Take Test
Influenza is a highly contagious respiratory infection that's caused by a variety of influenza viruses. The illness produced by the virus can be mild to severe, and can even lead to death. Seasonal flu refers to the anticipated outbreak that occurs each year usually in late fall and winter. Typically, between 5% and 20% of the population in the United States is infected each year.1
 | Figure. No caption available. |
Influenza isn't just a nuisance illness that causes misery for the infected; the tolls of the disease are far-reaching. More than 200,000 of those infected with influenza each year will require hospitalization, and 36,000 will die from complications related to influenza, such as pneumonia, encephalitis, and respiratory failure.2
Historically, influenza is responsible for a massive number of deaths worldwide. In the pandemic of 1918-1919 during World War I, more than 675,000 Americans died from influenza—10 times the number who died in the actual war. Moreover, 20 to 40 million people in the world died from influenza during that time period.3
Influenza spread
Influenza is a highly contagious viral illness that spreads readily via droplet transmission, primarily from coughing and sneezing. The incubation period is 1 to 4 days, and the average is 2 days.1,4 One factor that facilitates the spread of influenza is that people are able to transmit the disease even before they display noticeable symptoms, and remain contagious for up to 5 days after the symptoms appear. Children are often contagious 10 days after the onset of symptoms. People who are immunocompromised can shed the virus for up to 3 weeks after the illness begins.5
Influenza spreads readily in closed environments, particularly schools and daycare centers. Not only does it spread by person-to-person contact, influenza can also survive for up to 2 hours on surfaces such as doorknobs, desks, phones, and counters.5,6
The groups that are at risk for developing complications following infection with influenza include the following: over age 65, under age 5, concurrent medical illness for any age, and immunocompromised state. The two highest risk groups that are hospitalized most frequently are those over 65 and those under 2 years of age.6,7 Children are two to three times more likely to get the flu than adults, and they frequently spread the virus to others. Younger children are particularly vulnerable to influenza, as they don't have natural immunity. Children who suffer with chronic disease such as diabetes or asthma are more likely to be hospitalized with complications such as pneumonia, dehydration, Reye's syndrome, croup, bronchiolitis, and ear infections.6,7
The elderly account for up to 90% of the deaths related to influenza.7 The effects of influenza are more profound for the elderly for several reasons. First, they're more likely to suffer from comorbidities that predispose them to influenza complications6 and have diminished immunologic response to influenza antigens. This is mostly due to reduced T-cell response, which should assist with recognition of infected cells' outer layers. After age 50, T-cell response begins to lessen, and by age 70 or 80, the response is markedly reduced.8 There's recent evidence to suggest that in elderly patients, intradermal injection of influenza vaccine may be more effective than an intramuscular injection because a more rapid immune response can be produced where a higher concentration of immune cells reside.9
Data from one retrospective study suggest that morbidity associated with influenza may have a heritable component. In the study, family members of people who died from influenza were more likely to also suffer a poor outcome related to influenza, suggesting a predisposition to death.10
Types of influenza
The three types of influenza virus are A, B, and C. Influenza A and B are the culprits associated with seasonal epidemics, but influenza C generally causes a mild respiratory illness that doesn't instigate an epidemic.
