or sore throat) for laboratory-confirmed influenza virus infection is 30%–88%, depending on the level of influenza activity.

Diagnostic tests available for influenza include viral culture, rapid influenza diagnostic tests (RIDTs), immunofluorescence assays, and RT-PCR. Most patients with clinical illness consistent with uncomplicated influenza in an area where influenza viruses are circulating do not require diagnostic testing for clinical management. Patients who should be considered for influenza diagnostic testing include the following:

  • Hospitalized patients with suspected influenza
  • Patients for whom a diagnosis of influenza will inform decisions regarding clinical care, including patients who do not improve on antiviral therapy and those with medical conditions that place them at high risk of complications
  • Patients for whom results of influenza testing would affect infection control or management of close contacts, including other patients, such as in institutional outbreaks or other settings (cruise ships or tour groups, for example)

The sensitivity of RIDTs varies but is substantially lower than for RT-PCR or viral culture. The sensitivity of RIDTs to detect animal-origin influenza viruses, including avian influenza viruses, can vary by test type and virus subtype. Therefore, a negative RIDT result does not rule out influenza virus infection, and health care providers should not rely on a negative RIDT result to make decisions about treatment. The decision to start antiviral treatment should not be delayed while waiting for results of confirmatory laboratory testing.

Treatment

Early antiviral treatment can shorten the duration of fever and other symptoms and reduce the risk of complications from influenza. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness; or is at a higher risk for influenza-associated complications (www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm). Antiviral treatment can also be considered for any previously healthy patient with confirmed or suspected influenza not at high risk of complications.

Treatment is most effective if it can be initiated within 48 hours of illness onset. For hospitalized patients, those with severe illness, or those at higher risk of complications, antiviral therapy may still be beneficial if started >48 hours after illness onset. Three FDA-approved antiviral agents are recommended for the treatment and prophylaxis of influenza: oral oseltamivir (Tamiflu, Genentech), inhaled zanamivir (Relenza, GlaxoSmithKline), and intravenous (IV) peramivir (Rapivab, BioCryst Pharmaceuticals).

All 3 antiviral medications are neuraminidase inhibitors that have activity against both influenza A and B viruses. Oseltamivir is approved for treatment in children aged ≥14 days and for prophylaxis of patients aged ≥1 year. Oseltamivir is the preferred agent to treat patients with severe or complicated influenza illness who are able to tolerate oral medications. Zanamivir is approved to treat those aged ≥7 years and for prophylaxis in those aged ≥5 years. Inhaled zanamivir is not recommended for use in people with underlying chronic respiratory disease. Peramivir is approved to treat those aged ≥18 years and is indicated for use in patients unable to tolerate or absorb oral antiviral therapy (Table 3-5). Two other medications, amantadine and rimantadine, are not recommended for treatment or prophylaxis of influenza because of widespread viral resistance among circulating influenza A viruses. Amantadine and rimantadine are not active against influenza B viruses.

Table 3-5. Recommended dosage and duration of antiviral medications for treatment and prophylaxis of influenza A and B
Antiviral AgentUseChildrenAdults
Oseltamivir (Tamiflu)Treatment (5 days)
  • If child is <1 year old 1:
  • 3 mg/kg/dose twice daily 2, 3
  • If ≥1 year old, dose varies by child’s weight:
  • ≤15 kg, the dose is 30 mg twice a day.
  • >15–23 kg, the dose is 45 mg twice a day.
  • >23–40 kg, the dose is 60 mg twice a day.
  • >40 kg, the dose is 75 mg twice a day.
75 mg twice daily

Prophylaxis (7 days)
  • If child is <3 months old: use of oseltamivir for prophylaxis is not recommended unless situation is judged critical because data in this age group are limited.
  • If child is ≥3 months and <1 year old 1:
  • 3 mg/kg/dose once daily. 2
  • If ≥1 year old, dose varies by child’s weight:
  • ≤15 kg, the dose is 30 mg once a day.
  • >15–23 kg, the dose is 45 mg once a day.
  • >23–40 kg, the dose is 60 mg once a day.
  • >40 kg, the dose is 75 mg once a day.
75 mg once daily
Zanamivir (Relenza)Treatment (5 days)10 mg (two 5-mg inhalations) twice daily (FDA approved and recommended for use in children ≥7 years)
  • 10 mg (two 5-mg inhalations)
  • twice daily

