Prevention and Control of Influenza

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.

References

1. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179--86.
2. Monto AS, Kioumehr F. The Tecumseh Study of Respiratory Illness. IX. Occurence of influenza in the community, 1966--1971. Am J Epidemiol 1975;102:553--63.
3. Glezen WP, Couch RB. Interpandemic influenza in the Houston area, 1974--76. N Engl J Med 1978;298:587--92.
4. Glezen WP, Greenberg SB, Atmar RL, et al. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000;283:499--505.
5. Barker WH. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970--78. Am J Public Health 1986;76:761--5.
6. Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980;112:798--811.
7. Glezen WP. Serious morbidity and mortality associated with influenza epidemics. Epidemiol Rev 1982;4:25--44.
8. Office of Technology Assessment. Cost effectiveness of influenza vaccination. In: U.S. Congress. Washington, DC: Office of Technology Assessment; 1981.
9. Wilde JA, McMillan JA, Serwint J, et al. Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA 1999;281:908--13.
10. Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995;333:889--93.
11. Campbell DS, Rumley MH. Cost-effectiveness of the influenza vaccine in a healthy, working-age population. J Occup Environ Med 1997;39:408--14.
12. Bridges CB, Thompson WW, Meltzer MI, et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 2000;284:1655--63.
13. Patriarca PA, Weber JA, Parker RA, et al. Risk factors for outbreaks of influenza in nursing homes. A case-control study. Am J Epidemiol 1986;124:114--9.
14. Gross PA, Hermogenes AW, Sacks HS, et al. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med 1995;123:518--27.
15. Mullooly JP, Bennett MD, Hornbrook MC, et al. Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization. Ann Intern Med 1994;121:947--52.
16. Clements DA, Langdon L, Bland C, et al. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 1995;149:1113--7.
17. Heikkinen T, Ruuskanen O, Waris M, et al. Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 1991;145:445--8.
18. Nordin J, Mullooly J, Poblete S, et al. Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. J Infect Dis 2001;184:665--70.
19. CDC. Vaccine-preventable diseases: improving vaccination coverage in children, adolescents, and adults: a report on recommendations from the Task Force on Community Preventive Services. MMWR 1999;48(No. RR-8).
20. CDC. Use of standing orders programs to increase adult vaccination rates. MMWR 2000;49(No. RR-1).
21. CDC. Improving influenza, pneumococcal polysaccharide, and hepatitis B vaccination coverage among adults aged <65 years at high risk: a report on recommendations of the Task Force on Community Preventive Services. MMWR 2005;54(No. RR-5).
22. Ndiaye SM, Hopkins DP, Shefer AM, et al. Interventions to improve influenza, pneumococcal polysaccharide, and hepatitis B vaccination coverage among high-risk adults: a systematic review. Am J Prev Med 2005;28(5 Suppl):248--79.
23. CDC. High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents--- United States, 2005--06 influenza season. MMWR 2006;55:44--6.
24. Bright RA, Shay DK, Shu B, et al. Adamantane resistance among influenza A viruses isolated early during the 2005--2006 influenza season in the United States. JAMA 2006;295:891--4.
25. Wright PF, Webster RG. Orthomyxoviruses. In: Knipe DM, Howley PM, et al., eds. Fields virology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1534--79.
26. Clements ML, Betts RF, Tierney EL, et al. Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol 1986;24:157--60.
27. Couch RB, Kasel JA. Immunity to influenza in man. Annu Rev Microbiol 1983;37:529--49.
28. Cox NJ, Subbarao K. Influenza. Lancet 1999;354(9186):1277--82.
29. Frank AL, Taber LH, Wells CR, et al. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis 1981;144:433--41.
30. Klimov AI, Rocha E, Hayden FG, et al. Prolonged shedding of amantadine-resistant influenzae A viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis. J Infect Dis 1995;172:1352--5.
31. 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;26:1418--24.
32. Boivin G, Goyette N, Bernatchez H. Prolonged excretion of amantadine-resistant influenza a virus quasi species after cessation of antiviral therapy in an immunocompromised patient. Clin Infect Dis 2002;34:E23--5.
33. Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992;7:26--37.
34. Ryan-Poirier K. Influenza virus infection in children. Adv Pediatr Infect Dis 1995;10:125--56.
35. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B virus infections in children. Clin Infect Dis 2003;36:299--305.
36. Neuzil KM, Zhu Y, Griffin MR, et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis 2002;185:147--52.
37. Douglas R Jr. Influenza in man. In: Kilbourne ED, ed. Influenza viruses and influenza. New York, NY: Academic Press, Inc.; 1975:395--418.
38. Dagan R, Hall CB. Influenza A virus infection imitating bacterial sepsis in early infancy. Pediatr Infect Dis 1984;3:218--21.
39. Chiu SS, Tse CY, Lau YL, et al. Influenza A infection is an important cause of febrile seizures. Pediatrics 2001;108:E63.
40. McCullers JA, Facchini S, Chesney PJ, et al. Influenza B virus encephalitis. Clin Infect Dis 1999;28:898--900.
41. Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 2002;35:512--7.
42. Boivin G, Hardy I, Tellier G, et al. Predicting influenza infections during epidemics with use of a clinical case definition. Clin Infect Dis 2000;31:1166--9.
43. Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000;160:3243--7.
44. Orenstein WA, Bernier RH, Hinman AR. Assessing vaccine efficacy in the field. Further observations. Epidemiol Rev 1988;10:212--41.
45. Govaert TM, Dinant GJ, Aretz K, et al. The predictive value of influenza symptomatology in elderly people. Fam Pract 1998;15:16--22.
46. Walsh EE, Cox C, Falsey AR. Clinical features of influenza A virus infection in older hospitalized persons. J Am Geriatr Soc 2002;50:1498--503.
47. Neuzil KM, O'Connor TZ, Gorse GJ, et al. Recognizing influenza in older patients with chronic obstructive pulmonary disease who have received influenza vaccine. Clin Infect Dis 2003;36:169--74.
48. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333--40.
49. Simonsen L, Schonberger LB, Stroup DF, et al. Impact of influenza on mortality in the USA. In: Proceedings of the 3rd International Conference on Options for the Control of Influenza, Cairns, Australia. Brown LE, Webster RG, eds. Amsterdam: Elsevier Science; 1996:26--32.
50. Lui KJ, Kendal AP. Impact of influenza epidemics on mortality in the United States from October 1972 to May 1985. Am J Public Health 1987;77:712--6.
51. Noble G. Epidemiological and clinical aspects of influenza. In: Beare AS, ed. Basic and applied influenza research. Boca Raton, FL: CRC Press; 1982:11--50.
52. Eickhoff TC, Sherman IL, Serfling RE. Observations on excess mortality associated with epidemic influenza. JAMA 1961;176:776--82.
53. Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med 1982;142:85--9.
54. Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53--60.
55. Keren R, Zaoutis TE, Bridges CB, et al. Neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection. JAMA 2005;294:2188--94.
