Feature Article
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An Annotated Flu Quiz for Clinicians From the Beth Israel Deaconess Hospital Medical Center. Drs. Burke and Kandel are Geriatricians in the Department of Gerontology. Dr. Kandel is also a geriatrician in the Department of Medicine, Hebrew Rehabilitation Center for Aged.
Influenza has affected individuals since ancient times and continues to be an important cause of morbidity and mortality. More than 90% of deaths due to pneumonia and influenza occur in individuals age 65 years and older. Vaccination remains the most effective intervention to reduce the morbidity and mortality associated with influenza; however, antiviral agents may be beneficial in certain situations. Effective management of influenza requires an understanding of the impact of the disease as well as strategies to control it. The “Flu Quiz” included in this article, with detailed responses, will allow the reader to test his or her knowledge and review the current literature on prevention and treatment of influenza. (Annals of Long-Term Care: Clinical Care and Aging 2003;11[11]:40-47)
Flu Quiz
Directions: Select True or False for each statement.
1. The influenza vaccine can be administered every other year because of the persistence of predominate strains in the environment. True or False
2. The current recommendations of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices include vaccinating all adults starting at age 65. True or False
3. Vaccination is the most effective way to reduce morbidity and mortality due to influenza infection. True or False
4. There is a small risk of getting influenza from the vaccine. True or False
5. Every patient with an influenza-like illness should undergo rapid viral testing to confirm the diagnosis. True or False
6. Influenza often presents as an indolent infection. True or False
7. In the elderly, symptoms of influenza infection may be atypical. True or False
8. Influenza is often self-limited; however, complications can occur, especially in high-risk individuals. True or False
9. There are two main types of antiviral agents for influenza A: the neuraminidase inhibitors and the adamantanes. True or False
10. There are two main types of antiviral agents for influenza B: the neuraminidase inhibitors and the adamantanes. True or False
11. The mechanisms of action for the antiviral agents for influenza are the same. True or False
12. A 65-year-old female with chronic obstructive pulmonary disease (COPD) comes to the office with influenza-like symptoms for the past 4 days in the setting of an influenza outbreak in the community. She might benefit from an antiviral agent. True or False
13. A 65-year-old female with COPD comes to the office with influenza-like symptoms for the past 1.5 days in the setting of an influenza outbreak in the community. She might benefit from an antiviral agent. True or False
14. For the patient described above, zanamivir would be the drug of choice. True or False
15. Only the adamantanes, not the neuraminidase inhibitors, are currently approved for prophylaxis. True or False
16. Drug dosage is the same for treatment and prophylaxis. True or False
Annotated Responses
1. The influenza vaccine can be administered every other year because of the persistence of predominate strains in the environment. False.
The influenza vaccine must be administered annually in order to be effective. The vaccine is modified each year, in order to more closely match the predicted strains of virus in the community. It can be administered throughout the influenza season; however, the optimum time for administration is during October and November.1,2 The vaccine usually includes strains representing two influenza A subtypes (H1N1 and H3N2) and influenza B. Both influenza A and B are associated with severe infection, though mortality rates are usually highest when there is significant influenza A (H3N2) activity.3,4
Viral strains change from year to year, either by antigenic drift or shift, due to the propensity of the virus to undergo rapid evolution.5 Antigenic drift, which is more common, refers to minor antigenic changes due to point mutations in the genes that code for the viral surface proteins, hemagglutinin and neuraminidase.3,6 This contributes to epidemics because immunity acquired to prior strains is no longer as effective. In contrast, pandemics are associated with major antigenic changes or shifts resulting in a new virus subtype.7 This occurs because of reassortment due to exchange of components of the viral genome of human strains with closely related animal strains.5,8 With pandemics, there is a widespread increase in influenza infections and associated increase in morbidity and mortality due to lack of prior exposure to this totally new viral subtype. Antigenic shifts only occur with the influenza A virus. There have been three pandemics in the 20th century, including the 1918-1920 outbreak that resulted in 20-40 million deaths.9
2. The current recommendations of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices include vaccinating all adults starting at age 65. False.