The flu virus contains eight single strands of RNA to make new copies of the virus. The outer layer of spike-like projections is characteristic of flu virus. There are two types of spikes: protein hemagglutinin, which has a sticky surface that allows it to adhere to a cell to infect it, and protein neuraminidase, which facilitates the exit of newly formed virus cells from host cells.5,6
Type A is the most troublesome. It's responsible for the major influenza epidemics of 1918, 1957, and 1968. Type A subtypes are classified by naming the strain, a lab identification number, year discovered, and the type of protein (hemagglutinin [H] and neuraminidase [N]) it possesses. For example, consider A/Hong Kong/156/97 (H5N1).5,6
Influenza is divided into subtypes according to the two proteins on the viral surface: H and N. Although there are 16 different hemagglutinin subtypes and 9 different neuroaminidase subtypes, only subtype A (H1N1) and subtype A (H3N2) are found in people. Type B isn't divided into subtypes, but is further broken down into different strains. These three are included in a vaccine each year but subtype C isn't.11
Etiology of influenza
Influenza virus is found in aquatic birds (such as ducks and shore birds) where it has persisted for millions of years, incapable of hurting the host bird. However, if the virus mutates, it can “jump” the species barrier from wild birds to domesticated ducks and chickens to (eventually) pigs. Pigs can become infected by both avian and human influenza virus. In this setting, the reassorted flu virus may reflect an exchange of genes between the two viruses that can spread from pigs to humans.5,6,12
In 1997, scientists discovered that bird influenza skipped the pig and directly infected humans. As it didn't appear to spread from human to human, the virus didn't cause an epidemic. H5N1 avian flu virus would need to infect cells via hemagglutinin-binding proteins by adapting to the glycans of the upper respiratory tract. Currently, H5N1 virus binds to a different glycan than human influenza virus, preventing its efficient spread.13
Influenza virus is highly changeable. Small, continuous changes that happen in type A and type B influenza are called antigenic drift. Because this drift produces a new strain of virus that's unrecognized by the human immune system, a new flu vaccine must be produced each year to match that year's prevalent strain.5
Type A virus can also make sudden, infrequent changes called antigenic shift. This occurs when two different flu strains infect the same cell and exchange genetic material. This can create a new influenza subtype that's capable of producing a severe flu epidemic or pandemic because there's little to no immunity associated with it. The influenza epidemic of 1918 resulted from this pathophysiologic mechanism and was responsible for millions of deaths worldwide.3,5
Symptoms of influenza and diagnosis
The flu is different from a common cold in several respects. Influenza is notable for producing fever, usually quite high. Additional symptoms include headache, myalgia, fatigue, sore throat, cough, and stuffy or runny nose, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea (more common in children than adults). The symptoms of sudden onset, fever at onset, headache, and cough are most useful for making a clinical diagnosis and carry a 75% positive predictive value.4
Because early treatment with antivirals can mitigate some of the severe symptoms, influenza should be diagnosed quickly. Early diagnosis is also key to avoiding unnecessary antibiotics. Accurately diagnosing influenza is somewhat difficult because several bacterial infections can masquerade as influenza or coexist as a complication of influenza. It's important to identify bacterial infections and treat them appropriately.4,6
The diagnosis based on symptoms can be assisted by surveillance information as well as diagnostic testing. State and local health departments, as well as the CDC, can alert providers about the incidence of influenza and the influenza A subtypes and strains occurring in the community. Being aware of the presence of influenza and the particular strain assists healthcare providers in accurately diagnosing influenza by finetuning their index of suspicion.6,14,15
Viral culture, serology and rapid antigen testing, polymerase chain reaction (PCR), and immunofluorescence assays are available for the diagnosis of influenza. Nasopharyngeal swabs or nasal washing are preferred over throat swab specimens to enhance the sensitivity and specificity of the test. Some outpatient rapid commercial diagnostic tests are available as well; however, they differ in their ability to distinguish among viral types. Some can detect the presence of type A viruses only or both influenza A and B viruses, either with or without the ability to distinguish between the two types. None of them can detect A subtypes.6,14,15 PCR tests yield results in 30 minutes and are 85% to 95% sensitive.4