56. Grijalva CG, Craig AS, Dupont WD, et al. Estimating influenza hospitalizations among children. EID 2006;12:103--9.
57. Glezen WP, Decker M, Perrotta DM. Survey of underlying conditions of persons hospitalized with acute respiratory disease during influenza epidemics in Houston, 1978--1981. Am Rev Respir Dis 1987;136:550--5.
58. Neuzil KM, Wright PF, Mitchel EF Jr, et al. The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000;137:856--64.
59. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342:232--9.
60. Neuzil KM, Mellen BG, Wright PF, et al. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225--31.
61. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333--40.
62. Simonsen L, Fukuda K, Schonberger LB, et al. The impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831--7.
63. National Center for Health Statistics. Health, United States, 1998. Hyattsville, MD: US Department of Health and Human Services, CDC; 1998.
64. Simonsen L, Clarke MJ, Williamson GD, et al. The impact of influenza epidemics on mortality: introducing a severity index. Am J Public Health 1997;87:1944--50.
65. CDC. Update: influenza-associated deaths reported among children aged <18 years---United States, 2003--04 influenza season. MMWR 2004;52:1286--8.
66. CDC. Severe morbidity and mortality associated with influenza in children and young adults---Michigan, 2003. MMWR 2003;52:837--40.
67. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med 353;24:2559--67.
68. Kilbourne E. Influenza. New York, NY: Plenum Medical Book Company; 1987.
69. La Montagne JR, Noble GR, Quinnan GV, et al. Summary of clinical trials of inactivated influenza vaccine---1978. Rev Infect Dis 1983;5:723--36.
70. Oxford JS, Schild GC, Potter CW, et al. The specificity of the anti-haemagglutinin antibody response induced in man by inactivated influenza vaccines and by natural infection. J Hyg (Lond) 1979;82:51--61.
71. Neuzil KM, Dupont WD, Wright PF, et al. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience. Pediatr Infect Dis J 2001;20:733--40.
72. Potter CW, Oxford JS. Determinants of immunity to influenza infection in man. Br Med Bull 1979;35:69--75.
73. Hirota Y, Kaji M, Ide S, et al. Antibody efficacy as a keen index to evaluate influenza vaccine effectiveness. Vaccine 1997;15:962--7.
74. Gonzalez M, Pirez MC, Ward E, et al. Safety and immunogenicity of a paediatric presentation of an influenza vaccine. Arch Dis Child 2000;83:488--91.
75. Wright PF, Cherry JD, Foy HM, et al. Antigenicity and reactogenicity of influenza A/USSR/77 virus vaccine in children---a multicentered evaluation of dosage and safety. Rev Infect Dis 1983;5:758--64.
76. Daubeney P, Taylor CJ, McGaw J, et al. Immunogenicity and tolerability of a trivalent influenza subunit vaccine (Influvac) in high-risk children aged 6 months to 4 years. Br J Clin Pract 1997;51:87--90.
77. Wright PF, Thompson J, Vaughn WK, et al. Trials of influenza A/New Jersey/76 virus vaccine in normal children: an overview of age-related antigenicity and reactogenicity. J Infect Dis 1977;136(Suppl):S731--41.
78. Negri E, Colombo C, Giordano L, et al. Influenza vaccine in healthy children: a meta-analysis. Vaccine 2005;23:2851--61.
79. Jefferson T, Smith S, Demicheli V, et al. Assessment of the efficicacy and effectiveness of influenza vaccines in healthy children: a systematic review. Lancet 2005;365:773--80.
80. Groothuis JR, Lehr MV, Levin MJ. Safety and immunogenicity of a purified haemagglutinin antigen in very young high-risk children. Vaccine 1994;12:139--41.
81. Park CL, Frank AL, Sullivan M, et al. Influenza vaccination of children during acute asthma exacerbation and concurrent prednisone therapy. Pediatrics 1996;98(2 Pt 1):196--200.
82. Hoberman A, Greenberg DP, Paradise JL, et al. Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA 2003;290:1608--16.
83. Clover RD, Crawford S, Glezen WP, et al. Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses. J Infect Dis 1991;163:300--4.
84. Sugaya N, Nerome K, Ishida M, et al. Efficacy of inactivated vaccine in preventing antigenically drifted influenza type A and well-matched type B. JAMA 1994;272:1122--6.
85. Ritzwoller DP, Bridges CB, Sheetterly S, et al. Effectiveness of the 2003--04 influenza vaccine among children 6 months to 8 years for 1 versus 2 doses. Pediatrics 2005;116:153--9.
86. Shuler C, Iwamoto M, Neeman R, et al. Influenza vaccine effectiveness against laboratory-confirmed influenza among children age 6 to 59 Months---Georgia, 2003--2004 [Poster #1008]. Presented at the 43rd Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA; 2005.
87. Neuzil KM, Jackson LA, Nelson J, et al. Immunogenicity and reactogenicity of one versus two doses of trivalent inactivated influenza vaccine in vaccine-naïve 5-8-year-old children. J Infect Dis. In press 2006.
88. Englund JA, Walter EB, Fairchok MP, et al. A comparison of 2 influenza vaccine schedules in 6- to 23-month-old children. Pediatrics 2005;115:1039--47.
89. Walter EB, Neuzil KM, Zhu Y, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming? Pediatrics. In press 2006.
90. Palache AM. Influenza vaccines. A reappraisal of their use. Drugs 1997;54:841--56.
91. Demicheli V, Jefferson T, Rivetti D, et al. Prevention and early treatment of influenza in healthy adults. Vaccine 2000;18:957--1030.
92. Smith JW, Pollard R. Vaccination against influenza: a five-year study in the Post Office. J Hyg (Lond) 1979;83:157--70.
93. CDC. Assessment of the effectiveness of the 2003--04 influenza vaccine among children and adults---Colorado, 2003. MMWR 2004;53:707--10.
94. Hak E, Nordin J, Wei F, et al. Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations. Clin Infect Dis 2002;35:370--7.
95. Jefferson T, Rivetti D, Rudin M, et al. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005;366:1165--74.
96. Blumberg EA, Albano C, Pruett T, et al. The immunogenicity of influenza virus vaccine in solid organ transplant recipients. Clin Infect Dis 1996;22:295--302.
97. Dorrell L, Hassan I, Marshall S, et al. Clinical and serological responses to an inactivated influenza vaccine in adults with HIV infection, diabetes, obstructive airways disease, elderly adults and healthy volunteers. Int J STD AIDS 1997;8:776--9.
98. McElhaney JE, Beattie BL, Devine R, et al. Age-related decline in interleukin 2 production in response to influenza vaccine. J Am Geriatr Soc 1990;38:652--8.
99. Govaert TM, Thijs CT, Masurel N, et al. The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA 1994;272:1661--5.
100. Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med 1998;158:1769--76.
101. Patriarca PA, Weber JA, Parker RA, et al. Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA 1985;253:1136--9.
102. Arden NH, Patriarca PA, Kendal AP. Experiences in the use and efficacy of inactivated influenza vaccine in nursing homes. In: Options for the Control of Influenza. New York, NY: Alan R. Liss, Inc.; 1986.