Prophylaxis (7 days)10 mg (two 5-mg inhalations) once daily 4 (FDA approved for and recommended for use in children ≥5 years)
  • 10 mg (two 5-mg inhalations)
  • once daily
Peramivir 5 (Rapivab)Treatment (1 day)No FDA approval for use in children600 mg dose via IV infusion for 15–30 minutes 5
1 Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza with twice-daily dosing in people aged ≥14 days and for prophylaxis with once-daily dosing in people aged ≥1 year. Although not part of the FDA-approved indications, use of oral oseltamivir for treatment of influenza in infants <14 days old, and for prophylaxis in infants 3 months to 1 year of age, is recommended by CDC and the American Academy of Pediatrics.
2 This is the FDA-approved oral oseltamivir treatment dose for infants aged ≥14 days and <1 year old and provides oseltamivir exposure in children similar to that achieved by the approved dose of 75 mg orally twice daily for adults, as shown in 2 studies of oseltamivir pharmacokinetics in children. The American Academy of Pediatrics (AAP) recommended an oseltamivir treatment dose of 3.5 mg/kg orally twice daily for infants aged 9–11 months for the 2015–2016 season. It is unknown whether this higher dose will improve efficacy or prevent the development of antiviral resistance. However, there is no evidence that the 3.5 mg/kg dose is harmful or causes more adverse events to infants in this age group. The AAP also recommended an oseltamivir treatment dose of 3 mg/kg orally twice daily for term infants aged 0–8 months for the 2015–2016 season.
3 Current weight-based dosing recommendations are not appropriate for premature infants. Premature infants might have slower clearance of oral oseltamivir because of immature renal function, and doses recommended for full-term infants might lead to very high drug concentrations in this age group. CDC recommends dosing as also recommended by the American Academy of Pediatrics: 1.0 mg/kg/dose, orally, twice daily, for those <38 weeks postmenstrual age; 1.5 mg/kg/dose, orally, twice daily, for those 38–40 weeks postmenstrual age; 3.0 mg/kg/dose, orally, twice daily, for those >40 weeks postmenstrual age.
4 Inhaled zanamivir is approved to treat acute uncomplicated influenza with twice-daily dosing in people aged ≥7 years and for prophylaxis with once-daily dosing in people aged ≥5 years.
5 Intravenous peramivir is FDA approved and recommended for treatment in adults ≥18 years. If used to treat hospitalized patients, a minimum of 5 days of IV peramivir should be given (not a single dose as is recommended for outpatients with uncomplicated illness).

For severely ill hospitalized patients, IV peramivir or IV zanamivir (an investigational product) should be considered for those who cannot tolerate or absorb oral oseltamivir. IV zanamivir should be considered for severely ill patients with known or suspected oseltamivir/peramivir-resistant virus infection. IV zanimivir is available only under an approved emergency investigational new drug request in hospitalized patients with severe influenza.

People at increased risk for complications of influenza should discuss antiviral treatment and prophylaxis with their health care provider before travel to areas where influenza activity is occurring. CDC recommends antiviral treatment for human infection with avian or swine influenza viruses.

Prevention

Vaccine

Available Vaccine Products and Indications for Use

In the United States, annual influenza vaccination is recommended for those aged ≥6 months and is the most effective way to prevent influenza and its complications. Several influenza vaccines are approved for use in the United States (www.cdc.gov/flu/protect/vaccine/vaccines.htm) and can be grouped into categories: inactivated influenza vaccine (IIV), live attenuated influenza vaccine (LAIV), and recombinant influenza vaccine (RIV). However, for the 2016–2017 influenza season, CDC has recommended that LAIV not be used following analyses that indicated lower effectiveness of the vaccine compared with inactivated vaccine. (For updates and the following season recommendations, providers should access http://www.cdc.gov/flu/protect/vaccine/index.htm.) For people for whom more than 1 type of vaccine is indicated, there is no preference for any particular category. During their first influenza season, children aged 6 months through 8 years require 2 doses of influenza vaccine (given ≥4 weeks apart) to induce sufficient immune response.

IIV can be administered by intramuscular injection, transdermally via needle-free jet injector, or intradermal injection depending on the product. IIVs are labeled for use in people aged ≥6 months, but specific age indications vary by manufacturer and product; label instructions should be followed. High-dose IIV and adjuvanted IIV vaccines, which may elicit higher levels of antibodies than standard-dose vaccines, are available for people aged ≥65 years. RIV is labeled for use in people aged ≥18 years.

Influenza vaccine composition can be trivalent, protecting against 3 different influenza viruses (2 influenza subtype A and 1 type influenza B), or quadrivalent, with protection against 4 different influenza viruses (2 influenza subtype A and 2influenza type B strains). Quadrivalent vaccine includes a representative strain from 2 antigenically distinct influenza B lineages, Yamagata and Victoria.

