Influenza

Description

Influenza is caused by infection with either influenza A or B viruses. Influenza A viruses are further classified into subtypes on the basis of two surface proteins: hemagglutinin (H) and neuraminidase (N). Both influenza A and B viruses undergo continual minor antigenic change (i.e., drift), but influenza B viruses evolve more slowly and are not divided into subtypes. Influenza A (H1N1), A (H1N2), A (H3N2), and influenza B viruses currently circulate globally.

Occurrence

In the Northern Hemisphere, seasonal epidemics of influenza generally occur during the winter months on an annual or near annual basis and are responsible for approximately 36,000 deaths in the United States each year. Influenza virus infections cause disease in all age groups. Rates of infection are highest among infants, children, and adolescents, but rates of serious morbidity and mortality are highest among persons 65 years of age and persons of any age who have medical conditions that place them at high risk for complications from influenza (e.g., chronic cardiopulmonary disease). Children aged <2 years have rates of influenza-related hospitalization that are as high as those in the elderly. 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.

Risk for Travellers

The risk for exposure to 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, travellers can also be exposed to influenza during the summer, especially when travelling as part of large tourist groups with travellers from areas of the world where influenza viruses are circulating. Influenza vaccine should be recommended before travel for persons at high risk for complications of influenza if 1) influenza vaccine was not received during the preceding fall or winter, 2) travel is planned to the tropics, 3) travel is planned with large groups of tourists at any time of year, or 4) travel is planned to the Southern Hemisphere from April through September. In North America, travel-related influenza vaccination should take place by spring when possible, because influenza vaccine may not be available during the summer. Travellers at high risk for influenza-related complications who plan summer travel should consult with their physicians to discuss the symptoms and risks of influenza before embarking.

Clinical Presentation

Uncomplicated influenza illness is characterised 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. Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone, and laboratory testing can aid in diagnosis. Influenza illness typically resolves relatively quickly for most persons, although cough and malaise can persist for >2 weeks. Influenza can exacerbate chronic conditions (e.g., pulmonary or cardiac disease), leading to secondary infections and severe complications. Influenza-related deaths can result from pneumonia as well as from exacerbations of cardiopulmonary conditions and other chronic diseases.

Prevention

Vaccines

Annual vaccination of persons at high risk for complications before the influenza season is the most effective measure for preventing influenza and associated complications. Two types of influenza vaccine are currently available for use in the United States: inactivated vaccine, administered by intramuscular injection, and live, attenuated influenza vaccine (LAIV), administered by nasal spray. LAIV is approved for use only in healthy persons 5-49 years of age. Annual influenza vaccination is recommended for the following groups who are at high risk for complications from influenza:

Persons 50 years of age.
Residents of nursing homes and other chronic-care facilities that house people of any age who have chronic medical conditions.
Anyone 6 months of age who has a chronic disorder of the pulmonary or cardiovascular system, including asthma.
Anyone 6 months of age who has required regular medical follow-up or hospitalization during the preceding year because of a chronic metabolic disease (including diabetes mellitus), renal dysfunction, haemoglobinopathy, or immunosuppression (including immunosuppression caused by medications and HIV).
Anyone 6 months to 18 years of age who is receiving long-term aspirin therapy and might be at risk for developing Reye syndrome after influenza.
Women who will be pregnant during the influenza season.
Children aged 6-23 months.
Health-care workers and others (including household members) in close contact with persons at high risk for developing influenza-related complications.

Dosing, Timing, and Route of Vaccination

For persons at high risk for complications from influenza, annual vaccination is recommended because vaccine-derived immunity declines during the year and because the vaccine strains are continually updated to reflect ongoing antigenic changes among circulating influenza viruses. Dosage recommendations differ according to age group and type of vaccine used. For inactivated vaccine, two doses administered at least 1 month apart are required for previously unvaccinated infants and children <9 years of age. For previously unvaccinated children aged 5-8 years receiving LAIV, two doses are administered at least 6 weeks apart. For situations in which a child receives two different vaccine types, 4 weeks should separate doses if inactivated vaccine is used first, and 6 weeks should separate doses if LAIV is used first. 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. For inactivated vaccine, infants and young children should be vaccinated in the anterolateral aspect of the thigh; all other recipients should be vaccinated in the deltoid muscle. LAIV is administered by nasal spray.

The target groups for influenza and pneumococcal vaccination overlap considerably. For travellers 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.

Composition of the Vaccines

Both influenza vaccines contain three strains of inactivated influenza viruses. Viruses in inactivated vaccines are killed, while those in LAIV are live. These live viruses are attenuated and do not cause disease. 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. Influenza vaccine distributed in the United States may also contain thimerosal, a mercury-containing preservative. The package insert should be consulted regarding the use of other compounds to inactivate the viruses or limit bacterial contamination.

