Feature Article
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Prevention and Treatment of Influenza in the Long-Term Care Facility Ms. Arden is Research Associate, Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX; Adjunct Assistant Professor, School of Rural Public Health, and Program Coordinator, College of Medicine, Texas A&M University System Health Science Center, College Station, TX. Address for correspondence: Nancy Arden, MN, 9253 Brookwater Circle, College Station, TX 77845. E-mail: nancy.arden@alum.emory.edu .
Influenza is an important cause of acute respiratory illness among residents of nursing homes and other long-term care facilities, and can lead to serious complications and death. While annual vaccination of residents and staff is the primary method for preventing outbreaks, antiviral agents are useful adjuncts to vaccination, especially when outbreaks occur. There is extensive experience in the use of amantadine and rimantadine to control nursing home outbreaks. Two newer antiviral agents now available, zanamivir and oseltamivir, are less toxic than the older drugs and less likely to foster the emergence of resistance. However, the large disparities in the cost of these drugs complicate the choice of an agent, especially for prophylaxis. Contingency planning before the influenza season is needed to ensure that an outbreak can be recognized early on and that control measures can be carried out swiftly and efficiently. (Annals of Long-Term Care: Clinical Care and Aging 2001;9[6]:45-52)
I t is well-established that elderly persons, and others with certain chronic medical conditions, are at high risk for developing serious medical complications following influenza infection. In the United States, more than half of all influenza-associated hospitalizations and at least 90% of all influenza deaths occur among persons age 65 and older. Persons of all ages with certain chronic diseases also face a higher risk of severe influenza-associated complications or death.1-3 Residents of nursing homes and other long-term care facilities are at an even higher risk. In addition to the risks associated with advanced age and disability, nursing home residents also have a greater risk of being exposed to influenza. Compared to their peers living in other settings, they are more likely to be in relatively close contact with fellow residents, staff members, volunteers, and visitors who circulate between the community and the nursing home, providing frequent opportunities for the introduction and spread of influenza in the facility. When outbreaks occur in nursing homes, often 20-30% of residents are affected, and attack rates as high as 60% have been reported.4 Many of those infected may develop serious complications, with case-fatality ratios as high as 30-55%. 5-6
Inactivated Influenza Vaccine
The primary means for reducing the impact of influenza in nursing homes is annual influenza vaccination. Although frail elderly persons and others with compromised immune systems may have a relatively low antibody response to vaccination,7 it has been shown repeatedly that even when vaccinated nursing home residents do become ill with influenza, their illness is often more mild and of shorter duration than that of unvaccinated residents, and they are less likely to develop secondary complications or die as a result of the illness. Another consistent trend that has been observed is that the vaccine is more effective in preventing serious complications such as pneumonia than in preventing primary upper respiratory illness, and it is even more effective in preventing death. 4,8 While the effectiveness of inactivated influenza vaccine in preventing upper respiratory illness is often in the range of 30-40% among nursing home residents, it is approximately 50-60% effective in preventing serious complications and hospitalization, and approximately 80% effective in preventing influenza-associated deaths. 1 Although there are no measures presently available to improve the immunologic response to influenza vaccine in the frail elderly, it is possible to decrease the risk of exposure by taking advantage of the added protection conferred by herd immunity. Numerous studies have demonstrated that nursing homes with high rates of vaccination among residents are less likely to experience influenza outbreaks than those with lower vaccination coverage.8-11 Even though some nursing home residents will not develop optimally protective antibody responses, vaccination of a high percentage of residents confers a degree of herd immunity, reducing virus transmission and thereby indirectly protecting susceptible residents. Evidence from studies that examined the effect of influenza vaccination levels among nursing home staff suggests that high rates of vaccination among staff members may also reduce the risk of infection and outbreaks among residents.12-13 Because most staff members are relatively young and healthy, they are more likely to develop protective postvaccination antibody titers than the residents for whom they provide care. Thus, high rates of vaccination among staff