Prevention and Control of Influenza

Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Vaccination of Close Contacts of Persons at High Risk for Complications from Influenza

Close contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with severely immunocompromised persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunocompromised person requires care in a protective environment. The rationale for not using LAIV among health-care workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunocompromised person. If a health-care worker receives LAIV, that worker should refrain from contact with severely immunocompromised patients for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunocompromised persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunocompromised. ACIP has not indicated a preference for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunodeficiency (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with HIV) or for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5--49 years in close contact with all other groups at high risk.

Personnel Who May Administer LAIV

Low-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk for acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunocompromised persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.

Recommended Vaccines for Different Age Groups

When vaccinating children aged 6 months--3 years, health-care providers should use inactivated influenza vaccine that has been approved by FDA for this age group. Inactivated influenza vaccine from sanofi pasteur (Fluzone) is approved for use among persons aged >6 months. Inactivated influenza vaccine from Novartis, formerly Chiron (Fluvirin), is labeled in the United States for use among persons aged >4 years because data to demonstrate efficacy among younger persons have not been provided to FDA, whereas inactivated influenza vaccine from GlaxoSmithKline (FLUARIX) is labeled for use in persons aged >18 years. LAIV from MedImmune (FluMist) is approved for use by healthy persons aged 5--49 years (Table 4).

Influenza Vaccine Supply and Timing of Annual Influenza Vaccination

The annual supply of influenza vaccine and the timing of its distribution cannot be guaranteed in any year. Currently, influenza vaccine manufacturers are projecting that approximately 100 million doses of influenza vaccine will be available in the United States for the 2006--07 influenza season, an amount that is approximately 16% more doses than were available for the 2005--06 season. An additional 15 million--20 million doses might be available if a new vaccine is licensed in 2006. (Information about the status of licensure of new vaccines is available at http://aapredbook.aappublications.org/news/vaccstatus.pdf.) However, influenza vaccine distribution delays or vaccine shortages remain possible in part because of the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. To ensure optimal use of available doses of influenza vaccine, health-care providers, those planning organized campaigns, and state and local public health agencies should

1) develop plans for expanding outreach and infrastructure to vaccinate more persons than last year and

2) develop contingency plans for the timing and prioritization of administering influenza vaccine, if the supply of vaccine is delayed and/or reduced.

CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will inform both providers and the general public if a substantial delay or an inadequate supply occurs. Because LAIV is approved for use in healthy persons aged 5--49 years, no recommendations exist for limiting the timing and prioritization of administering LAIV. Administration of LAIV is encouraged as soon as it is available and throughout the season.

If the supply of inactivated influenza vaccine is adequate and a sufficient number of doses will be available beginning in September, vaccination efforts should be structured to ensure the vaccination of as many persons as possible over the course of several months. Even if vaccine distribution begins in September, distribution probably will not be completed until December or January; therefore, the following recommendations reflect this phased distribution during the months of October, November, and December, and possibly later. The prioritized (tiered) use of influenza vaccine during inactivated influenza vaccine shortages applies only to the use of inactivated vaccine and not to LAIV. When feasible, during shortages of inactivated influenza vaccine, LAIV should be used preferentially for all healthy persons aged 5--49 years (including health-care workers) to increase the availability of inactivated vaccine for groups at high risk.

The following section provides guidance regarding the timing of vaccination under two scenarios: 1) if the supply of inactivated influenza vaccine is adequate, and 2) if a reduced or delayed supply of inactivated vaccine occurs.

Materials to assist providers are available at http://www.cdc.gov/flu/professionals/vaccination/index.htm (see also Travelers section).

Vaccination Before October

To avoid missed opportunities for vaccination of persons at increased risk for serious complications and their household contacts (including out-of-home caregivers and household contacts of children aged 0--59 months), such persons should be offered vaccine beginning in September during routine health-care visits or during hospitalizations, if vaccine is available. However, in facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because antibody levels in such persons can begin to decline more rapidly after vaccination (264). If vaccine supplies are sufficient, vaccination of other persons also may begin before October.

In addition, because children aged 6 months--<9 years who have not been previously vaccinated need 2 doses of vaccine, they should receive their first dose in September, if vaccine is available, so that both doses can be administered before the onset of influenza activity. For previously vaccinated children, only 1 dose is needed.

