Margaret McCarron, David K. Shay

Infectious Agent

• Influenza is caused by infection with influenza viruses.
• Human influenza viruses can be divided into three types: A, B, and C. Only types A and B cause widespread illness in humans.
• Influenza A viruses are further classified into subtypes on the basis of two surface proteins: hemagglutinin (H) and neuraminidase (N). There are 16 different hemagglutinin subtypes and 9 different neuraminidase subtypes.

Mode of Transmission

• Person-to-person transmission results from respiratory droplets of coughs and sneezes.
  • Most healthy adults can infect others beginning 1 day before symptoms develop and up to 5 days after becoming sick.
  • Children can pass the virus for longer than 7 days.
  • Fomite transmission is also possible.

Occurrence

Seasonal Influenza

• Infection with seasonal influenza viruses is common.
• In temperate climates in the Northern Hemisphere, annual seasonal epidemics of influenza generally occur during the winter months, while in the temperate regions of the Southern Hemisphere most activity occurs from April through September.
• In tropical and subtropical areas, influenza can occur throughout the year.
• CDC has estimated that U.S. epidemics during the 1990s were associated with an annual average of 36,000 influenza-related deaths.
• Influenza virus infections cause disease in all age groups. Rates of infection are highest among infants and children, but rates of serious morbidity and mortality are highest among persons ≥65 years of age and persons of any age who have medical conditions (e.g., chronic cardiopulmonary disease) that place them at increased risk for complications from influenza. Children <2 years of age have rates of influenza-related hospitalization that are as high as those in the elderly.

Avian Influenza

• Avian influenza refers to influenza A viruses usually found in birds. Influenza A viruses infect a broad range of avian species and several mammalian species, including humans, swine, and horses.
  • Most cases of avian influenza infection in humans have resulted from contact with infected poultry (e.g., domesticated chickens, ducks, and turkeys) or surfaces contaminated with secretions or excretions from infected birds.
  • The spread of avian influenza viruses from one ill person to another has been reported very rarely and has thus far been limited, inefficient, and unsustained.
• H5N1 is an influenza A virus, which is a type characterized by the ability to constantly undergo change. H5N1 virus has caused serious disease among wild birds and poultry on multiple continents. Human cases of H5N1 are very rare but have occurred in countries in Asia, Africa, Eastern Europe, and the Middle East since 2003. As of June 2008, only 385 human cases of H5N1 infection have been reported worldwide. These cases, however, are a concern because the mortality rate is high. There is a concern that H5N1 may gain the ability to spread easily between people. Vigilant monitoring for human infection and person-to-person transmission has become an important component of pandemic preparedness. For a current list of countries reporting outbreaks of H5N1 among birds, see the World Organization for Animal Health (OIE) website at www.oie.int/.
• The global influenza research community conducts surveillance for novel influenza viruses in travelers. In a 2007 review of returned U.S. travelers suspected of having H5N1 infection, no evidence of infection with novel viruses was reported. Surveillance continues for human infection with H5N1 in travelers.
• For current, continuously updated information, see CDC’s Avian Influenza website (www.cdc.gov/flu/avian/index.htm).

Pandemic Influenza

• The emergence of a novel human influenza A virus could lead to a global pandemic, during which rates of morbidity and mortality from influenza-related complications could increase dramatically. The public health threat of a pandemic arising from novel influenza A viruses, including influenza A (H5N1), becomes imminent only if the virus gains the ability to spread efficiently from one human to another.
• Such transmission has not yet been observed with the currently circulating A (H5N1) viruses. Although a few cases of limited person-to-person spread of H5N1 viruses have been reported as of June 2008, no instances of transmission continuing beyond one person are thought to have occurred.
• Because the situation has and may continue to evolve, for current information see the official U.S. government website for pandemic influenza (www.pandemicflu.gov).

Risk for Travelers

Seasonal Influenza

• The risk for exposure to seasonal influenza during international travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year, while in the temperate regions of the Southern Hemisphere most activity occurs from April through September.
• In temperate climates, travelers can also be exposed to influenza during the summer, especially when traveling as part of large tourist groups with travelers from areas of the world where influenza viruses are circulating.

Avian Influenza

• In those countries where H5N1 has occurred most people become infected through direct contact with birds (e.g., domesticated chickens, ducks, and turkeys) that were carrying the H5N1 virus or from surfaces contaminated with secretions or excretions from these birds. Direct contact could happen during activities such as—
  • Visiting poultry farms
  • Visiting live bird or poultry markets
  • Preparing or consuming uncooked or undercooked bird products (such as meat, eggs, or blood).
• Because the situation has and may continue to evolve, travelers can stay abreast of new developments by checking the following websites that are updated regularly:
  • U.S. government website for pandemic influenza (www.pandemicflu.gov/)
  • CDC’s Travelers’ Health website (wwwn.cdc.gov/travel/contentAvianFluInformation.aspx)
  • CDC’s Avian Influenza website (www.cdc.gov/flu/avian/)
  • WHO website (www.who.int/csr/disease/avian_influenza/en/index.html).