may contribute substantially to protecting residents by reducing the potential for both introduction and transmission of influenza. High staff vaccination rates can offer the additional benefit of reducing absenteeism. The Advisory Committee on Immunization Practices (ACIP) recommended that health care workers who have contact with patients at high risk for severe influenza-related complications receive influenza vaccine every year. 1 Although high levels of influenza vaccine coverage among residents and staff can reduce the probability of an outbreak, influenza outbreaks can still occur. Vaccine failure can be caused by antigenic changes in the circulating influenza virus that occur after the vaccine strains have been chosen. Influenza viruses continually evolve, necessitating changes in vaccine formulation almost every year. Antigens for each year’s vaccine must be chosen by February or March for the following influenza season. If sufficient antigenic changes occur in one or more of the circulating influenza virus strains after the vaccine stains are selected, vaccine efficacy will be compromised even though the vaccine may still be beneficial in reducing the severity of illness and the frequency and severity of complications.14 Influenza outbreaks in long-term care facilities often begin with a cluster of cases of acute respiratory illness occurring within a few days. Infection can then spread rapidly, with larger numbers of secondary cases following within days of the primary cases. The initial approach to controlling a suspected outbreak should include early recognition of an increase in influenza-like illness, followed by the use of rapid diagnostic testing to confirm or rule out influenza as the cause. There are a number of commercially available assays that can be used to rapidly detect influenza from nasopharyngeal, nasal, or throat swab specimens, although the types of specimens suitable for a given test vary.15 One enzyme immunoassay, Directigen Flu A®, will only detect influenza type A.16 A newer enzyme immunoassay, Directigen Flu A&B®, detects both influenza A and B, and indicates a positive or negative result for each influenza virus type.17 Other available rapid diagnostic tests for point-of-care use detect both influenza types A and B, but do not distinguish between the two. The ZstatFlu® test is a colorimetric enzyme assay that detects activity of the influenza neuraminidase enzyme.18 AB Flu OIA® is an optical immunoassay that detects antibody–antigen interactions that are registered visually on a slide. 19 QuickVue® is an immunoassay using monoclonal antibodies; a color indicator on a test strip is used to determine if influenza virus antigens are present in throat swab, nasal wash, or nasal aspirate specimens. 20 Estimates of the sensitivity and specificity of these assays have varied considerably from one study to another. To some extent, this variation may be due to differences in the timing and method of specimen collection, level of expertise of the laboratory personnel performing the tests, and the populations that were sampled. The quantity of virus obtained in a sample can influence the test result. Samples obtained within the first few days of illness onset are likely to contain larger quantities of influenza virus than those obtained later in the course of the illness, and the elderly generally shed lower quantities of virus than younger patients, especially children. Samples with fewer virus particles are more likely to yield false-negative test results. For this reason, as many new cases as possible of influenza-like illness should be tested in the early stages of a suspected outbreak. In general, the rapid tests are more likely to yield a false-negative result than a false-positive one, but overall, none of these tests are as sensitive or specific as viral culture.1 Plans for rapid diagnostic testing should be in place before the influenza season and should include stocking supplies for obtaining and transporting specimens, and making arrangements with a qualified laboratory for specimen transport, prompt testing, and notification of results. Specimens obtained for rapid testing should also be sent to state or local health departments for viral culture, which is necessary to characterize the influenza virus, to determine how similar it is to the vaccine strains, or to test for other agents if influenza is not detected.21,22
Antiviral Agents
Antiviral agents offer another option for controlling influenza in long-term care facilities, and are especially useful for controlling outbreaks. If an influenza outbreak is confirmed by laboratory testing, chemoprophylaxis with an antiviral agent can stop further progression of the outbreak, and early treatment of ill residents may decrease the duration and severity of the illness. Four antiviral drugs with specific activity against influenza are now available (Table). Two of these drugs, amantadine and rimantadine, are effective only against influenza type A. The other two more recently approved drugs, zanamivir and oseltamivir, are effective against both influenza types A and B.