Vaccination in October and November

The optimal time for vaccination efforts is usually during October--November. In October, vaccination in provider-based settings should start or continue for all patients---both high risk and healthy---and extend throughout November. Vaccination of children aged 6 months--<9 years who are receiving vaccine for the first time should also begin in October, if not done earlier, because those children need a booster dose 4--10 weeks after the initial dose, depending upon whether they are receiving inactivated influenza vaccine or LAIV.

If supplies of inactivated influenza vaccine are not adequate, ACIP recommends that vaccine providers focus their vaccination efforts in October, primarily on persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6--59 months), household contacts of persons at high risk (including out-of-home caregivers and household contacts of children aged 0--59 months), and health-care workers (178). Efforts to vaccinate other persons who wish to decrease their risk for influenza virus infection should not begin until November; however, if such persons request vaccination in October, vaccination should not be deferred, unless vaccine supplies dictate otherwise.

Vaccination in December and Later

When inactivated vaccine is delayed, a substantial proportion of doses often do not become available until December or later. Nevertheless, even when supply is not delayed or reduced, as demonstrated by the relatively low vaccination coverage levels among persons in the defined priority groups, many persons who should receive influenza vaccine remain unvaccinated (Table 3).

Providers should routinely offer influenza vaccine throughout the influenza season even after influenza activity has been documented in the community. In the United States, seasonal influenza activity can begin to increase as early as October or November, but influenza activity has not reached peak levels until late December--early March in the majority of recent seasons (Table 5). Although the timing of influenza activity can vary by region, vaccine administered after November is likely to be beneficial in the majority of influenza seasons. Adults have peak antibody protection against influenza virus infection 2 weeks after vaccination (265,266).

Timing of Organized Vaccination Campaigns

Persons and institutions planning substantial organized vaccination campaigns (e.g., health departments, occupational health clinics, and community vaccinators) should consider scheduling these events after at least mid-October because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancellations because vaccine is unavailable. These vaccination clinics should be scheduled through November, with attention to settings that serve children aged 6--59 months, pregnant women, other persons aged <50 years at increased risk for influenza-related complications, persons aged >50 years, health-care workers, and household contacts and out-of-home caregivers of persons at high risk (including children aged 0--59 months) to the extent feasible. Planners are encouraged to schedule at least one vaccination clinic in December.

During a vaccine shortage or delay, substantial proportions of inactivated influenza vaccine doses may not be released until November and December or later. Beginning in November, vaccination campaigns can be broadened to include healthy persons who wish to reduce their risk for influenza virus infection. ACIP recommends organizers schedule these vaccination clinics throughout November and December. When the vaccine is significantly delayed, agencies should consider offering vaccination clinics into January as long as vaccine supplies are available. Campaigns using LAIV are optimally conducted in October and November but can also extend into January.

Strategies for Implementing Vaccination Recommendations in Health-Care Settings

Successful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, assessment of practice-level vaccination rates with feedback to staff, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (19,267). Since October 2005, the Centers for Medicare and Medicaid Services (CMS) has required nursing homes participating in the Medicare and Medicaid programs to offer all residents influenza and pneumococcal vaccines and to document the results. According to the requirements, each resident is to be vaccinated unless it is medically contraindicated or the resident or his/her legal representative refuses vaccination. This information is to be reported as part of the CMS Minimum Data Set, which tracks nursing home health parameters (268).

The use of standing orders programs by long-term--care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies might help to ensure the administration of recommended vaccinations for adults (269). Standing orders programs for both influenza and pneumococcal vaccination should be conducted under the supervision of a licensed practitioner according to a physician-approved facility or agency policy by health-care workers trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. CMS has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term--care facilities, and home health agencies (269). To the extent allowed by local and state law, these facilities and agencies may implement standing orders for influenza and pneumococcal vaccination of Medicare- and Medicaid-eligible patients. Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs as well (20). In addition, physician reminders (e.g., flagging charts) and patient reminders are recognized strategies for increasing rates of influenza vaccination. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.

Outpatient Facilities Providing Ongoing Care

Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in September (if vaccine is available) and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended and who do not have regularly scheduled visits during the fall should be reminded by mail, telephone, or other means of the need for vaccination.