Immunization guidelines have recently been expanded to include individuals age 50 years and older based on the increased prevalence of high-risk conditions (see statement 3) in people 50-64 years old.1 Age-based strategies are believed to be more effective than those centered on medical problems. Individuals in this age group, without high-risk conditions, may also benefit from vaccination due to decreased risk of infection, decreased medical visits and antibiotic use, and fewer days absent from work.1, 2
Established guidelines have long included adults age 65 years and older based on studies that have consistently shown the benefits of vaccination. A retrospective, cohort study examined outcomes in elderly members of a managed care organization with a history of chronic lung disease.10 Over three influenza seasons, the study found that influenza vaccination was associated with a 52% reduction in hospitalizations for pneumonia and influenza and a 70% reduction in risk of death. When elderly individuals were stratified according to low, intermediate, or high risk based on underlying disease, the benefits of vaccination (ie, reduction of hospitalization for respiratory conditions and reduced deaths from all causes) were demonstrated in all three groups.11 In a prospective study conducted in Sweden, large-scale intervention with influenza and 23-valent pneumococcal vaccination of adults age 65 years and older resulted in a 46% reduction in hospitalizations for influenza, a 29% reduction for pneumonia, and a 57% reduction in overall mortality.12 In elderly nursing home residents, while vaccination was only 30-40% effective in preventing symptoms due to influenza, it was 50-60% effective in reducing hospitalizations and pneumonia and 80% effective in reducing death.1 In a recent study, influenza vaccination was associated with fewer strokes, especially in patients younger than 75 years old.13 It was unclear, though, whether this was due to a reduction of infection or some other cause, such as lack of access to health care.
3. Vaccination is the most effective way to reduce morbidity and mortality due to influenza infection. True.
Vaccination is the most effective way to reduce morbidity and mortality due to influenza infection. When there is a good match between the vaccine and circulating virus, effectiveness can be as high as 70-100% in protecting healthy adults.14 One of the main functions of the vaccine is to prevent complications associated with influenza, including pneumonia, hospitalizations, and death. On average, influenza epidemics have resulted in approximately 20,000 deaths in the United States annually (range 10,000-40,000), with the number increasing markedly during pandemic years.1 From 1968-1995, approximately 114,000 hospitalizations per year (range 16,000-220,000) were connected to influenza infections. Influenza vaccination is recommended for the following groups who are considered to be at increased risk for these complications:1
• Individuals age 50 years and older.
• Residents of long-term care facilities where individuals with chronic medical problems reside.
• Adults and children with chronic pulmonary or cardiovascular disease and active medical problems, including metabolic conditions (ie, diabetes), renal dysfunction, hemoglobinopathies, or immuno - suppression (eg, transplantation recipients or patients with HIV infection).
• Children or teenagers on long-term aspirin therapy due to the increased risk of Reye’s syndrome.
• Women in their second or third trimester of pregnancy during the influenza season.
Vaccination is also recommended for persons who may transmit influenza to high-risk individuals. These include health care workers, home care providers, household members, employees of assisted living and other similar facilities, and employees of long-term care facilities who have contact with high-risk individuals. Mortality rate is reduced among elderly residents when health care workers of long-term care facilities are vaccinated.15,16
Finally, anyone who wants the influenza vaccine should be allowed to have it based on availability.
4. There is a small risk of getting influenza from the vaccine. False.
The influenza vaccine is an inactivated preparation; it is noninfectious and cannot cause influenza. Viral infections associated with vaccine administration may be due to infection with other circulating respiratory diseases at time of vaccination. It is recommended that individuals with an acute febrile illness not be vaccinated until their infection has resolved.1
The influenza vaccine is usually well tolerated. Local side effects (ie, soreness at vaccination site) associated with vaccination are usually mild and self-limited. Systemic side effects (ie, fever, malaise, muscle aches) occur most often in persons, such as young children, with no history of exposure to viral antigens in the vaccine.1
The vaccine is contraindicated in individuals with severe allergy to eggs—the vaccine may include a small amount of egg protein because the virus is grown in eggs—and severe reaction to the vaccine, which is usually due to the egg allergy noted above. Rarely, there may be a delayed-type hypersensitivity reaction to the thimerosal preservative in the vaccine.14
It has been suggested to avoid use of the vaccine in individuals who are not at high risk for severe influenza complications and who have developed the Guillain- Barré syndrome (GBS) within 6 weeks after getting the influenza vaccine.1 The swine influenza vaccine of 1976 was associated with isolated cases of the GBS (attributable risk of one case per 100,000 persons vaccinated).2 The risk with current vaccines is reported to be extremely low. During the 1992-1993 and 1993-1994 influenza seasons, there was a slight excess risk of approximately one case per 1 million persons vaccinated, a risk substantially lower than the risk for severe influenza infection.1,14 For high-risk persons with a history of GBS, the decision regarding vaccination should be made on an individual basis. (Bridges et al1 cover this topic in more detail.)