Clinical Presentation

• Onset of symptoms typically occurs 1–4 days after infection.
• Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness.
• Influenza illness typically resolves within 1 week for most persons, although cough and malaise can persist for >2 weeks. However, influenza virus infections can cause primary influenza viral pneumonia; exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease); lead to secondary bacterial pneumonia, sinusitis, or otitis; or contribute to co-infections with other viral or bacterial pathogens. Influenza-related deaths can result from primary illnesses, secondary bacterial pneumonia, or exacerbations of chronic cardiac or pulmonary conditions.
• Young children with influenza virus infection may have initial symptoms mimicking bacterial sepsis with high fevers, and febrile seizures have been reported in 6%–20% of children hospitalized with influenza virus infection. Population-based studies among hospitalized children with laboratory-confirmed influenza have demonstrated that, although the majority of hospitalizations are brief (2 days or less), 4%–11% of children hospitalized with laboratory-confirmed influenza required treatment in the intensive-care unit and 3% required mechanical ventilation. Among 1,308 hospitalized children in one study, 80% were <5 years of age and 27% were <6 months of age. Influenza virus infection also has been uncommonly associated with encephalopathy, transverse myelitis, myositis, myocarditis, pericarditis, and Reye syndrome.

Diagnosis

• Respiratory illnesses caused by influenza virus infection are difficult to distinguish from illnesses caused by other respiratory pathogens on the basis of signs and symptoms alone. Sensitivity and predictive value of clinical definitions can vary, depending on the degree of circulation of other respiratory pathogens and the level of influenza activity. Among studies conducted with children and adults, the positive predictive value of clinical signs and symptoms for laboratory-confirmed influenza virus infection has ranged from 30% to 88%.
• Laboratory testing can aid in diagnosis. Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction, and immunofluorescence assays.
• Respiratory specimens obtained via nasopharyngeal swabs typically yield better detection of influenza than specimens obtained via oropharyngeal swabs.
• Commercial rapid diagnostic tests are available that can detect influenza viruses within 30 minutes. Some tests are approved for use in any outpatient setting, whereas others must be used in a moderately complex clinical laboratory. These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Some tests can detect only influenza A viruses, some detect both influenza A and B viruses, but cannot distinguish between the two types, and some detect both influenza A and B and can distinguish between the two.
• None of the commercially available rapid tests provides any information about influenza A subtypes. The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal aspirates, swabs, or washes) also vary by test. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test. Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means because of the possibility of false-negative rapid test results.

Treatment

• Influenza-specific antiviral drugs for chemoprophylaxis of influenza are important adjuncts to the influenza vaccine.
• The four currently licensed U.S. antiviral agents are amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine have a mechanism of action effective only against influenza A viruses, while the neuraminidase inhibitors oseltamivir and zanamivir are effective against both influenza A and B viruses.
• Antiviral drug testing results conducted at CDC during the 2005–2006 influenza season, indicated 79% resistance among influenza A H3N2 viruses and 10% among H1N1. CDC recommends that neither amantadine nor rimantadine be used for the treatment or chemoprophylaxis of influenza A in the United States until susceptibility to these antiviral medications has been re-established among circulating influenza A viruses.
• Oseltamivir or zanamivir can be prescribed if antiviral treatment of influenza is indicated. Oseltamivir is approved for treatment of persons aged ≥1 year, and zanamivir is approved for treatment of persons ≥7 years of age. Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza; oseltamivir is licensed for use in persons ≥1 year of age, and zanamivir is licensed for use in persons ≥5 years of age. These two drugs differ in dosing, approved age groups for use, side effects, and cost. The package inserts should be consulted for more information.