Outpatient Facilities Providing Episodic or Acute Care

Beginning each September, acute health-care facilities (e.g., emergency departments and walk-in clinics) should offer vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.

Nursing Homes and Other Residential Long-Term--Care Facilities

During October and November each year, vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. Ideally, all residents should be vaccinated at one time, before influenza season. Residents admitted through March after completion of the vaccination program at the facility should be vaccinated at the time of admission.

Acute-Care Hospitals

Persons of all ages (including children) with high-risk conditions and persons aged >50 years who are hospitalized at any time during September--March should be offered and strongly encouraged to receive influenza vaccine before they are discharged if they have not already received the vaccine during that season. In one study, 39%--46% of adult patients hospitalized during the winter with influenza-related diagnoses had been hospitalized during the preceding fall (270). Thus, the hospital serves as a setting in which persons at increased risk for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (271). Using standing orders in hospitals increases vaccination rates among hospitalized persons (272).

Visiting Nurses and Others Providing Home Care to Persons at High Risk

Beginning in September, nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.

Other Facilities Providing Services to Persons Aged >50 Years

Beginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccination on-site before the start of the influenza season. Staff education should emphasize the need for influenza vaccine.

Health-Care Workers

Beginning in October each year, health-care facilities should offer influenza vaccinations to all workers, including night and weekend staff. Particular emphasis should be placed on providing vaccinations to persons who care for members of groups at high risk. Efforts should be made to educate health-care workers regarding the benefits of vaccination and the potential health consequences of influenza illness for their patients, themselves, and their family members. All health-care workers should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (146,177,179).

Future Directions for Research and Recommendations Related to Influenza Vaccine

The relatively low effectiveness of influenza vaccine administered to older adults highlights the need for more immunogenic influenza vaccines for the elderly (273) and the need for additional research to understand potential biases in estimating the benefits of vaccination among older adults in reducing hospitalizations and deaths (274--276). Additional studies of the relative cost-effectiveness and cost utility of influenza vaccination among children and adults, especially those aged <65 years, are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, hospitalization costs and rates, and vaccine effectiveness (277). Additional data also are needed to quantify the benefits of influenza vaccination of health-care workers in protecting their patients (278). Furthermore, larger consortia of networks are needed that are able to assess rare events that occur after vaccination, including GBS.

ACIP continues to review new vaccination strategies to protect against influenza, including the possibility of expanding routine influenza vaccination recommendations toward universal vaccination or other approaches that will help greatly reduce or prevent the transmission of influenza (279--282). In addition, as noted by the National Vaccine Advisory Committee, strengthening the U.S. influenza vaccination system will require improving vaccine financing, increasing demand, and implementing systems to help better understand the burden of influenza in the United States (283). Strategies to evaluate the effect of vaccination recommendations remain critical.

Recommendations for Using Antiviral Agents for Influenza

Although annual vaccination is the primary strategy for preventing complications of influenza virus infections, antiviral medications with activity against influenza viruses can be effective for the chemoprophylaxis and treatment of influenza. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Influenza A virus resistance to amantadine and rimantadine can emerge rapidly during treatment. On the basis of antiviral testing results conducted at CDC and in Canada indicating high levels of resistance (23,24,284), ACIP 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 aged >7 years. Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza; oseltamivir is licensed for use in persons aged >1 year, and zanamivir is licensed for use in persons aged >5 years.

Antiviral Agents for Influenza

Zanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treatment of uncomplicated influenza virus infections. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged >13 years and was approved for chemoprophylaxis of children aged >1 year in 2005. In 2006, zanamivir was approved for chemoprophylaxis of children aged >5 years.

The two drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections. Package inserts should be consulted for additional information. Detailed information regarding amantadine and rimantadine is available in the previous publication of the ACIP influenza recommendations (285).

Role of Laboratory Diagnosis

Appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Influenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. For example, early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.

The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza (33,42,43). Because testing all patients who might have influenza is not feasible, influenza surveillance by state and local health departments and CDC can provide information regarding the presence of influenza viruses in the community. Surveillance also can identify the predominant circulating types, influenza A subtypes, and strains of influenza viruses.

Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR), and immunofluorescence assays (28). The sensitivity and specificity of any test for influenza can vary by the laboratory that performs the test, the type of test used, the type of specimen tested, and the timing of specimen collection. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens (286). As with any diagnostic test, results should be evaluated in the context of other clinical and epidemiologic information available to health-care providers.

Commercial rapid diagnostic tests are available that can detect influenza viruses in 30 minutes (28,287). 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. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two.

None of the rapid tests provide any information regarding influenza A subtypes. The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal; and 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 (288,289). 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, especially during periods of peak community influenza activity. In contrast, false-positive rapid test results are less likely but can occur during periods of low influenza activity. Therefore, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning diagnostic testing is available at http://www.cdc.gov/flu/professionals/labdiagnosis.htm.

Despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical because only culture isolates can provide specific information regarding circulating strains and subtypes of influenza viruses. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.

Antiviral Drug-Resistant Strains of Influenza Virus

CDC recently reported that 193 (92%) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes (23,24). In addition, two of eight influenza A (H1N1) viruses tested were resistant (24). Canadian health authorities also have reported the same mutation in a comparable proportion of isolates recently tested (284). Until these findings, previous screenings of epidemic strains of influenza A viruses found few amantadine- and rimantadine-resistant viruses (290--292).

Viral resistance to adamantanes can emerge rapidly during treatment because a single point mutation at amino acid positions 26, 27, 30, 31, or 34 of the M2 protein can confer cross resistance to both amantadine and rimantadine (293,294). Drug-resistant viruses can emerge in approximately one third of patients when either amantadine or rimantadine is used for therapy (293,295,296). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2--3 days of starting therapy (290,297). Resistant viruses have been isolated from persons who live at home or in an institution in which other residents are taking or have taken amantadine or rimantadine as therapy (298,299); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown.

Persons who have influenza A virus infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drug-resistant viruses, including after 5--7 days of therapy (295).

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (300--307), but induction of resistance usually requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (308,309). Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (310--314). In one pediatric study, 5.5% of patients treated with oseltamivir had posttreatment isolates that were resistant to neuraminidase inhibitors. One small study of Japanese children treated with oseltamivir reported a high frequency of resistant viruses (315). However, no transmission of neuraminidase inhibitor-resistant viruses in humans has been documented to date. No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited (316), and the risk for emergence of zanamivir-resistant isolates cannot be quantified (317). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (312). Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed (316,318). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted (319).

Indications for Use of Antivirals When Susceptibility Exists

Treatment

When administered within 2 days of illness onset to otherwise healthy adults, zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day compared with placebo (91,320--334). More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A virus infection than for treatment of influenza B virus infection (324,335--344). However, in vitro data and studies of treatment among mice and ferrets (345--352), in addition to clinical studies, have documented that zanamivir and oseltamivir have activity against influenza B viruses (310,317,325,329,353,354).

Data are limited regarding the effectiveness of the antiviral agents in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these antiviral drugs is principally based on studies of patients with uncomplicated influenza (355). Data are limited concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza (31,321,322,324,325,330--338). Among influenza virus infected participants in 10 clinical trials, the risk for pneumonia among those participants receiving oseltamivir was approximately 50% lower than among those persons receiving a placebo (339). A similar significant reduction was also found for hospital admissions; a 50% reduction was observed in the small subset of high-risk participants, although this reduction was not statistically significant. Fewer studies of the efficacy of influenza antivirals have been conducted among pediatric populations (295,322,328,329). One study of oseltamivir treatment documented a decreased incidence of otitis media among children (323). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year (289).

Initiation of antiviral treatment within 2 days of illness onset is recommended. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.

Chemoprophylaxis

Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. In community studies of healthy adults, both oseltamivir and zanamivir are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (324,340,356). Both antiviral agents also have been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member had influenza diagnosed (341,353,356). Experience with chemoprophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes (310,337,338,342--344). One 6-week study of oseltamivir chemoprophylaxis among nursing home residents reported a 92% reduction in influenza illness (310,357). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine (317,358). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among severely immunocompromised persons.

When determining the timing and duration for administering influenza antiviral medications for chemoprophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as chemoprophylaxis, the drug must be taken each day for the duration of influenza activity in the community.

Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, development of antibodies in adults after vaccination takes approximately 2 weeks (265,266). When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can require 6 weeks of chemoprophylaxis (i.e., chemoprophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of chemoprophylaxis after the second dose).