103. Monto AS, Hornbuckle K, Ohmit SE. Influenza vaccine effectiveness among elderly nursing home residents: a cohort study. Am J Epidemiol 2001;154:155--60.
104. Riddiough MA, Sisk JE, Bell JC. Influenza vaccination. JAMA 1983;249:3189--95.
105. King JC Jr, Lagos R, Bernstein DI, et al. Safety and immunogenicity of low and high doses of trivalent live cold-adapted influenza vaccine administered intranasally as drops or spray to healthy children. J Infect Dis 1998;177:1394--7.
106. Belshe RB, Gruber WC, Mendelman PM, et al. Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis 2000;181:1133--7.
107. Boyce TG, Gruber WC, Coleman-Dockery SD, et al. Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children. Vaccine 1999;18:82--8.
108. Zangwill KM, Droge J, Mendelman P, et al. Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children. Pediatr Infect Dis J 2001;20:740--6.
109. Bernstein DI, Yan L, Treanor J, et al. Effect of yearly vaccinations with live, attenuated, cold-adapted, trivalent, intranasal influenza vaccines on antibody responses in children. Pediatr Infect Dis J 2003;22:28--34.
110. Nolan T, Lee MS, Cordova JM, et al. Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities. Vaccine 2003;21:1224--31.
111. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 1998;338:1405--12.
112. Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 2000;136:168--75.
113. Halloran ME, Longini IM Jr, Gaglani MJ, et al. Estimating efficacy of trivalent, cold-adapted, influenza virus vaccine (CAIV-T) against influenza A (H1N1) and B using surveillance cultures. Am J Epidemiol 2003;158:305--11.
114. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 1999;282:137--44.
115. Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine 1999;18:899--906.
116. Mixeu MA, Vespa GN, Forleo-Neto E, et al. Impact of influenza vaccination on civilian aircrew illness and absenteeism. Aviat Space Environ Med 2002;73:876--80.
117. Nichol KL, Mallon KP, Mendelman PM. Cost benefit of influenza vaccination in healthy, working adults: an economic analysis based on the results of a clinical trial of trivalent live attenuated influenza virus vaccine. Vaccine 2003;21:2207--17.
118. Nichol KL, Mendelman P. Influence of clinical case definitions with differing levels of sensitivity and specificity on estimates of the relative and absolute health benefits of influenza vaccination among healthy working adults and implications for economic analyses. Virus Res 2004;103:3--8.
119. Nichol KL. Cost-benefit analysis of a strategy to vaccinate healthy working adults against influenza. Arch Intern Med 2001;161:749--59.
120. Cohen GM, Nettleman MD. Economic impact of influenza vaccination in preschool children. Pediatrics 2000;106:973--6.
121. White T, Lavoie S, Nettleman MD. Potential cost savings attributable to influenza vaccination of school-aged children. Pediatrics 1999;103:e73.
122. Dayan GH, Nguyen VH, Debbag R, et al. Cost-effectiveness of influenza vaccination in high-risk children in Argentina. Vaccine 2001;19:4204--13.
123. Luce BR, Zangwill KM, Palmer CS, et al. Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children. Pediatrics 2001;108:E24.
124. Prosser LA, Bridges CB, Uyeki TM, et al. Values for preventing influenza-related morbidity and vaccine adverse events in children. Health and Quality of Life Outcomes 2005;3. Available at http://www.hqlo.com/content/3/1/18.
125. US Department of Health and Human Services. Healthy people 2010 (conference ed., in 2 vols). Washington, DC: US Department of Health and Human Services; 2000.
126. CDC. Influenza and pneumococcal vaccination coverage levels among persons aged >65 years---United States, 1973--1993. MMWR 1995;44:506--7, 513--5.
127. CDC. National Health Interview Survey---2002. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics; 2002. Available at http://www.cdc.gov/nchs/about/major/nhis/quest_data_related_1997_forward.htm.
128. US Department of Health and Human Services. Healthy people 2000: national health promotion and disease prevention objectives---full report, with commentary. Washington, DC: US Department of Health and Human Services, Public Health Service; 1991.
129. CDC. Health objectives for the nation implementation of the Medicare influenza vaccination benefit---United States, 1993. MMWR 1994;43:771--3.
130. Singleton JA, Greby SM, Wooten KG, et al. Influenza, pneumococcal, and tetanus toxioid vaccination of adults---United States, 1993--1997. In: Surveillance Summaries, September 22, 2000. MMWR 2000;49(No. SS-9):39--62.
131. CDC. Racial/ethnic disparities in influenza and pneumococcal vaccination levels among persons aged >65 years---United States, 1989--2001. MMWR 2003;52:958--62.
132. Herbert PL, Frick KD, Kane RL, McBean AM. The causes of racial and ethnic differences in influenza vaccination rates among elderly Medicare beneficiaries. Health Serv Res 2005;40:517--37.
133. Winston CA, Wortley PM, Lees KA. Factors associated with vaccination of Medicare beneficiaries in five U.S. communities: Results from the Racial and Ethnic Adult Disparities in Immunization Initiative survey, 2003. J Am Geriatr Soc 2006;54:303--10.
134. Buikema AR, Singleton JA, Sneller VP, Strikas RA. Influenza vaccination in nursing homes, United States, 1995 and 1997 [Abstract P2-49]. Presented at the Options for the Control of Influenza IV Conference, Crete, Greece; September 23--28, 2000.
135. Zadeh MM, Buxton Bridges C, Thompson WW, et al. Influenza outbreak detection and control measures in nursing homes in the United States. J Am Geriatr Soc 2000;48:1310--5.
136. Kramarz P, DeStefano F, Gargiullo PM, et al. Influenza vaccination in children with asthma in health maintenance organizations. Vaccine Safety Datalink Team. Vaccine 2000;18:2288--94.
137. Chung EK, Casey R, Pinto-Martin JA, et al. Routine and influenza vaccination rates in children with asthma. Ann Allergy Asthma Immunol 1998;80:318--22.
138. Gaglani M, Riggs M, Kamenicky C, et al. A computerized reminder strategy is effective for annual influenza immunization of children with asthma or reactive airway disease. Pediatr Infect Dis J 2001;20:1155--60.
139. Marshall BC, Henshaw C, Evans DA, et al. Influenza vaccination coverage level at a cystic fibrosis center. Pediatrics 2002;109:E80--0.
140. CDC. Childhood influenza vaccination coverage---United States, 2003--04 influenza season. MMWR 2006;55:100--3.
141. CDC. Rapid assessment of influenza vaccination coverage among HMO members---Northern California Influenza Seasons, 2001--02 through 2004--05. MMWR 2005;54:676--8.
142. CDC. Estimated influenza vaccination coverage among adults and children---United States, September 1, 2004--January 31, 2005. MMWR 2005;54:304--7.
143. Nowalk MP, Zimmerman RK, Lin CJ, et al. Parental perspectives on influenza immunization of children aged 6 to 23 months. Am J Prev Med 2005;29:210--4.