Rapid tests have lower specificity and sensitivity than viral culture; therefore, all negative results should be further tested by viral culture to reduce the chance of false negativity, especially during the peak flu season.6,14 The positive and negative predictive values should be considered in context with the community's influenza activity. The CDC recommends obtaining viral cultures for the following reasons: to detect circulating strains and subtypes of virus, to compare strains with vaccine strains, to specify proper treatment, to help predict vaccine content for the coming year, to identify antiviral resistance patterns, and to survey for new influenza A subtypes that may bring a pandemic outbreak.14,15
Treatment of influenza
Although not all patients require antiviral medications, the high risk or severely ill should receive them within 48 hours of symptoms to lessen the likelihood of complications.6 There are four available antiviral medications used to treat influenza. (See Pharmacologic agents to treat influenza.) The first two are neuroaminidase inhibitors that block the ability of the virus to infect and spread to other cells. Oseltamivir (Tamiflu) is indicated for preventing and treating uncomplicated influenza A and B in adults and children age 1 and older. It's available in pill form as well as a pediatric liquid formulation.5,6
Zanamivir (Relenza) is indicated for treating uncomplicated influenza A and B in children age 7 or older, or for adults who have had symptoms for no more than 2 days. It's approved for preventing influenza A and B virus in adults and children age 5 and older. It's delivered as an inhaled powder via a dry-powder inhaler.5,6
 | Table. Pharmacologic agents to treat influenza |
The next two compounds inhibit viral replication in the host cell. Rimantadine (Flumadine) is indicated for adults with influenza A virus; it has no effect on influenza B. Amantadine (Symmetrel) is indicated for adults and children 1 year or older; it's used to prevent and treat type A influenza only. To maximize effectiveness, these medications need to be started within 48 hours of onset of influenza. They reduce the length of time symptoms persist, particularly fever. They both are available in pill form.5,6
The CDC no longer recommends use of rimantadine or amantadine due to the high resistance of influenza A virus. Resistance to both was high among influenza A (H3N2) viruses globally and variable among influenza A (H1N1).6,16
Oseltamivir resistance was detected in A (H1N1) viruses in several countries in varied places, and those viruses remained sensitive to amantadine and rimantadine. Recently, oseltamivir and zanamivir received safety warnings regarding the risk for neuropsychiatric adverse effects, including delirium, abnormal behavior, fatal self-injury, and seizures, particularly in children and adolescents.17
Influenza vaccines
The most effective way to manage influenza is to prevent the illness with a yearly administration of influenza vaccination. The vaccine is estimated at 70% to 90% effective for healthy adults and children.6 While October and November are the best times to receive a flu shot, it's never too late in the flu season to be vaccinated. The Advisory Committee on Immunization Practices (ACIP) of the CDC recently expanded recommendations to include 5- to 18-year-olds. Because of the necessity for widespread planning to ensure vaccination of all appropriate children, the ACIP has targeted the 2009-2010 season for full implementation of the new recommendation. It's anticipated that full-scale campaigns, such as school-based vaccine clinics, may be necessary to implement the goal of vaccinating children.6
The CDC specifically recommends vaccination for:
* children 6 months to 18 years of age
* children and adolescents at high risk for influenza complications should continue to be the focus of vaccination efforts, including children 6 months to 4 years of age, those with chronic conditions, and those receiving long-term aspirin therapy (may be at risk for Reye syndrome after influenza infection)
* anyone 50 years of age and older
* women who will be pregnant during the flu season
* adults or children with chronic pulmonary, cardiovascular, renal, hepatic, hematological, or metabolic disorders
* adults and children with immunosuppression or HIV
* individuals with any condition that can compromise respiratory function
* residents of long-term-care facilities, such as nursing homes
* healthcare workers
* healthy household contacts.6
Because children are frequent carriers of disease to others in close contact with them (other children, family members, caregivers, babysitters, teachers), it's vital to vaccinate them to prevent the spread of influenza. The vaccine isn't approved for use in children under the age of 6 months, so all who come into contact with them should be vaccinated to help provide herd immunity. Children under 9 years of age who are being vaccinated for the first time or who only received one dose the first year need to receive vaccination early in the flu season, as they require two doses (1 month apart) to be fully effective.6
The influenza vaccine can induce an immune reaction to the two surface glycoproteins—neuraminidase and hemagglutinin—that offer protection from influenza infection. There are two vaccines available: trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV). (See Approved influenza vaccines for different age groups—United States 2008-2009 season.)
