Treatment of Seasonal Influenza A and B Virus Infections
Oseltamivir is used for the treatment of acute, uncomplicated illness caused by influenza A or B viruses in adults, adolescents, and pediatric patients 2 weeks of age or older. Although safety and efficacy have not been established in neonates younger than 2 weeks of age, oseltamivir also is recommended when treatment of influenza is necessary in this age group.
The US Centers for Disease Control and Prevention (CDC), US Public Health Service Advisory Committee on Immunization Practices (ACIP), and American Academy of Pediatrics (AAP) recommend antiviral treatment of seasonal influenza illness as soon as possible in all individuals with suspected or confirmed influenza if they require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness). These experts also recommend early empiric antiviral treatment in individuals with suspected or confirmed influenza of any severity who are at high risk for influenza-related complications because of age or underlying medical conditions. Individuals at increased risk for influenza-related complications include children younger than 2 years of age; adults 65 years of age or older; individuals of any age with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), or metabolic disorders (including diabetes mellitus); individuals with neurologic and neurodevelopmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury); individuals with immunosuppression (including that caused by medications or human immunodeficiency virus [HIV] infection); women who are pregnant or up to 2 weeks postpartum; individuals younger than 19 years of age receiving long-term aspirin therapy; American Indians or Alaskan natives; morbidly obese individuals with a body mass index (BMI) of 40 or greater; and residents of any age in nursing homes or other long-term care facilities.
CDC, ACIP, and AAP also state that empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed seasonal influenza who are not known to be at increased risk of developing severe or complicated illness if such treatment can be initiated within 48 hours of illness onset. Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness). The use of antiviral treatment in such individuals should be based on clinical judgment and is not necessary in those who are already beginning to recover. In areas with limited availability of antiviral agents, local public health authorities might provide additional guidance about prioritizing use of antivirals within groups at higher risk for complications.
When treatment of seasonal influenza is indicated, an appropriate antiviral agent should be initiated as soon as possible after illness onset (ideally within 48 hours), and should not be delayed while waiting for laboratory confirmation. The manufacturer states that oseltamivir should be used for the treatment of influenza only in patients who have been symptomatic for no more than 2 days since efficacy of the drug has not been established in those whose symptoms have been present for more than 48 hours. However, although clinical benefit is greatest when oseltamivir is initiated within 48 hours of onset of influenza symptoms, there is some evidence from observational studies of hospitalized patients that antiviral treatment may still be beneficial when initiated up to 4 or 5 days after illness onset. Therefore, CDC, ACIP, and AAP recommend that antiviral treatment be initiated in all patients with severe, complicated, or progressive illness attributable to influenza and all hospitalized patients and patients at increased risk of influenza complications (either hospitalized or outpatient) who have suspected or confirmed influenza, even if it has been more than 48 hours after illness onset. Decisions regarding use of empiric antiviral treatment in outpatients, especially high-risk patients, should be based on disease severity and progression, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms. If empiric antiviral treatment is considered warranted in previously healthy, symptomatic outpatients not considered at increased risk of influenza complications, such treatment should be initiated within 48 hours after illness onset, but some experts state treatment can be considered in such patients even if it has been more than 48 hours after illness onset.
An age-appropriate neuraminidase inhibitor antiviral agent (oral oseltamivir, IV peramivir, inhaled zanamivir) should be used when treatment of suspected or confirmed acute, uncomplicated influenza is indicated in outpatients. Oseltamivir usually is the preferred neuraminidase inhibitor in hospitalized patients and patients with severe or complicated influenza because of the lack of data regarding use of IV peramivir or inhaled zanamivir in such patients. Although controlled clinical trials evaluating oseltamivir for the treatment of influenza generally only included patients with acute, uncomplicated influenza illness, observational studies indicate that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza. Limited data suggest that oral oseltamivir usually is well absorbed in critically ill influenza patients, including patients in intensive care units and those requiring continuous renal replacement therapy and/or extracorporeal membrane oxygenation, but there have been rare reports of suspected decreased oral absorption of the drug in patients with decreased gastric motility or GI bleeding. For the treatment of hospitalized patients with severe influenza who cannot tolerate or absorb oral oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding), CDC states that use of IV peramivir or investigational IV zanamivir may be considered. Use of investigational IV zanamivir also should be considered for treatment of severe influenza caused by oseltamivir-resistant strains. Oseltamivir is the preferred antiviral agent for treatment of suspected or confirmed influenza in pregnant women.