Persons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities; household members; visiting nurses; and volunteer workers. If an outbreak is caused by a strain of influenza that might not be covered by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status.

Persons Who Have Immune Deficiencies. Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered.

Other Persons. Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis also can be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make this decision on an individual basis.

Control of Influenza Outbreaks in Institutions

Using antiviral drugs for treatment and chemoprophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, reoffering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (359--361) (see Additional Information Regarding Influenza Virus Infection Control Among Specific Populations).

The majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among nursing home populations that received amantadine or rimantadine (335,362--366). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (337,338,344,357,367). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications.

When outbreaks occur in institutions, chemoprophylaxis should be administered to all residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff members who provide care to persons at high risk. Chemoprophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is suspected to be caused by a strain of influenza virus that is not well-matched to the vaccine.

In addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings in which persons live in close proximity).

To limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza Virus).

Dosage

Dosage recommendations vary by age group and medical conditions (Table 6).

Children

Zanamivir. Zanamivir is approved for treatment of influenza among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart); the chemoprophylaxis dosage of zanamivir for children aged >5 years is 10 mg (two inhalations) once a day (317).

Oseltamivir. Oseltamivir is approved for treatment and chemoprophylaxis among persons aged >1 year. Recommended treatment and chemoprophylaxis dosages of oseltamivir for children vary by the weight of the child. The treatment dosage recommendation of oseltamivir for children who weigh <15 kg is 30 mg twice a day; for children weighing >15--23 kg, 45 mg twice a day; for those weighing >23--40 kg, 60 mg twice a day; and for children weighing >40 kg, 75 mg twice a day (310). The chemoprophylaxis recommended dosage of oseltamivir for children weighing <15 kg is 30 mg once a day; for those weighing >15--23 kg, 45 mg once a day; for those weighing >23--40 kg, 60 mg once a day; and for those weighing >40 kg, 75 mg once a day.

Persons Aged >65 Years

Zanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone.

Persons with Impaired Renal Function

Zanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were observed (317,368). However, a limited number of healthy volunteers who received high doses of zanamivir intravenously tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (369,370). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (317).

Oseltamivir. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function (310,371). For patients with creatinine clearance of 10--30 mL/min (310), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the chemoprophylaxis dosage to 75 mg every other day is recommended. No treatment or chemoprophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.

Persons with Liver Disease

Zanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction.

Persons with Seizure Disorders

Zanamivir and Oseltamivir. Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.

Route

Oseltamivir is administered orally in capsule or oral suspension form. Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of correct use of this device.

Pharmacokinetics

Zanamivir

In studies of healthy volunteers, approximately 7%--21% of the orally inhaled zanamivir dose reached the lungs, and 70%--87% was deposited in the oropharynx (317,372). Approximately 4%--17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5--5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (317,370).

Oseltamivir

Approximately 80% of orally administered oseltamivir is absorbed systemically (371). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6--10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (310,373). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (325).

Side Effects and Adverse Reactions

When considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient's age, weight, and renal function (Table 6); presence of other medical conditions; indications for use (i.e., chemoprophylaxis or treatment); and the potential for interaction with other medications.

Zanamivir

In a study of zanamivir treatment of ILI among persons with asthma or chronic obstructive pulmonary disease where study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (317,330). However, in a phase I study of persons with mild or moderate asthma who did not have ILI, one of 13 patients experienced bronchospasm after administration of zanamivir (317). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Certain patients had underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (317). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of appropriate monitoring and supportive care, including the availability of short-acting bronchodilators (355). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to 1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact their physician if they experience difficulty breathing (317). No definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (355). Allergic reactions, including oropharyngeal or facial edema, also have been reported during postmarketing surveillance (317,337).

In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and for those receiving placebo (i.e., inhaled lactose vehicle alone) (320--325,337). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (317).

Oseltamivir

Nausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (310,326,327,374). Among children treated with oseltamivir, 14% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (329), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (310). Similar types and rates of adverse events were reported in studies of oseltamivir chemoprophylaxis (310). Nausea and vomiting might be less severe if oseltamivir is taken with food (317,310).