TIV is injected intramuscularly. It has been the most extensively studied and has a well-established safety profile. Soreness at the injection site is the most commonly reported adverse reaction versus placebo in adults. The vaccine still suffers from perceptions that it can cause influenza or Guillain-Barré syndrome. Because of well-publicized vaccine shortages, the public still erroneously perceives that it isn't widely available. The vaccine is still somewhat less effective in preventing influenza in the very young (younger than 9 years) and in the frail and elderly (65 and older).6
 | Table. Approved influenza vaccines for different age groups–United States 2008-2009 season |
In a Cochrane review of vaccination effectiveness for young adults that included a review of 48 reports, TIV was 80% (95% confidence interval [CI] 56% to 91%) efficacious against influenza when the vaccine matched the circulating strain and circulation was high; however, it decreased to 50% (95% CI 27% to 65%) when it didn't.18
Although widely available and considered highly effective, the vaccine is still underutilized among certain groups, such as minority ethnic groups, low socioeconomic status, young people with chronic diseases, and healthcare professionals.19 Healthcare professionals are most often cited as avoiding the influenza vaccine due to the need for an intramuscular injection, and consequently, the rate of vaccination is estimated at only 40%.20
LAIV was created to help address the perceived problems associated with TIV. Because it's given intranasally, an intramuscular injection is eliminated. As it needs to be in a cool environment to replicate, LAIV doesn't replicate at core body temperature; instead it only produces immunity in the cooler upper airways. This favors its inability to produce illness in the recipient when it's systemically absorbed.6
LAIV is slightly more expensive than TIV and may be associated with mild upper respiratory infection. There are five other misconceptions regarding the vaccine that need to be addressed to improve its acceptance in the community. (See Five myths associated with live attenuated influenza vaccine.) Of note, none of the common myths have been reproduced in trials or with use in the community since 2003.19
The current recommendation for LAIV is for healthy people ages 2 to 49 years. People with underlying chronic conditions such as pulmonary, cardiovascular, metabolic, renal, or hematologic diseases should receive TIV instead. Healthcare professionals can receive either vaccine; however, it's recommended that if they're in contact with severely immunocompromised patients, they should receive the TIV.6,19
Strategies to increase vaccination rates
Vaccinations are usually conducted in primary care or public health settings across the country. However, rates of vaccination against a potentially deadly disease remain low in spite of the presence of highly effective, safe vaccines. New evidence shows that in the National Health Interview Survey study of 1,248 subjects with asthma, only 36% were vaccinated against influenza between September 2005 and February 2006. Because of the risk of severe complications, people with asthma should receive the influenza vaccine.21
Investigators noted several strategies to increase vaccination rates that are useful in practice. In general, reminder systems implemented to prompt people to seek vaccination, such as postcards, letters, telephone, or auto dialer calls, are highly effective but can be costly and time consuming for primary care and public health agencies.22
The CDC recommends several other strategies to improve vaccination rates. Maintaining standing orders at primary care offices, implementing computerized record reminders, chart reminders (colorful stickers or checklists), performance feedback for healthcare providers (tracking percentage of vaccinated patients in the agency), using home health workers to reach home-bound patients, and implementing drop-in clinic access for patients are highly effective ways to improve rates of vaccination.6,21,22
Influenza vaccine
The forecast for flu season 2008-2009 is formulated on the data collected over the previous year. The World Health Organization recommends obtaining and distributing flu vaccine information twice a year, with pertinent data collected from 118 influenza centers in 84 countries. In the United States, the FDA determines the flu vaccine constituents.
Influenza vaccine for the 2008-2009 season consists of three viral strains: influenza A (H3N2), influenza A (H1N1), and influenza B virus. When the vaccine is well-matched with the anticipated strains, the vaccine can be expected to reduce the chances of getting influenza by 70% to 90% among healthy adults. Even if not well-matched, receiving vaccination will lessen the patient's impact of illness.6 Based on surveillance data and forecasts from the previous years, the FDA's Vaccines and Related Biological Products Advisory Committee recommend the following constituents for the trivalent vaccine for 2008–2009:
* A/Brisbane/59/2007 (H1N1)-like virus
* A/Brisbane/10/2007 (H3N2)-like virus
* B/Florida/4/2006-like virus.23,24
Rapid diagnosis important
Because it's linked with high morbidity and mortality rates among vulnerable populations, influenza should be regarded as a potentially deadly condition. It's important to diagnose it rapidly so that antiviral medications can be used. Still, the best approach is prevention with influenza vaccine.