144. Potter J, Stott DJ, Roberts MA, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175:1--6.
145. Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of health-care personnel on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000;355(9198):93--7.
146. National Foundation for Infectious Diseases. Call to action: influenza immunization among health-care personnel, 2003. Bethesda, MD: National Foundation for Infectious Diseases; 2003. Available at http://www.nfid.org.
147. Poland GA, Tosh P, Jacobson RM. Requiring influenza vaccination for health care workers: seven truths we must accept. Vaccine 2005;23:2251--5.
148. Lu P, Singleton J. Influenza vaccination of pregnant women: Behavioral Risk Factor Surveillance System (BRFSS), 1997--2001. Presented at the Annual Behavioral Risk Factor Surveillance System Conference; St. Louis, Missouri, 2003.
149. Yeager DP, Toy EC, Baker B III. Influenza vaccination in pregnancy. Am J Perinatol 1999;16:283--6.
150. Gonik B, Jones T, Contreras D, et al. The obstetrician-gynecologist's role in vaccine-preventable diseases and immunization. Obstet Gynecol 2000;96:81--4.
151. Zimmerman RK, Raymund M, Janosky JE, et al. Sensitivity and specificity of patient self-report of influenza and pneumococcal polysaccharide vaccinations among elderly outpatients in diverse patient care strata. Vaccine 2003;21:1486--91.
152. Poehling KA, Edwards KM, Weinberg GA, et al. The Under-Recognized Burden of Influenza Illness in Young Children. N Engl J Med. In press 2006.
153. Iwane MK, Edwards KM, Szilagyi PG, et al. Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children. Pediatrics 2004;113:1758--64.
154. Schrag SJ, Shay DK, Gershman K, et al. Multistate surveillance for laboratory-confirmed influenza-associated hospitalizations in children, 2003--2004. Pediatr Infect Dis J 2006;25:395--400.
155. Mullooly JP, Barker WH. Impact of type A influenza on children: a retrospective study. Am J Public Health 1982;72:1008--16.
156. Glezen WP, Decker M, Joseph SW, et al. Acute respiratory disease associated with influenza epidemics in Houston, 1981--1983. J Infect Dis 1987;155:1119--26.
157. Louie JK, Schechter R, Honarmand S, et al. Severe pediatric influenza in California, 2003--2005: Implications for immunization recommendations. Pediatrics 2006;117:610--8.
158. Cooney MK, Fox JP, Hall CE. The Seattle Virus Watch. VI. Observations of infections with and illness due to parainfluenza, mumps and respiratory syncytial viruses and Mycoplasma pneumoniae. Am J Epidemiol 1975;101:532--51.
159. Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:543--6.
160. Glezen WP. Morbidity associated with the major respiratory viruses. Pediatr Ann 1990;19:535--6, 538, 540, passim.
161. Harris JW. Influenza occurring pregnant women: a statistical study of thirteen hundred and fifty cases. JAMA 1919;72:978--80.
162. Widelock D, Csizmas L, Klein S. Influenza, pregnancy, and fetal outcome. Public Health Rep 1963;78:1--11.
163. Freeman DW, Barno A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959;78:1172--5.
164. Shahab SZ, Glezen WP. Influenza virus. In: Gonik B, ed. Viral diseases in pregnancy. New York, NY: Springer-Verlag; 1994:215--23.
165. Schoenbaum SC, Weinstein L. Respiratory infection in pregnancy. Clin Obstet Gynecol 1979;22:293--300.
166. Kirshon B, Faro S, Zurawin RK, et al. Favorable outcome after treatment with amantadine and ribavirin in a pregnancy complicated by influenza pneumonia. A case report. J Reprod Med 1988;33:399--401.
167. Kort BA, Cefalo RC, Baker VV. Fatal influenza A pneumonia in pregnancy. Am J Perinatol 1986;3:179--82.
168. Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 2000;107:1282--9.
169. Neuzil KM, Reed GW, Mitchel EF, et al. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094--102.
170. Heinonen OP, Shapiro S, Monson RR, et al. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol 1973;2:229--35.
171. Munoz FM, Greisinger AJ, Wehmanen OA, et al. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2005;192:1098--106.
172. O'Mara D, Fukuda K, Singleton JA. Influenza vaccine: ensuring timely and adequate supply. Infect Med 2003;20:548--54.
173. CDC. Assessing adult vaccination status at age 50 years. MMWR 1995;44:561--3.
174. Fedson DS. Adult immunization. Summary of the National Vaccine Advisory Committee Report. JAMA 1994;272:1133--7.
175. Piedra PA, Gaglani MJ, Kozinetz CA, et al. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine 2005;23:1540--8.
176. King JC Jr, Cummings GE, Stoddard J, et al. A pilot study of the effectiveness of a school-based vaccination program. Pediatrics 2005;116:868--73.
177. CDC. Influenza vaccination of healthcare 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).
178. Talbot TR, Bradley SF, Cosgrove SE, et al. SHEA Position Paper: Influenza vaccination of healthcare workers and vaccine allocation for health care workers during vaccine shortages. Infection Control and Hospital Epidemiology 2005;26:882--90.
179. CDC. Interventions to increase influenza vaccination of health-care workers---California and Minnesota. MMWR 2005;54:196--9.
180. Stewart A, Cox M, Rosenbaum S. The epidemiology of U.S. immunization law: immunization requirements for staff and residents of long-term care facilities under state laws/regulations. Available at http://www.gwumc.edu/sphhs/healthpolicy/immunization/EUSIL-LTC-report.pdf.
181. Couch RB. Influenza, influenza virus vaccine, and human immunodeficiency virus infection. Clin Infect Dis 1999;28:548--51.
182. Tasker SA, O'Brien WA, Treanor JJ, et al. Effects of influenza vaccination in HIV-infected adults: a double-blind, placebo-controlled trial. Vaccine 1998;16:1039--42.
183. Neuzil KM, Reed GW, Mitchel EF Jr, et al. Influenza-associated morbidity and mortality in young and middle-aged women. JAMA 1999;281:901--7.
184. Lin JC, Nichol KL. Excess mortality due to pneumonia or influenza during influenza seasons among persons with acquired immunodeficiency syndrome. Arch Intern Med 2001;161:441--6.
185. Safrin S, Rush JD, Mills J. Influenza in patients with human immunodeficiency virus infection. Chest 1990;98:33--7.
186. Radwan HM, Cheeseman SH, Lai KK, et al. Influenza in human immunodeficiency virus-infected patients during the 1997--1998 influenza season. Clin Infect Dis 2000;31:604--6.
187. Fine AD, Bridges CB, De Guzman AM, et al. Influenza A among patients with human immunodeficiency virus: an outbreak of infection at a residential facility in New York City. Clin Infect Dis 2001;32:1784--91.
188. Chadwick EG, Chang G, Decker MD, et al. Serologic response to standard inactivated influenza vaccine in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1994;13:206--11.
189. Huang KL, Ruben FL, Rinaldo CR Jr, et al. Antibody responses after influenza and pneumococcal immunization in HIV-infected homosexual men. JAMA 1987;257:2047--50.