The adamantane derivatives, amantadine and rimantadine, are chemically-related, orally-administered drugs that prevent influenza A virus replication by the same mechanism. However, the pharmacokinetics of these drugs are markedly different. While both drugs have high oral bioavailability, amantadine is largely unmetabolized and is associated with a higher incidence of central nervous system and neuropsychiatric side effects, especially among the elderly. Both drugs require dosage adjustments for patients with renal insufficiency, and rimantadine requires adjustment in patients with severe hepatic dysfunction.23 Amantadine and rimantadine are both approximately 60-90% effective in preventing illness caused by influenza A. When administered within 48 hours of illness onset, they have also been found to decrease the severity and duration of symptoms, but have not been proven to reduce the incidence of serious complications.1, 24 The neuraminidase inhibitors zanamivir and oseltamivir interfere with the replication of both influenza type A and type B viruses by inhibiting enzymatic activity of the viral neuraminidase, which plays an important role in the release of virus from infected cells. Zanamivir is administered as a fine powder directly to the respiratory tract by oral inhalation using a specially designed breath-activated device. Only about 4-17% of the inhaled dose is absorbed systemically and is excreted, unchanged, in the urine. Overall systemic exposure and toxicity are very low, and no dosage adjustment is required for elderly patients.25 In clinical trials adverse events were uncommon and the incidence was similar in treatment and placebo groups. However, after zanamivir was approved for marketing in 1999, cases of bronchospasm and respiratory function deterioration following inhalation of zanamivir were reported; most—but not all cases—involved patients with asthma or chronic obstructive pulmonary disease.1 Therefore, zanamivir is generally not recommended for patients with underlying airways disease. Although elderly persons with chronic diseases have been included in clinical trials of zanamivir, there are relatively few data regarding the use and efficacy of zanamivir among residents of long-term care facilities. The breath-activated delivery device requires the patient’s cooperation and the ability to inspire effectively. It has been reported that in one nursing home in which zanamivir was used to control transmission of adamantane-resistant influenza, more than 70% of residents to whom zanamivir was offered had no difficulty following instructions and complying with inhalations. However, 58% of patients who were fully dependent in activities of daily living, and 45% of patients who were not oriented to person, place, or time did have difficulty with inhalations.26 Another study concluded that most elderly persons could not effectively use the inhalation device, but that the delivery system could be improved for use in this population. 27 Oseltamivir can be administered as a capsule or as a liquid suspension. It is well-absorbed after oral administration and metabolized in the liver to the active compound GS4071. GS4071 is excreted in the urine by glomerular filtration and tubular secretion, and a reduction in dosage is recommended for patients with creatinine clearance < 30 mL/min. Because oseltamivir is metabolized by high-capacity esterases, no dosage adjustment has been recommended for patients with liver disease. In addition, there is no need to adjust the dosage for elderly patients. In clinical trials, mild and transient gastrointestinal disturbances, primarily nausea and vomiting, were reported more frequently among subjects receiving oseltamivir than those receiving placebo. These events generally occurred upon initiation of treatment and resolved within two days; dropout rates were low and similar between both the treatment and placebo groups. There is also growing evidence that taking the drug with food reduces the incidence of these side effects. 28, 29 Zanamivir and oseltamivir are effective in treating influenza type A or B when administered within 30-48 hours of illness onset. Early treatment significantly reduces the severity and duration of symptoms, and some studies have shown a reduction in complications and antibiotic use. Oseltamivir was approved for prevention of influenza types A and B in November 2000 after it was shown to be effective in preventing influenza illness and infection in studies of both naturally occurring and experimental influenza A and B infections.24, 28, 29 There is now considerable evidence that zanamivir is also effective as prophylaxis, and it may be approved for this indication in the future.30
Control of Influenza Outbreaks
The ACIP recommends chemoprophylaxis when confirmed or suspected influenza type A outbreaks occur in nursing homes and similar facilities housing high-risk populations. It is recommended that chemoprophylaxis should be administered to all residents as early as possible and continued for at least two weeks, or until approximately one week after the end of the outbreak.1 Although the ACIP does not recommend the use of one antiviral agent over another, it can be expected that amantadine will continue to be the drug of choice for many nursing homes. In spite of its less favorable safety profile, amantadine is often chosen over rimantadine because it is less expensive. The safety profile of oseltamivir is superior to that of amantadine or rimantadine, but the cost of the neuraminidase inhibitors is substantially higher than either of the adamantanes.24 While there is extensive experience in the use of amantadine for control of influenza A outbreaks in nursing homes, there is relatively little experience in the use of zanamivir and oseltamivir for this purpose. Many controlled and observational studies have shown that chemoprophylaxis with amantadine or rimantadine has been effective in stopping outbreaks in long-term