Five myths associated with live attenuated influenza vaccine
REFERENCES
1. Centers for Disease Control and Prevention. 2007-2008 Influenza prevention and control recommendations. Clinical signs and symptoms. http://www.cdc.gov/flu/professionals/acip/clinical.htm . [Context Link]
2. Thompson WW, Shay DK, Weintraub E, et al. Influenza activity-associated hospitalizations in the United States. JAMA. 2004;292:1333–1340. [Context Link]
3. Billings M. The influenza pandemic of 1918. RDS 2005. http://virus.stanford.edu/uda/ . [Context Link]
4. Worrall G. Influenza. Canadian Family Physician. 2008;54:415–416. [Context Link]
5. National Institute of Allergy and Infectious Disease (NIAID). Understanding the flu virus. http://www3.niaid.nih.gov/topics/Flu/understandingFlu/ . [Context Link]
6. Centers for Disease Control and Prevention. Prevention and control of influenza-recommendations of the Advisory Committee on Immunization Practices (ACIP). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.htm . [Context Link]
7. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333–1340. [Context Link]
8. Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis. 2007;7:658–666. [Context Link]
9. Bennett S. Flu shot under skin may improve protection for aged. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=auHDkkYbFF8Y . [Context Link]
10. Albright FS, Orlando P, Pavia AT, et al. Evidence for a heritable predisposition to death due to influenza. J Infect Dis. 2008;197:18–24 [Context Link]
11. Centers for Disease Control and Prevention. Types of flu viruses. http://www.cdc.gov/flu/about/viruses/types.htm . [Context Link]
12. Centers for Disease Control and Prevention. Infection control guidance for prevention and control of influenza in acute care facilities. http://www.cdc.gov/flu/professionals/infectioncontrol/healthcarefacilities.htm . [Context Link]
13. Carlson E. Study of sugars on cell surface identifies key factor in flu infection. US Department of Health and Human Services. NIH News 2008. http://www.nih.gov/news/pr/jan2008/nigms-06.htm . [Context Link]
14. Centers for Disease Control and Prevention. Influenza-testing and antiviral-agent prescribing practices-Connecticut, Minnesota, New Mexico, and New York, 2006–07 influenza season. MMWR. 2008; 57(3):61–65. [Context Link]
15. Centers for Disease Control and Prevention. Role of laboratory diagnosis of influenza. http://www.cdc.gov/flu/professionals/diagnosis/labrole.htm . [Context Link]
16. Altman LK. Mutant flu virus is found that resists popular drug. http://www.nytimes.com/2008/01/31/health/31flu.html?_r=1&oref=slogin . [Context Link]
17. Waknine Y. Antiviral drug labels get warnings for neuropsychiatric changes. http://www.medscape.com/viewarticle/570996_print . [Context Link]
18. Jefferson TO, Rivetti D, DiPietrantoni C, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database of Syst Rev. 2006;4. [Context Link]
19. Tosh PK, Boyce TG, Jacobson RM. Five myths associated with live attenuated influenza vaccine. Mayo Clin Proc. 2008;83:77–84. [Context Link]
20. Poland GA, Tosh P, Jacobson RM. Requiring influenza vaccination for healthcare workers: seven truths we must accept. Vaccine. 2005; 23(17–18):2251–2255. [Context Link]
21. Centers for Disease Control and Prevention. Department of Health and Human Services. Strategies for increasing adult vaccination rates. http://www.cdc.gov/vaccines/recs/ratestrategies/adultstrat.htm . [Context Link]
22. Jacobson Vann JC, Szilagyi P. Patient reminder and patient recall systems for improving immunization rates. [Systematic review] Cochrane Effective Practice and Organisation of Care Group. Cochrane Database of Syst Rev. 2005;2. [Context Link]
23. Centers for Disease Control and Prevention. Department of Health and Human Services. Interim within-season estimate of the effectiveness of trivalent inactivated influenza vaccine-Marshfield, Wisconsin, 2007-2008 influenza season. MMWR. 2008;57(15): 393–397;404–409. [Context Link]
24. World Health Organization. Recommended composition of the influenza virus vaccines for use in the 2008-2009 influenza season. http://www.who.int/csr/disease/influenza/recommended_compositionFeb08FullReport.pdf . [Context Link]