5. Every patient with an influenza-like illness should undergo rapid viral testing to confirm the diagnosis. False.
The value of routine rapid viral testing in individual patients with influenza-like illness is unclear at present.8,17 When there is a localized outbreak, clinical diagnosis of influenza is very accurate.3,18 During peak activity in localized outbreaks, 50-70% of individuals with clinical symptoms have confirmed influenza infection.19 These findings highlight the importance of surveillance for influenza in guiding decisions.18,20 Websites that will alert the physician to influenza activity in the community include http://www.flustar.com and http://www.state(enter local state).us/dph.
Rapid diagnostic testing for influenza may be useful in institutional settings to aid in early detection of influenza and to exclude infections, such as respiratory syncytial virus, that may mimic influenza.3 Testing can also help in confirming diagnoses in critically ill patients or those with atypical presentations.8 The sensitivities of these tests range from 45-90% and the specificities from 60-95%.17
6. Influenza often presents as an indolent infection. False.
Influenza often presents abruptly, with some individuals recalling the exact hour of onset. Common signs and symptoms include chills, fever, myalgia, fatigue, headache, anorexia, nonproductive cough, sore throat, and rhinitis.1,3 A feature distinguishing influenza from other viral respiratory infections is the predominance of systemic symptoms. Of note, some healthy adults may have very mild or no symptoms.
7. In the elderly, symptoms of influenza infection may be atypical. True.
As with many conditions in the elderly, influenza can have an atypical presentation. Symptoms may include confusion, fatigue, and fever, though the temperature spike may not be as high as in younger individuals.3,21
8. Influenza is often self-limited; however, complications can occur, especially in high-risk individuals. True.
Influenza predisposes high-risk individuals to bacterial superinfections often presenting as pneumonia.22 The most common bacterial pathogens contributing to pneumonia in this setting include Streptococcus pneumoniae (most common), Haemophilus influenza, or Staphylococcus aureus.3 A public health advisory has been issued by the U.S. Food and Drug Administration (FDA) for clinicians to consider primary or concomitant bacterial infections in individuals with influenza. This was written in response to several reported cases of serious bacterial infections treated with antiviral medications alone.23 Primary viral pneumonia due to influenza is associated with high mortality but is rare.3
Other complications associated with influenza infections include exacerbation of COPD and cardiac conditions such as congestive heart failure.6,24 Rare complications include myocarditis, pericarditis, transverse myelitis, and encephalitis.1,3 Myositis and myoglobinuria occur more commonly in children but can be seen in adults.3
9. There are two main types of antiviral agents for influenza A: the neuraminidase inhibitors and the adamantanes. True.
There are currently four antiviral agents approved for the treatment of influenza A. Neuraminidase inhibitors include oseltamivir and zanamivir. The adamantanes include amantadine and rimantadine.
10. There are two main types of antiviral agents for influenza B: the neuraminidase inhibitors and the adamantanes. False.
Only the neuraminidase inhibitors are approved for treatment of influenza B based on their mechanisms of action. The adamantanes are beneficial only for the treatment of influenza A (see statement 11).
11. The mechanisms of action for the antiviral agents for influenza are different. True.
The mechanisms of action for the two classes of antiviral agents are different.
Neuraminidase Inhibitors . Neuraminidase and hemagglutinin are glycosylated surface antigens that form spike-like protrusions on the influenza virus.20,25 In order for the virus to replicate within the host cell, hemagglutinin must first bind to sialic acid residues on the host cell surface, facilitating entry.8 After the virus replicates in the cell, newly formed viral particles are released that contain sialic acid residues on their surface. Hemagglutinin could potentially bind to these sialic acid residues on the newly formed viral particles (as well as on the host cell), resulting in self-aggregation of the virus and limiting the spread of infection. This does not occur, because neuraminidase enzymatically removes sialic acid from both the newly formed viral particles and the host cell. Neuraminidase inhibitors, analogues of sialic acid, competitively inhibit neuraminidase by binding to it more readily than sialic acid. These drugs may also prevent viral penetration through mucous secretions.25
Adamantanes. The adamantanes block the ion-channel activity of the influenza A virus M2 protein. This inhibits viral replication by causing interference with both viral uncoating and transfer of viral RNA to the host cell cytoplasm and their transition to the nucleus. Because only influenza A has M2 proteins, the adamantanes are not effective against influenza B.14,26
12. A 65-year-old female with COPD comes to the office with influenza-like symptoms for the past 4 days in the setting of an influenza outbreak in the community. She might benefit from an antiviral agent. False.