Antiviral Resistance

• In the winter of 2007–2008, oseltamivir-resistant influenza A (H1N1) viruses were found to be circulating in several countries, including the United States, but the highest rates of resistance were found in Northern Europe. Oseltamivir resistance appears to be geographically variable, both within Europe and globally. In the United States, approximately 12% of H1N1 viruses from the 2007–2008 season were resistant to oseltamivir, resistance was highest in Europe at 26%, and overall global resistance was approximately 16%. The oseltamivir-resistant H1N1 viruses remained sensitive to amantadine and rimantadine. This strain of oseltamivir-resistant influenza A (H1N1) may continue to circulate in future seasons or may spread geographically. Oseltamivir and zanamivir remain the preferred antiviral drugs to be used in the treatment of influenza virus infection, given their relatively low levels of resistance compared with the high resistance found to amantadine and rimantadine among currently circulating influenza A viruses.
• Some H5N1 viruses currently infecting birds and humans are resistant to amantadine and rimantadine. Most of the H5N1 viruses tested have been susceptible to the antiviral medications oseltamivir and zanamivir, but resistance has been reported. The effectiveness of antivirals for treating H5N1 virus infections is unknown. For more information about influenza antiviral drugs, see www.cdc.gov/flu/avian/gen-info/avian-flu-humans.htm#antiviral.
• For more detailed information on influenza vaccines, treatment, and general prevention and control, please refer to “Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP)” (the most recent version is available at: www.cdc.gov/vaccines/pubs/ACIP-list.htm).

Preventive Measures for Travelers

• Handwashing and cough hygiene can play important roles in limiting person-to-person transmission of influenza. Where handwashing is not available, use of hand sanitizing gels containing greater than 60% alcohol can be used.
• Annual vaccination of persons at high risk for complications and vaccination of health-care workers and close contacts of high risk persons before the influenza season are the most effective measure for preventing seasonal influenza and associated complications.
• Vaccination of travelers is recommended when the vaccine is available and if there are no contraindications.

Vaccine

• Two types of influenza vaccines are currently available for use in the United States: trivalent inactivated vaccine (TIV), administered by intramuscular injection; and live, attenuated influenza vaccine (LAIV), administered by nasal spray. LAIV is approved currently for use only in healthy persons 2–49 years of age who are not pregnant.
• In the United States, annual influenza vaccination is recommended by CDC and ACIP for certain groups of people, primarily those who are at high risk of having serious flu complications or those who live with or care for those at high risk for serious complications. Annual recommendations are published by CDC and ACIP, including information about the season’s vaccine composition, dosage and administration, and recommendations for specific populations. The current version of these routine recommendations is available at www.cdc.gov/vaccines/pubs/ACIP-list.htm.
• The influenza vaccine must be administered annually to optimize protection because vaccine-derived immunity declines over time and because the vaccine strains must be updated regularly to reflect ongoing antigenic changes among circulating influenza viruses.
• Dosages differ according to age group and type of vaccine used. For inactivated vaccines, two doses administered at least 1 month apart are required for previously unvaccinated infants and children through 8 years of age. In adults, studies have indicated little or no improvement in antibody response when a second dose of inactivated vaccine is administered during the same season; therefore, a booster is not recommended. Inactivated vaccine should be administered in infants and young children in the anterolateral aspect of the thigh; all other recipients should be vaccinated in the deltoid muscle.
• The age groups for which influenza and pneumococcal vaccination are recommended overlap considerably. For travelers at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering pneumococcal and influenza vaccines concurrently. Both vaccines can be administered at the same time at different sites without increasing side effects. Infants and children can receive influenza vaccine at the same time they receive other routine vaccinations.
• Both influenza vaccines contain three strains of influenza viruses. Viruses in inactivated vaccines are killed, while those in LAIV are live. These live viruses are attenuated and do not cause influenza illnesses. The viruses used in both vaccines are representative of viruses likely to circulate in the upcoming season, and usually one or more vaccine strains are updated annually. Because the vaccine is grown in hen eggs, the vaccine may contain small amounts of egg protein. The package insert should be consulted regarding the use of other compounds to inactivate the viruses or to limit bacterial contamination.

Avian Influenza

• H5N1 infections in humans, though rare, can cause serious disease and death.
• CDC advises travelers to countries with known outbreaks of H5N1 to avoid—
  • Poultry farms
  • All poultry, whether or not symptomatic, and especially contact with sick or dead poultry
  • Contact with surfaces that may have been contaminated by poultry feces or secretions
  • Contact with animals in live food markets
• Since transmission of H5N1 viruses to two persons through consumption of uncooked duck blood may have occurred in Vietnam in 2005, uncooked poultry or poultry products, including blood, should not be consumed. Care should be taken when preparing these foods.
• For more information, see Human Infection with Avian Influenza A (H5N1) Virus Advice for Travelers (wwwn.cdc.gov/travel/contentAvianFluAsia.aspx) and the WHO Avian Influenza Fact Sheet (www.who.int/mediacentre/factsheets/avian_influenza/en/index.html#humans).
• A vaccine to protect humans against influenza A (H5N1) is not yet available commercially, but candidate vaccines are undergoing human clinical trials in the United States, with one vaccine currently licensed in the United States. This vaccine is approved by the U.S. FDA for stockpiling purposes only.

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