Use During Pregnancy

No clinical studies have been conducted regarding the safety or efficacy of zanamivir or oseltamivir for pregnant women. Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these two drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus. Oseltamivir and zanamivir are both "Pregnancy Category C" medications (see manufacturers' package inserts) (317,375).

Drug Interactions

Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro data and data from studies using rats (310,373).

Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (304,367).

No published data are available concerning the safety or efficacy of using combinations of any of these influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, package inserts should be consulted.

Information Regarding the Vaccines for Children Program

The Vaccines for Children (VFC) program supplies vaccine to all states, territories, and the District of Columbia for use by participating providers. These vaccines are to be administered to eligible children without vaccine cost to the patient, as well as the provider. All routine childhood vaccines recommended by ACIP are available through this program. The program saves parents and providers out-of-pocket expenses for vaccine purchases and provides cost-savings to states through the CDC vaccine contracts. The program results in lower vaccine prices and assures that all states pay the same contract prices. Detailed information regarding the VFC program is available at http://www.cdc.gov/nip/vfc/default.htm.

Sources of Information Regarding Influenza and Its Surveillance

Information regarding influenza surveillance, prevention, detection, and control is available at http://www.cdc.gov/flu/weekly/fluactivity.htm. Surveillance information is available through the CDC Voice Information System (influenza update) at 888-232-3228 or CDC Fax Information Service at 888-232-3299. During October--May, surveillance information is updated weekly. In addition, periodic updates regarding influenza are published in the MMWR Weekly Report (http://www.cdc.gov/mmwr). Additional information regarding influenza vaccine can be obtained by calling 800-CDC-INFO (800-232-4636). State and local health departments should be consulted concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, reporting of influenza outbreaks and influenza-related pediatric deaths, and advice concerning outbreak control.

Reporting of Adverse Events Following Vaccination

Clinically significant adverse events that follow vaccination should be reported through VAERS at http://vaers.hhs.gov or by calling the 24-hour national toll-free hotline at 800-822-7967.

Additional Information Regarding Influenza Virus Infection Control Among Specific Populations

Each year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, health-care workers, hospital patients, pregnant women, children, and travelers) also are available in the following publications:

• American Academy of Pediatrics. 2006 red book: report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.
• American College of Obstetricians and Gynecologists. Influenza vaccination and treatment during pregnancy. ACOG committee opinion no. 305. Obstet Gynecol 2004;104:1125--6.
• Bodnar UR, Maloney SA, Fielding KL, et al. Preliminary guidelines for the prevention and control of influenza-like illness among passengers and crew members on cruise ships. Atlanta, GA: US Department of Health and Human Services, CDC, National Center for Infectious Diseases; 1999.
• Bradley SF. The Long-Term--Care Committee of the Society for Health-care Epidemiology of America. Prevention of influenza in long-term care facilities. Infect Control Hosp Epidemiol 1999;20:629--37.
• CDC. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-2).
• CDC. Recommended adult immunization schedule---United States, October 2005--September 2006. MMWR 2005;54:Q1--4.
• CDC. Guidelines for preventing health-care--associated pneumonia, 2003: recommendations of CDC and the Health-care Infection Control Practices Advisory Committee. MMWR 2003;53(No. RR-3).
• CDC. Respiratory hygiene/cough etiquette in healthcare settings. Atlanta, GA: US Department of Health and Human Services, CDC; 2003. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm.
• CDC. Prevention of specific infectious diseases [Chapter 4]. In: Travelers' Health: Yellow Book. Health information for international travel, 2005--2006. Atlanta, GA: US Department of Health and Human Services, CDC; 2006. Available at http://www2.ncid.cdc.gov/travel/yb/utils/ybGet.asp?section=dis&obj=influenza.htm.
• CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(No. RR-2).
• CDC. Detection and control of influenza outbreaks in acute care facilities. Atlanta, GA: US Department of Health and Human Services, CDC, National Center for Infections Diseases; 2001.
• Garner JS, Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53--80.
• Sneller V-P, Izurieta H, Bridges C, et al. Prevention and control of vaccine-preventable diseases in long-term care facilities. Journal of the American Medical Directors Association 2000;1(Suppl):S2--37.
• US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). USPHS/IDSA Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Final November 28, 2001:1--65. Available at http://www.aidsinfo.nih.gov.

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Date last reviewed: 6/28/2006