190. Staprans SI, Hamilton BL, Follansbee SE, et al. Activation of virus replication after vaccination of HIV-1-infected individuals. J Exp Med 1995;182:1727--37.
191. Kroon FP, van Dissel JT, de Jong JC, et al. Antibody response after influenza vaccination in HIV-infected individuals: a consecutive 3-year study. Vaccine 2000;18:3040--9.
192. Miotti PG, Nelson KE, Dallabetta GA, et al. The influence of HIV infection on antibody responses to a two-dose regimen of influenza vaccine. JAMA 1989;262:779--83.
193. Ho DD. HIV-1 viraemia and influenza. Lancet 1992;339(8808):1549.
194. O'Brien WA, Grovit-Ferbas K, Namazi A, et al. Human immunodeficiency virus-type 1 replication can be increased in peripheral blood of seropositive patients after influenza vaccination. Blood 1995;86:1082--9.
195. Glesby MJ, Hoover DR, Farzadegan H, et al. The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double-blind, placebo-controlled study. J Infect Dis 1996;174:1332--6.
196. Fowke KR, D'Amico R, Chernoff DN, et al. Immunologic and virologic evaluation after influenza vaccination of HIV-1-infected patients. AIDS 1997;11:1013--21.
197. Fuller JD, Craven DE, Steger KA, et al. Influenza vaccination of human immunodeficiency virus (HIV)-infected adults: impact on plasma levels of HIV type 1 RNA and determinants of antibody response. Clin Infect Dis 1999;28:541--7.
198. Amendola A, Boschini A, Colzani D, et al. Influenza vaccination of HIV-1-positive and HIV-1-negative former intravenous drug users. J Med Virol 2001;65:644--8.
199. Sullivan PS, Hanson DL, Dworkin MS, et al. Effect of influenza vaccination on disease progression among HIV-infected persons. AIDS 2000;14:2781--5.
200. Gunthard HF, Wong JK, Spina CA, et al. Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy. J Infect Dis 2000;181:522--31.
201. Miller JM, Tam TW, Maloney S, et al. Cruise ships: high-risk passengers and the global spread of new influenza viruses. Clin Infect Dis 2000;31:433--8.
202. Uyeki TM, Zane SB, Bodnar UR, et al. Large summertime influenza A outbreak among tourists in Alaska and the Yukon Territory. Clin Infect Dis 2003;36:1095--102.
203. Nichol KL, D'Heilly S, Ehlinger E. Colds and influenza-like illness in university students: impact on health, academic and work performance, and health care use. Clin Infect Dis 2005;40:1263--70.
204. Gross PA, Weksler ME, Quinnan GV Jr, et al. Immunization of elderly people with two doses of influenza vaccine. J Clin Microbiol 1987;25:1763--5.
205. Feery BJ, Cheyne IM, Hampson AW, et al. Antibody response to one and two doses of influenza virus subunit vaccine. Med J Aust 1976;1:186, 188--9.
206. Levine M, Beattie BL, McLean DM. Comparison of one- and two-dose regimens of influenza vaccine for elderly men. CMAJ 1987;137:722--6.
207. Cate TR, Couch RB, Parker D, et al. Reactogenicity, immunogenicity, and antibody persistence in adults given inactivated influenza virus vaccines---1978. Rev Infect Dis 1983;5:737--47.
208. Kunzel W, Glathe H, Engelmann H, et al. Kinetics of humoral antibody response to trivalent inactivated split influenza vaccine in subjects previously vaccinated or vaccinated for the first time. Vaccine 1996;14:1108--10.
209. Poland GA, Borrud A, Jacobson RM, et al. Determination of deltoid fat pad thickness. Implications for needle length in adult immunization. JAMA 1997;277:1709--11.
210. 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).
211. Govaert TM, Dinant GJ, Aretz K, et al. Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial. BMJ 1993;307:988--90.
212. Margolis KL, Nichol KL, Poland GA, et al. Frequency of adverse reactions to influenza vaccine in the elderly. A randomized, placebo-controlled trial. JAMA 1990;264:1139--41.
213. Nichol KL, Margolis KL, Lind A, et al. Side effects associated with influenza vaccination in healthy working adults. A randomized, placebo-controlled trial. Arch Intern Med 1996;156:1546--50.
214. American Lung Association Asthma Clinical Research Centers. The safety of inactivated influenza vaccine in adults and children with asthma. N Engl J Med 2001;345:1529--36.
215. Piedra PA, Glezen WP, Mbawuike I, et al. Studies on reactogenicity and immunogenicity of attenuated bivalent cold recombinant influenza type A (CRA) and inactivated trivalent influenza virus (TI) vaccines in infants and young children. Vaccine 1993;11:718--24.
216. Scheifele DW, Bjornson G, Johnston J. Evaluation of adverse events after influenza vaccination in hospital personnel. CMAJ 1990;142:127--30.
217. Barry DW, Mayner RE, Hochstein HD, et al. Comparative trial of influenza vaccines. II. Adverse reactions in children and adults. Am J Epidemiol 1976;104:47--59.
218. France EK, Jackson L, Vaccine Safety Datalink Team. Safety of the trivalent inactivated influenza vaccine among children: a population-based study [Abstract 76]. Presented at the National Immunization Conference, Chicago, Illinois; 2003.
219. Groothuis JR, Levin MJ, Rabalais GP, et al. Immunization of high-risk infants younger than 18 months of age with split-product influenza vaccine. Pediatrics 1991;87:823--8.
220. McMahon AW, Iskander J, Haber P, et al. Adverse events after inactivated influenza vaccination among children less than 2 years of age: analysis of reports from the vaccine adverse event reporting system, 1990--2003. Pediatrics 2005;115:453--60.
221. France EK, Glanz JM, Xu S, et al. Safety of the trivalent inactivated influenza vaccine among children: a population-based study. Arch Pediatr Adolesc Med 2004;158:1031--6.
222. Bierman CW, Shapiro GG, Pierson WE, et al. Safety of influenza vaccination in allergic children. J Infect Dis 1977;136(Suppl):S652--5.
223. James JM, Zeiger RS, Lester MR, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatr 1998;133:624--8.
224. Murphy KR, Strunk RC. Safe administration of influenza vaccine in asthmatic children hypersensitive to egg proteins. J Pediatr 1985;106:931--3.
225. Zeiger RS. Current issues with influenza vaccination in egg allergy. J Allergy Clin Immunol 2002;110:834--40.
226. Aberer W. Vaccination despite thimerosal sensitivity. Contact Dermatitis 1991;24:6--10.
227. Kirkland LR. Ocular sensitivity to thimerosal: a problem with hepatitis B vaccine? South Med J 1990;83:497--9.
228. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976--1977. Am J Epidemiol 1979;110:105--23.
229. Safranek TJ, Lawrence DN, Kurland LT, et al. Reassessment of the association between Guillain-Barre syndrome and receipt of swine influenza vaccine in 1976--1977: results of a two-state study. Expert Neurology Group. Am J Epidemiol 1991;133:940--51.