Antiviral agents are only effective in reducing illness duration when treatment is initiated within 48 hours of disease onset.
13. A 65-year-old female with COPD comes to the office with influenza-like symptoms for the past 1.5 days in the setting of an influenza outbreak in the community. She might benefit from an antiviral agent. True.
As noted above, antiviral agents cause a reduction in symptom duration by about 1 day if started within 48 hours of symptom onset. This, therefore, would be the correct time to start treatment. While it seems reasonable to initiate antiviral therapy in this case (or in similar cases of influenza occurring within high-risk groups), it is not entirely clear if there are any additional benefits of treatment for these individuals.
The effectiveness of oseltamivir and zanamivir in reducing duration of symptoms has been demonstrated in numerous trials. In large, randomized studies, treatment with oseltamivir within 36 hours of symptom onset for 5 days resulted in a 1-day reduction in illness duration with greater reduction (1.5-2 days) if the drug was started within 24 hours.27,28 Treatment was associated with less viral shedding, improved health, better functional ability, and less sleep disturbance.27 Numerous studies have shown that treatment with zanamivir reduced duration of symptoms by 1 day when administered within 48 hours of influenza-like illness and continued for 5 days29-34 with greater reduction if the drug is started earlier (30-36 hours of symptom onset).29-31
The main problems with these studies have been the lack of representation of both high-risk individuals and those with influenza B infection. In one oseltamivir treatment study, some secondary complications (ie, sinusitis, bronchitis) were significantly reduced; however, these problems occurred in a limited number of participants.28 In the few zanamivir studies that included a small subset of high-risk individuals, treatment resulted in a shorter duration of symptoms, fewer complications, and less antibiotic use.30,31 Of note, only a minority of these participants were elderly, and most were considered high-risk based on the diagnosis of asthma. Finally, a pooled analysis of randomized controlled trials was conducted to examine the efficacy of zanamivir treatment in high-risk individuals (ie, elderly, those with chronic respiratory disease).33 Participants treated with zanamivir had a reduction of symptoms by about 2.5 days compared with placebo and reduction of the incidence of complications requiring antibiotics, and the drug was well-tolerated. Although these preliminary results are promising, there is insufficient information at present regarding the effectiveness of neuraminidase inhibitors in reducing the morbidity and mortality associated with influenza.
The adamantanes appear to have similar efficacy in treatment of influenza, and in reducing viral shedding and symptom duration when begun within 48 hours of disease onset. However, as noted above, they are limited to the treatment of influenza A.1,35,26 As with the neuraminidase inhibitors, reduction of serious complications of influenza has not been clearly documented with the adamantanes either.
14. For the patient described above, zanamivir would be the drug of choice. False.
Although efficacy is similar among the antiviral agents, their side-effect profiles differ. Zanamivir is administered by oral inhalation using a specially designed device. Although it is usually well tolerated, some problems have been noted with the drug. Use of zanamivir has been associated with bronchospasm in individuals with underlying asthma or COPD. The FDA has issued a warning that the drug is not generally recommended for individuals with these conditions due to risk of serious adverse events.23,36 There is also evidence that some elderly people have a difficult time using the inhalation device required for administration of the drug.37
Oseltamivir could be used in this case because it is not associated with respiratory complications. It is generally well tolerated, with main side effects including mild-to-moderate gastrointestinal symptoms (ie, nausea, vomiting) that are diminished by taking the medicine with food.
One might also consider the adamantanes if influenza A is circulating in the community. The adamantanes are less expensive than the neuraminidase inhibitors but have more side effects. Although amantadine and rimantadine are both associated with central nervous system adverse events (eg, confusion, anxiety, difficulty concentrating, lightheadedness, and hallucinations),1 these events are significantly less with rimantadine than amantadine.38 Amantadine may lower seizure threshold in patients with preexisting seizure disorders. While seizures have also been associated with rimantadine use, occurrence is less frequent.1,35 Both drugs are associated with gastrointestinal side effects, including nausea and anorexia (1-3%).1 Of note, the dosing regimen for amantadine is more complicated than with rimantadine in individuals with renal insufficiency.