carefacilities, boarding schools, and other institutions, and in limiting transmission within households.23, 31-33 However, those who are given amantadine or rimantadine to treat infection may shed resistant virus during the course of therapy, and efforts should be made to isolate persons who are being treated from those who are taking medication for prophylaxis. Emergence of resistance during treatment has not been shown to reduce therapeutic efficacy in persons shedding resistant virus; however, resistant viruses can be transmitted to contacts, whether or not they are undergoing chemoprophylaxis. Apparent transmission of resistant virus has been described in nursing homes and within households.34-36 The extent of transmission of resistant viruses is unknown. Most amantadine- and rimantadine-resistant viruses have been isolated from persons undergoing drug treatment, or less often, from their contacts. In situations when only prophylaxis has been used, isolation of resistant virus has been uncommon. International surveillance for drug-resistant influenza A viruses has shown that few isolates obtained from patients with no known history of antiviral treatment are resistant.34, 37 Studies to date suggest that resistant virus does not readily emerge during treatment with zanamivir and oseltamivir, although strains of influenza virus resistant to these compounds have been identified in in vitro and in vivo. Resistant viruses however do not emerge as rapidly during passage in tissue culture in the presence of zanamivir and oseltamivir as they do in the presence of amantadine and rimantadine. In clinical trials resistant strains have rarely been isolated from subjects taking these drugs for the treatment of influenza infection. In vitro studies have shown that amantadine- and rimantadine-resistant viruses are sensitive to zanamivir and oseltamivir.29 Although studies have not been conducted using amantadine or rimantadine in combination with neuraminidase inhibitors, a useful strategy for limiting the emergence and spread of adamantane-resistant viruses during nursing home outbreaks might be to use zanamivir or oseltamivir for treatment of residents who become ill before or during the period of amantadine or rimantadine prophylaxis. Adamantane-resistant viruses are more likely to emerge during treatment, and prophylaxis failures in outbreak situations are thought to be caused, to a large extent, by circulation of resistant viruses shed by persons undergoing amantadine or rimantadine treatment. 24,34 Persons who begin amantadine or rimantadine prophylaxis while they are incubating infection, but before they are symptomatic, may also shed resistant viruses, but the extent to which such resistant viruses could be spread might be decreased if amantadine or rimantadine prophylaxis were stopped and these persons were treated with zanamivir or oseltamivir as soon as their illness became apparent. The same principles could be applied when staff are offered chemoprophylaxis or therapy. Early recognition of outbreaks and prompt initiation of chemoprophylaxis are critical for successful outbreak control, but are not likely to occur without contingency planning. Before the influenza season, nursing homes need to develop policies and have plans in place in the event of an outbreak. A system must be developed to quickly obtain physicians’ orders to administer antiviral agents. Because adjustments in dosage are needed based on estimated creatinine clearance and other considerations when amantadine and rimantadine are used, there should also be a system to quickly determine drug dosages for individual patients. This is particularly important when amantadine is used, since dosage adjustments are more complex and adverse reactions are more common. These factors can be minimized with proper dosing and active monitoring for possible adverse reactions during the period of chemoprophylaxis.21
Other Control Measures
In addition to the use of antiviral agents, there are other measures that may help to control an influenza outbreak in the early stages. When an outbreak is recognized, isolation of ill residents and restriction of group activities may reduce the spread of infection. Floating of staff between units should be avoided, and staff should be prohibited from working if they develop influenza-like illness. Although hand washing is important in preventing the spread of many infectious diseases, in itself, it has little impact on the spread of influenza since the primary mode of its spread is through aerosol and droplet transmission. The use of surgical masks by staff caring for acutely ill residents may help limit transmission, especially from residents to staff, but this measure alone is unlikely to have an important impact on the progression of an outbreak. If the circulating influenza stain or strains are known to be similar to those included in the vaccine, immunizing unvaccinated residents and staff may also help prevent reintroduction of the virus into the facility.4,21
Conclusion
Influenza infections pose a serious threat to residents of nursing homes and other long-term care facilities. While annual vaccination of residents and staff continues to be the mainstay of prevention, antiviral agents can offer protection when outbreaks occur. With four different antiviral agents now available to treat or prevent influenza, the options for antiviral chemoprophylaxis and treatment of influenza have increased, as has the complexity of choosing strategies for the control of influenza. Contingency planning before the influenza season is essential in order to ensure that an outbreak can be recognized early on and that control measures can be carried out swiftly and efficiently.
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37. Hayden FG, Hay AJ. Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine. Curr Top Microbiol Immunol 1992;176:119-130. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 9 - Issue 06 - June 2001 |