230. Ropper AH. The Guillain-Barre syndrome. N Engl J Med 1992;326:1130--6.
231. Hurwitz ES, Schonberger LB, Nelson DB, et al. Guillain-Barre syndrome and the 1978--1979 influenza vaccine. N Engl J Med 1981;304:1557--61.
232. Kaplan JE, Katona P, Hurwitz ES, et al. Guillain-Barre syndrome in the United States, 1979--1980 and 1980--1981. Lack of an association with influenza vaccination. JAMA 1982;248:698--700.
233. Chen R, Kent J, Rhodes P, et al. Investigations of a possible association between influenza vaccination and Guillain-Barre syndrome in the United States, 1990--1991 [Abstract 040]. Post Marketing Surveillance 1992;6:5--6.
234. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre syndrome and the 1992--1993 and 1993--1994 influenza vaccines. N Engl J Med 1998;339:1797--802.
235. Haber P, DeStefano F, Angulo FJ, et al. Guillain-Barre syndrome following influenza vaccination. JAMA 2004;292:2478--81.
236. Flewett TH, Hoult JG. Influenzal encephalopathy and postinfluenzal encephalitis. Lancet 1958;2(7036):11--5.
237. Horner FA. Neurologic disorders after Asian influenza. N Engl J Med 1958;258:983--5.
238. Jacobs BC, Rothbarth PH, van der Meche FG, et al. The spectrum of antecedent infections in Guillain-Barre syndrome: a case-control study. Neurology 1998;51:1110--5.
239. Guarino M, Casmiro M, D'Alessandro R. Campylobacter jejuni infection and Guillain-Barre syndrome: a case-control study. Emilia-Romagna Study Group on Clinical and Epidemiological problems in neurology. Neuroepidemiology 1998;17:296--302.
240. Sheikh KA, Nachamkin I, Ho TW, et al. Campylobacter jejuni lipopolysaccharides in Guillain-Barre syndrome: molecular mimicry and host susceptibility. Neurology 1998;51:371--8.
241. Prevots DR, Sutter RW. Assessment of Guillain-Barre syndrome mortality and morbidity in the United States: implications for acute flaccid paralysis surveillance. J Infect Dis 1997;175(Suppl 1):S151--5.
242. Barohn RJ, Saperstein DS. Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Semin Neurol 1998;18:49--61.
243. CDC. Recommendations regarding the use of vaccines that contain thimerosal as a preservative. MMWR 1999;48:996--8.
244. Stratton K, Gable A, McCormick MC, eds. Immunization safety review: thimerosal-containing vaccines and neurodevelopmental disorders. Washington, DC: National Academy Press; 2001.
245. Pichichero ME, Cernichiari E, Lopreiato J, et al. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet 2002;360(9347):1737--41.
246. CDC. Summary of the joint statement on thimerosal in vaccines. MMWR 2000;49:622, 631.
247. Verstraeten T, Davis RL, DeStefano F, et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 2003;112:1039--104.
248. McCormick M, Bayer R, Berg A, et al. Report of the Institute of Medicine. Immunization Safety Review: Vaccines and Autism. Washington, DC: National Academy Press; 2004.
249. Vesikari T. Randomized, double-blind, placebo-controlled trial of the safety, transmissibility and phenotypic stability of a live, attenuated, cold-adapted influenza virus vaccine (CAIV-T) in children attending day care [Abstract G-450]. Presented at the 41st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2001.
250. Talbot TR, Crocker DD, Peters J. Degree and duration of mucosal shedding following use of trivalent intranasal live attenuated influenza vaccine in adults [Abstract]. Presented at 14th Annual Meeting, Society for Health-care Epidemiology in America, Philadelphia, Pennsylvania; 2004.
251. Ali T, Scott N, Kallas W, et al. Detection of influenza antigen with rapid antibody-based tests after intranasal influenza vaccination (FluMist). Clin Infect Dis 2004;38:760--2.
252. Cha TA, Kao K, Zhao J, et al. Genotypic stability of cold-adapted influenza virus vaccine in an efficacy clinical trial. J Clin Microbiol 2000;38:839--45.
253. Buonagurio DA, O'Neill RE, Shutyak L, et al. Genetic and phenotypic stability of cold-adapted influenza viruses in a trivalent vaccine administered to children in a day care setting. Virology 2006;347:296--306.
254. King JC Jr, Fast PE, Zangwill KM, et al. Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children. Pediatr Infect Dis J 2001;20:1124--31.
255. Redding G, Walker RE, Hessel C, et al. Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J 2002;21:44--8.
256. Piedra PA, Yan L, Kotloff K, et al. Safety of the trivalent, cold-adapted influenza vaccine in preschool-aged children. Pediatrics 2002;110:662--72.
257. Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J 2004;23:138--44.
258. Belshe RB, Nichol KL, Black SB, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5--49 years. Clin Infect Dis 2004;39:920--7.
259. Piedra PA, Gaglani MJ, Riggs M, et al. Live attenuated influenza vaccine, trivalent, is safe in healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-based, nonrandomized, open-label tiral. Pediatrics 2005;11:397--407.
260. Jackson LA, Holmes SJ, Mendelman PM, et al. Safety of a trivalent live attenuated intranasal influenza vaccine, FluMist, administered in addition to parenteral trivalent inactivated influenza vaccine to seniors with chronic medical conditions. Vaccine 1999;17:1905--9.
261. King JC Jr, Treanor J, Fast PE, et al. Comparison of the safety, vaccine virus shedding, and immunogenicity of influenza virus vaccine, trivalent, types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults. J Infect Dis 2000;181:725--8.
262. Izurieta HS, Haber P, Ball R, et al. Post-licensure surveillance of the first live, cold-adapted influenza vaccine in the U.S. [Abstract]. Pharmacoepidemiology and Drug Safety 2004;13:S145.
263. Izurieta HS, Haber P, Wise RP, et al. Adverse events reported following live, cold-adapted, intranasal influenza vaccine. JAMA 2005;294:2720--5.
264. McElhaney JE, Gravenstein S, Upshaw CM, et al. Immune response to influenza vaccination in institutionalized elderly: effect on different T-cell subsets. Vaccine 1998;16:403--9.
265. Gross PA, Russo C, Dran S, et al. Time to earliest peak serum antibody response to influenza vaccine in the elderly. Clin Diagn Lab Immunol 1997;4:491--2.
266. Brokstad KA, Cox RJ, Olofsson J, et al. Parenteral influenza vaccination induces a rapid systemic and local immune response. J Infect Dis 1995;171:198--203.
267. Lawson F, Baker V, Au D, et al. Standing orders for influenza vaccination increased vaccination rates in inpatient settings compared with community rates. J Gerontol A Biol Sci Med Sci 2000;55:M522--6.
268. Centers for Medicare and Medicaid Services. Medicare and Medicaid Programs; Condition of Participation: Immunization Standard for Long Term Care Facilities. Final rule. Federal Register 2005;70:58834--52.