Finally, resistance to the adamantanes develops frequently and rapidly.35,39 In immunocompetent adults, resistant viral isolates occur in 10-30% of individuals, although the incidence is probably higher in immunocompromised patients.40 Although resistance to the neuraminidase inhibitors has been documented in vitro and in treated patients, it appears to be an uncommon problem.41-43 When rimantadine was used for both treatment of influenza and prophylaxis of household contacts, resistant strains were transmitted to contacts and resulted in a typical influenza infection.44 To limit drug resistance, treatment with the adamantanes is usually discontinued after 3-5 days or within 24-48 hours after symptom resolution.1,35 Zanamivir was effective at terminating an amantadine-resistant influenza A outbreak in a nursing home.45
15. Only the adamantanes, not the neuraminidase inhibitors, are currently approved for prophylaxis. False.
Vaccination is the most effective intervention to prevent influenza. Antiviral agents, however, may be beneficial in certain situations. The adamantanes, approved for prophylaxis of influenza A, are 70-90% effective in prevention of illness due to influenza A infection.1,35,46 Oseltamivir is approved for prophylaxis of influenza A and B. Though zanamivir has not been approved, studies suggest that it is effective for prophylaxis as well.
There are numerous drug trials demonstrating the effectiveness of the neuraminidase inhibitors for the prophylaxis of influenza. Oseltamivir administered to household contacts within 48 hours of exposure to a family member with influenza resulted in an 89% reduction of clinical influenza.47 When administered to healthy, nonvaccinated adults (18-65 years old) for 6 weeks during peak influenza season, oseltamivir significantly reduced laboratory-confirmed influenza.48 A recent study demonstrated its effectiveness in a frail, older population (mean age, 81 years; vaccination rate more than 80%) living in residential homes for the elderly.49 Oseltamivir resulted in a significant reduction in the incidence of laboratory-confirmed clinical influenza, and in secondary complications, and was well tolerated. Of note, the overall number of confirmed cases of influenza in both treatment and placebo groups was low. Effectiveness of zanamivir for prophylaxis of influenza has been demonstrated as well. In one study, zanamivir effectively prevented laboratory-confirmed clinical influenza (67%), confirmed influenza with fever (84%), and influenza infections with and without symptoms (31%) in healthy adults (age 18-69 years) when administered daily for four weeks during an influenza outbreak.50 Spread of influenza within families was significantly reduced by zanamivir in a placebo-controlled study.51
Antiviral agents may be helpful for prophylaxis against influenza for the following persons:
• High-risk individuals, during the influenza season or with peak activity, who cannot take the vaccine due to severe egg allergy.
• High-risk individuals who have just been vaccinated during an influenza outbreak or after exposure to a known case (it takes 2 weeks for the vaccine to be effective).
• All nursing home residents (independent of vaccination status) during institutional influenza outbreaks.
• High-risk individuals when there is a poor antigenic match between circulating virus and vaccine.
• Persons (especially high-risk individuals) exposed to influenza in the household.
(Of note, if one of the adamantanes is used for prophylaxis, consider concurrent treatment of index case with a neuraminidase inhibitor to avoid transmission of resistant strains).
16. Drug dosage is the same for treatment and prophylaxis. False.
Treatment and prophylaxis dosages are as follows. (Please refer to product information for latest recommendations.) G
Ruth Kandel, MD, was an investigator in a Glaxo Wellcome-sponsored multicenter research project investigating the efficacy and safety of zanamivir in a nursing home population during the 1997-1998 influenza season.
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40. Englund JA, Champlin RE, Wyde PR, et al. Common emergence of amantadine and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis 1998;26(6):1418-1424.
41. Barnett J, Cadman A, Gor D, et al. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother 2000;44(1):78-87.
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43. Gubareva LV, Kaiser L, Matrosovich MN, et al. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 2001;183(4):523-531.
44. Hayden FG, Belshe RB, Clover RD, et al. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 1989;321(25):1696-1702.
45. Lee C, Loeb M, Phillips A, et al. Zanamivir use during transmission of amantadine-resistant influenza A in a nursing home. Infect Control Hosp Epidemiol 2000;21(11):700-704.
46. Sears SD, Clements ML. Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus. Antimicrob Agents Chemother 1987;31(10):1470-1473.
47. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: A randomized controlled trial. JAMA 2001;285(6):748-754.
48. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341(18):1336-1343.
49. Peters PH Jr, Gravenstein S, Norwood P, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001;49(8):1025-1031.
50. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: A randomized controlled trial. JAMA 1999;282(1):31-35.
51. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med 2000;343(18):1282-1289. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 11 - Issue 11 - November 2003 |