Adverse Reactions

Inactivated Vaccine

The most frequent side effect of vaccination with inactivated vaccine is soreness at the vaccination site that lasts up to 2 days. These local reactions generally are mild and rarely interfere with the ability to conduct usual daily activities. Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect people who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6 to 12 hours after vaccination and can persist for 1 to 2 days.

LAIV

The most frequent side effects of vaccination with LAIV include nasal congestion, headache, fever, vomiting, abdominal pain, and myalgia. These symptoms are associated more often with the first dose and are self-limited. There may be an increase in asthma or reactive airway disease in children aged <5 years, and LAIV is not approved for use among children in this age group.

Other Reactions

Allergic

Immediate reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions probably result from hypersensitivity to some vaccine component; most reactions likely are caused by residual egg protein and occur among people who have severe egg allergy. People who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to determine if vaccine should be administered. People who have documented immune globulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses due to exposure to egg protein, may also be at increased risk for reactions from influenza vaccine, and similar consultation should be advised. Protocols have been published for safely administering influenza vaccine to people with egg allergies.

Guillain-Barré Syndrome (GBS)

Investigations to date indicate no substantial increase in GBS associated with influenza vaccines (other than the "swine flu" vaccine of 1976). A study of the 1992-93 and 1993-94 influenza seasons estimated a risk of GBS of slightly more than 1 case per million people vaccinated. The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death greatly outweigh the possible risks for developing vaccine-associated GBS.

Precautions and Contraindications

Pregnancy

Many experts consider influenza vaccination with inactivated vaccine safe during any stage of pregnancy. A study of influenza vaccination of more than 2,000 pregnant women demonstrated no adverse foetal effects associated with influenza vaccine. Influenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect immune response and is not a contraindication for vaccination.

Persons Infected with HIV

Information is limited on the frequency and severity of influenza illness or the benefits of influenza vaccination among HIV-infected persons. On the basis of a risk-modeling study, the risk for influenza-related death among persons with AIDS appears higher than among those without AIDS. In addition, symptoms of influenza might be prolonged and the risk for complications from influenza increased for certain HIV-infected persons. HIV-infected persons who have minimal AIDS-related symptoms and high CD4+ T-lymphocyte cell counts can develop protective influenza antibody titers from influenza vaccine, and vaccination has been shown to prevent influenza in this group. However, influenza vaccine might not induce protective antibody titers in people who have advanced HIV disease and low CD4+ T-lymphocyte cell counts; a second dose of vaccine does not improve the immune response in these persons. Deterioration of CD4+ T-lymphocyte cell counts and progression of HIV disease have not been demonstrated among HIV-infected people who receive the vaccine. The effect of antiretroviral therapy on potential increases in HIV ribonucleic acid (RNA) levels following either natural influenza infection or influenza vaccine is unknown. Because influenza can result in serious illness and complications and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit many HIV-infected persons, including HIV-infected pregnant women.

Antiviral Medications

Influenza-specific antiviral drugs for chemoprophylaxis of influenza are important adjuncts to vaccine. The four currently licensed U.S. antiviral agents are amantadine, rimantadine, zanamivir, and oseltamivir. Amantadine and rimantadine are active against influenza A viruses but not influenza B viruses. Both drugs are approved by the U.S. Food and Drug Administration for the prophylaxis of influenza A virus infections. Oseltamivir has activity against both influenza A and B viruses and has been approved for prophylaxis. Amantadine and rimantadine are approved for prophylaxis in persons aged 1 year, and oseltamivir is approved for prophylaxis in persons aged 13 years.

Treatment

Amantadine and rimantadine are approved by the U.S. Food and Drug Administration for the treatment of influenza A virus infections. Zanamivir and oseltamivir are currently approved for treatment of both influenza A and B virus infections. These four drugs differ in dosing, approved age groups for use, side effects, and cost. The package inserts should be consulted for more information.

Bibliography

Harper SA, Fukuda K, Uyeki T, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunisation Practices (ACIP). Morbid Mortal Wkly Rep MMWR. 2004 May 28;53(RR-6):1-40.
Marsden AG. Influenza outbreak related to air travel. Med J Aust. 2003 Aug 4;179(3):172-3.
O'Brien D, Tobin S, Brown GV, et al. Fever in returned travellers: review of hospital admissions for a 3-year period. Clin Infect Dis. 2001 Sep 1;33(5):603-9.
Uyeki TM, Zane SB, Bodnar UR, et al. Large summertime influenza A outbreak among tourists in Alaska and the Yukon Territory. Clin Infect Dis. 2003 May 1;36(9):1095-102.
Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J. 2003;22(2):164-77.

- Scott Harper

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