269. Centers for Medicare and Medicaid Services. Medicare and Medicaid programs; conditions of participation: immunization standards for hospitals, long-term care facilities, and home health agencies. Final rule with comment period. Federal Register 2002;67:61808--14.
270. Fedson DS, Wajda A, Nicol JP, et al. Disparity between influenza vaccination rates and risks for influenza-associated hospital discharge and death in Manitoba in 1982--1983. Ann Intern Med 1992;116:550--5.
271. Bratzler DW, Houck PM, Jiang H, et al. Failure to vaccinate Medicare inpatients: a missed opportunity. Arch Intern Med 2002;162:2349--56.
272. Fedson DS, Houck P, Bratzler D. Hospital-based influenza and pneumococcal vaccination: Sutton's Law applied to prevention. Infect Control Hosp Epidemiol 2000;21:692--9.
273. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 2006;24:1159--69.
274. Simonsen L, Reichert TA, Viboud C, et al. Impact of influenza vaccination on seasonal mortality in the US elderly population. Arch Intern Med 2005;165:265--72.
275. Jackson LA, Jackson ML, Nelson JC, et al. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol 2006;35:337--44.
276. Jackson LA, Nelson JC, Benson P, et al. Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors. Int J Epidemiol 2006;35:345--52.
277. Nichol KL, Nordin J, Mullooly J. Influence of clinical outcome and outcome period definitions on estimates of absolute clinical and economic benefits of influenza vaccination in community dwelling elderly persons. Vaccine 2006;24:1562--8.
278. Thomas RE, Jefferson TO, Demicheli V, Rivetti D. Influenza vaccination for health-care workers who work with elderly people in institutions: a systematic review. Lancet Infect Dis 2006;6:273--9.
279. Weycker D, Edelsberg J, Halloran ME, et al. Population-wide benefits of routine vaccination of children against influenza. Vaccine 2005;23:1284--93.
280. Longini IM Jr, Halloran ME. Strategy for distribution of influenza vaccine to high-risk groups and children. Am J Epidemiol 2005;161:303--6.
281. King JC, Cummings GE, Stoddard J, et al. A pilot study of the effectiveness of a school-based influenza vaccination program. Pediatrics 2005;116:868--73.
282. Jordan R, Connock M, Albon E, et al. Universal vaccination of children against influenza: Are there indirect benefits to the community? A systematic review of the evidence. Vaccine 2006;24:1047--62.
283. Helms CM, Guerra FA, Klein JO, et al. Strengthening the nation's influenza vaccination system: A National Vaccine Advisory Committee assessment. Am J Prev Med 2005;29:221--6.
284. Public Health Agency of Canada. Interim recommendation for use of amantadine for influenza. Available at http://www.phac-aspc.gc.ca/media/advisories_avis/2006/statement060115.html.
285. CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54(No. RR-8).
286. Schmid ML, Kudesia G, Wake S, et al. Prospective comparative study of culture specimens and methods in diagnosing influenza in adults. BMJ 1998;316:275.
287. Letter M. Rapid diagnostic tests for influenza. Medical Letter 1999;41:121--22.
288. Storch GA. Rapid diagnostic tests for influenza. Curr Opin Pediatr 2003;15:77--84.
289. Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J 2003;22:164--77.
290. Hayden FG, Sperber SJ, Belshe RB, et al. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine. Antimicrob Agents Chemother 1991;35:1741--7.
291. Degelau J, Somani SK, Cooper SL, et al. Amantadine-resistant influenza A in a nursing facility. Arch Intern Med 1992;152:390--2.
292. Ziegler T, Hemphill ML, Ziegler ML, et al. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis 1999;180:935--9.
293. Belshe RB, Smith MH, Hall CB, et al. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection. J Virol 1988;62:1508--12.
294. Hay AJ, Zambon MC, Wolstenholme AJ, et al. Molecular basis of resistance of influenza A viruses to amantadine. J Antimicrob Chemother 1986;18(Suppl B):19--29.
295. Hall CB, Dolin R, Gala CL, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics 1987;80:275--82.
296. Saito R, Oshitani H, Masuda H, et al. Detection of amantadine-resistant influenza A virus strains in nursing homes by PCR-restriction fragment length polymorphism analysis with nasopharyngeal swabs. J Clin Microbiol 2002;40:84--8.
297. Houck P, Hemphill M, LaCroix S, et al. Amantadine-resistant influenza A in nursing homes. Identification of a resistant virus prior to drug use. Arch Intern Med 1995;155:533--7.
298. 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;321:1696--702.
299. Mast EE, Harmon MW, Gravenstein S, et al. Emergence and possible transmission of amantadine-resistant viruses during nursing home outbreaks of influenza A (H3N2). Am J Epidemiol 1991;134:988--97.
300. Gubareva LV, Robinson MJ, Bethell RC, et al. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. J Virol 1997;71:3385--90.
301. Colacino JM, Laver WG, Air GM. Selection of influenza A and B viruses for resistance to 4-guanidino-Neu5Ac2en in cell culture. J Infect Dis 1997;176(Suppl 1):S66--8.
302. Gubareva LV, Bethell R, Hart GJ, et al. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J Virol 1996;70:1818--27.
303. Blick TJ, Tiong T, Sahasrabudhe A, et al. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Virology 1995;214:475--84.
304. McKimm-Breschkin JL, Blick TJ, Sahasrabudhe A, et al. Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en. Antimicrob Agents Chemother 1996;40:40--6.
305. Staschke KA, Colacino JM, Baxter AJ, et al. Molecular basis for the resistance of influenza viruses to 4-guanidino-Neu5Ac2en. Virology 1995;214:642--6.
306. McKimm-Breschkin JL, Sahasrabudhe A, Blick TJ, et al. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol 1998;72:2456--62.
307. Tai CY, Escarpe PA, Sidwell RW, et al. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother 1998;42:3234--41.
308. Hay AJ, Wolstenholme AJ, Skehel JJ, et al. The molecular basis of the specific anti-influenza action of amantadine. Embo J 1985;4:3021--4.
309. Appleyard G. Amantadine-resistance as a genetic marker for influenza viruses. J Gen Virol 1977;36:249--55.
310. Roche Laboratories I. Tamiflu (oseltamivir phosphate) capsules and oral suspension [Product infomation]. Nutley, NJ: Roche Laboratories, Inc.; 2005.
311. Barnett JM, 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;44:78--87.
312. Gubareva LV, Matrosovich MN, Brenner MK, et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998;178:1257--62.
313. Gubareva LV, Kaiser L, Matrosovich MN, et al. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 2001;183:523--31.
314. Jackson HC, Roberts N, Wang ZM, et al. Management of influenza: use of new antivirals and resistance in perspective. Clin Drug Invest 2000;20:447--54.
315. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759--65.
316. Tisdale M. Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors. Rev Med Virol 2000;10:45--55.
317. Glaxo Wellcome. Relenza (zanamivir for inhalation) [Product information]. Research Triangle Park, NC: Glaxo Wellcome, Inc.; 2001.