Any traveler, including people at high risk for complications of influenza, who did not receive influenza vaccine during the preceding fall or winter and wants to reduce the risk for influenza infection should consider influenza vaccination ≥2 weeks before departure if he or she plans to travel to the tropics, with organized tourist groups at any time of year, or to the Southern Hemisphere from April through September.

No information is available about the benefits of revaccinating people before summer travel who were vaccinated during the preceding fall, and revaccination is not recommended. People at higher risk for influenza complications should consult with their health care provider to discuss the risk for influenza or other travel-related diseases before traveling during the summer.

Seasonal influenza vaccines are not expected to provide protection against human infection with animal-origin influenza viruses, including avian influenza A (H5N1 and H7N9) viruses.

Vaccine Safety and Adverse Reactions

Inactivated influenza vaccine (IIV)

The most frequent side effects of vaccination with intramuscular and intradermal IIV in adults are soreness and redness at the vaccination site. These local injection-site reactions are slightly more common with vaccine administered intradermally, with needle-free jet injection and with high-dose IIV. They generally are mild and rarely interfere with the ability to conduct usual activities. Fever, malaise, myalgia, headache, and other systemic symptoms sometimes occur after vaccination; these may be more frequent in people with no previous exposure to the influenza virus antigens in the vaccine (such as young children) and are generally short-lived.

Guillain-Barré syndrome (GBS) was associated with the 1976 swine influenza vaccine, with an increased risk of 1 additional case of GBS per 100,000 people vaccinated. None of the studies of influenza vaccines other than the 1976 influenza vaccine have demonstrated a risk of GBS of similar magnitude. Currently, the estimated risk for vaccine-related GBS is low, approximately 1 additional case per 1 million people vaccinated.

Live attenuated influenza vaccine (LAIV)

The most frequent side effects of LAIV reported in healthy adults include minor upper respiratory symptoms, runny nose, and sore throat, which are generally well tolerated. Some children and adolescents have reported fever, vomiting, myalgia, and wheezing. These symptoms, particularly fever, are more often associated with the first administered LAIV dose and are self-limited.

Although LAIV is licensed for people aged 2–49 years, CDC recommended that LAIV not be used during the 2016–2017 season following analyses that indicated lower effectiveness of LAIV compared with IIV. (Recommendations for subsequent seasons may be found at www.cdc.gov/flu/protect/vaccine/index.htm.) Children aged 2–4 years who have a history of wheezing in the past year or who have a diagnosis of asthma should not receive LAIV. Children and adults aged 2–49 years who have conditions that increase the risk of severe influenza, including pregnancy and immunocompromising conditions, should receive IIV or RIV and not LAIV. Caretakers of severely immunocompromised people should also not receive LAIV or should avoid contact with such people for 7 days after receipt of LAIV to decrease the risk of live virus transmission.

Recombinant influenza vaccine (RIV)

The first RIV was licensed in the United States in January 2013. Limited postmarketing safety data are available, but prelicensure safety data indicate that the most common reactions were headache, fatigue, and myalgia. RIV is not indicated for people <18 years.

Precautions and Contraindications

Influenza vaccine is contraindicated in people who have had a previous severe allergic reaction to influenza vaccine, regardless of which vaccine component was responsible for the reaction. Immediate hypersensitivity reactions (such as hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions likely result from hypersensitivity to vaccine components, one of which is residual egg protein. Vaccine options are available for people with a history of egg allergy who have experienced only hives after exposure to egg, people with a history of severe reaction to egg, and people with no known history of egg allergy but who are suspected of being egg-allergic; these are outlined at www.cdc.gov/flu/professionals/vaccination/vax-summary.htm#egg-allergy.

Personal Protection Measures

Measures that may help prevent influenza virus infection and other infections during travel include avoiding close contact with sick people and washing hands often with soap and water (where soap and a safe source of water are not available, use of an alcohol-based hand sanitizer containing ≥60% alcohol is recommended). If you are ill, you can help prevent the spread of illness to others by covering your nose and mouth when coughing and sneezing and avoiding close contact with others during the illness.

The best way to prevent infection with animal-origin influenza viruses, including H5N1 and H7N9, is to follow standard travel safety precautions: follow good hand hygiene and food safety practices and avoid contact with sources of exposure. Most human infections with avian influenza viruses have occurred after direct or close contact with infected poultry. In countries where avian influenza virus outbreaks are occurring, travelers or those living abroad should avoid markets and farms where live animals are sold or raised, avoid contact with sick or dead animals, not eat undercooked or raw animal products (including eggs), and not eat or drink foods or beverages that contain animal blood.

CDC website: www.cdc.gov/flu

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Authors

Grace Appiah, Joseph Bresee