318. Gubareva LV, Webster RG, Hayden FG. Detection of influenza virus resistance to neuraminidase inhibitors by an enzyme inhibition assay. Antiviral Res 2002;53:47--61.
319. Zambon M, Hayden FG. Position statement: global neuraminidase inhibitor susceptibility network. Antiviral Res 2001;49:147--56.
320. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GG167 Influenza Study Group. N Engl J Med 1997;337:874--80.
321. MIST (Management of Influenza in the Southern Hemisphere Trialists). Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet 1998;352(9144):1877--81.
322. Makela MJ, Pauksens K, Rostila T, et al. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect 2000;40:42--8.
323. Matsumoto K, Ogawa N, Nerome K, et al. Safety and efficacy of the neuraminidase inhibitor zanamivir in treating influenza virus infection in adults: results from Japan. GG167 Group. Antivir Ther 1999;4:61--8.
324. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999;180:254--61.
325. Lalezari J, Campion K, Keene O, et al. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Arch Intern Med 2001;161:212--7.
326. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000;283:1016--24.
327. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 2000;355(9218):1845--50.
328. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J 2000;19:410--7.
329. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001;20:127--33.
330. Murphy KR, Eivindson A, Pauksens K. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomised, placebo-controlled, multicentre study. Clin Drug Invest 2000;20:337--49.
331. Uyeki T, Winquist A. Influenza. Clin Evid 2002;(7):645--51.
332. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003;326:1235.
333. Jefferson T, Demicheli V, Deeks J, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev 2000;(2):CD001265.
334. Jefferson T, Demicheli V, Mones M, et al. Antivirals for influenza in healthy adults: systematic review. Lancet 2006;367:303--13.
335. Nicholson KG. Use of antivirals in influenza in the elderly: prophylaxis and therapy. Gerontology 1996;42:280--9.
336. Martin C, Mahoney P, Ward P. Oral oseltamivir reduces febrile illness in patients considered at high risk of influenza complications [Abstract W22-7]. In: Options for the control of influenza IV. New York, NY: Excerpta Medica; 2001:807--11.
337. Gravenstein S, Johnston SL, Loeschel E, et al. Zanamivir: a review of clinical safety in individuals at high risk of developing influenza-related complications. Drug Saf 2001;24:1113--25.
338. Bowles SK, Lee W, Simor AE, et al. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999--2000. J Am Geriatr Soc 2002;50:608--16.
339. Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003;163:1667--72.
340. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341:1336--43.
341. 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;343:1282--9.
342. Schilling M, Povinelli L, Krause P, et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine 1998;16:1771--4.
343. 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;21:700--4.
344. Parker R, Loewen N, Skowronski D. Experience with oseltamivir in the control of a nursing home influenza B outbreak. Can Commun Dis Rep 2001;27:37--40.
345. Woods JM, Bethell RC, Coates JA, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993;37:1473--9.
346. Hayden FG, Rollins BS, Madren LK. Anti-influenza virus activity of the neuraminidase inhibitor 4-guanidino-Neu5Ac2en in cell culture and in human respiratory epithelium. Antiviral Res 1994;25:123--31.
347. Mendel DB, Tai CY, Escarpe PA, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother 1998;42:640--6.
348. Sidwell RW, Huffman JH, Barnard DL, et al. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res 1998;37:107--20.
349. Hayden FG, Rollins BS. In vitro activity of the neuraminidase inhibitor GS4071 against influenza viruses [Abstract 159]. Antiviral Res 1997;34:A86.
350. Mendel DB, Tai CY, Escarpe PA. GS4071 is a potent and selective inhibitor of the growth and neuraminidase activity of influenza A and B viruses in vitro [Abstract 111]. Antiviral Res 1997;34:A73.
351. Ryan DM, Ticehurst J, Dempsey MH, et al. Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase). Antimicrob Agents Chemother 1994;38:2270--5.
352. Ryan DM, Ticehurst J, Dempsey MH. GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a potent inhibitor of influenza virus in ferrets. Antimicrob Agents Chemother 1995;39:2583--4.
353. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001;285:748--54.
354. Hayden FG, Jennings L, Robson R, et al. Oral oseltamivir in human experimental influenza B infection. Antivir Ther 2000;5:205--13.
355. Food and Drug Administration. Subject: safe and appropriate use of influenza drugs [Public Health Advisory]. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2000.
356. Monto AS, Pichichero ME, Blanckenberg SJ, et al. Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households. J Infect Dis 2002;186:1582--8.
357. 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;49:1025--31.
358. Webster A, Boyce M, Edmundson S, et al. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Clin Pharmacokinet 1999;36(Suppl 1):51--8.
359. Gomolin IH, Leib HB, Arden NH, et al. Control of influenza outbreaks in the nursing home: guidelines for diagnosis and management. J Am Geriatr Soc 1995;43:71--4.
360. Garner JS. Guideline for isolation precautions in hospitals. The Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1996;17:53--80.
361. Bradley SF. Prevention of influenza in long-term-care facilities. Long-Term-Care Committee of the Society for Health-care Epidemiology of America. Infect Control Hosp Epidemiol 1999;20:629--37.
362. Tominack RL, Hayden FG. Rimantadine hydrochloride and amantadine hydrochloride use in influenza A virus infections. Infect Dis Clin North Am 1987;1:459--78.
363. Guay DR. Amantadine and rimantadine prophylaxis of influenza A in nursing homes. A tolerability perspective. Drugs Aging 1994;5:8--19.
364. Patriarca PA, Kater NA, Kendal AP, et al. Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes. Antimicrob Agents Chemother 1984;26:101--3.
365. Arden NH, Patriarca PA, Fasano MB, et al. The roles of vaccination and amantadine prophylaxis in controlling an outbreak of influenza A (H3N2) in a nursing home. Arch Intern Med 1988;148:865--8.
366. Patriarca PA, Arden NH, Koplan JP, et al. Prevention and control of type A influenza infections in nursing homes. Benefits and costs of four approaches using vaccination and amantadine. Ann Intern Med 1987;107:732--40.
367. Shijubo N, Yamada G, Takahashi M, et al. Experience with oseltamivir in the control of nursing home influenza A outbreak. Intern Med 2002;41:366--70.
368. Cass LM, Efthymiopoulos C, Marsh J, et al. Effect of renal impairment on the pharmacokinetics of intravenous zanamivir. Clin Pharmacokinet 1999;36(Suppl 1):13--9.
369. Calfee DP, Peng AW, Cass LM, et al. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616--20.
370. Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 1999;36(Suppl 1):1--11.
371. Bardsley-Elliot A, Noble S. Oseltamivir. Drugs 1999;58:851--60; discussion:861--2.
372. Cass LM, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet 1999;36(Suppl 1):21--31.
373. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999;37:471--84.
374. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA 1999;282:1240--6.
375. Daniel MJ, Barnett JM, Pearson BA. The low potential for drug interactions with zanamivir. Clin Pharmacokinet 1999;36(Suppl 1):41--50.

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Date last reviewed: 6/28/2006