(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Viral surveillance data available from local and state health departments and CDC should be considered when selecting an antiviral for treatment of seasonal influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and the possibility that emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug should be considered. Although influenza A and B viruses circulating in the US during the last few years generally have been susceptible to oseltamivir
(see Resistance), clinicians should consult the most recent information.
CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at http://www.cdc.gov/flu.
Adults and Adolescents
Efficacy of oseltamivir for the treatment of seasonal influenza in adults 18 years of age or older has been established in randomized placebo-controlled studies in which the predominant influenza infection was influenza A; only a limited number of adults in studies to date have been infected with influenza B. When initiated within 40 hours of onset of symptoms in otherwise healthy adults 18-65 years of age with uncomplicated influenza, the drug has decreased the severity of influenza symptoms (i.e., nasal congestion, sore throat, cough, aches, fatigue, headache, chills/sweats) and shortened the average duration of these symptoms by about 1.3 days. When used in geriatric patients 65 years of age or older, oseltamivir has reduced the time to symptom improvement by 1 day.
Analysis of data from several studies indicated that adults who received oseltamivir for seasonal influenza had a lower incidence of respiratory complications requiring anti-infective therapy and hospitalization. Individuals who initiate therapy sooner (i.e., no later than 24 hours after symptom onset) exhibit greater benefit (e.g., a 2-day decrease in symptom duration). Oseltamivir therapy also has reduced the magnitude and duration of viral replication.
Children 1-12 Years of Age
Efficacy of oseltamivir for the treatment of seasonal influenza in children 1-12 years of age has been established in a placebo-controlled study in children infected with influenza A (67%) or influenza B (33%). When used in these children within 48 hours of symptom onset, the drug reduced influenza symptoms (i.e., cough, coryza, duration of fever) and shortened the average duration of illness by about 1.5 days. Data from this study also indicate that children who received oseltamivir had a lower incidence of newly diagnosed otitis media (a common secondary complication of influenza) than those who received placebo.
In a study in children 6-12 years of age with asthma who received oseltamivir or placebo for the treatment of acute influenza virus infection, use of oseltamivir improved pulmonary function and reduced the risk of influenza-induced asthma exacerbations. When initiated within 48 hours of symptom onset, oseltamivir shortened the duration of illness in these children by about 24 hours; however, if initiated within 24 hours of symptom onset, oseltamivir shortened the duration of illness by about 40 hours.
Although the manufacturer states that efficacy of oseltamivir for the treatment of influenza in immunocompromised patients has not been established, oseltamivir has been used to treat seasonal influenza A or B virus infections in bone marrow transplant (BMT) recipients in a prospective, uncontrolled study. This study provides some evidence that oseltamivir treatment (75 mg twice daily for 5 days) may prevent influenza complications and is not associated with any unusual adverse effects in these patients. Oseltamivir also has been used for the treatment of influenza infections in hematopoietic stem cell transplant (HSCT) recipients. Treatment with oseltamivir prevented progression to pneumonia in influenza-infected HSCT recipients in a small study.
Prevention of Seasonal Influenza A and B Virus Infections
Oseltamivir is used for prophylaxis of influenza A or B virus infections in adults, adolescents, and children 1 year of age or older.
Annual vaccination with seasonal influenza virus vaccine, as recommended by ACIP, is the primary means of preventing seasonal influenza and its severe complications. Prophylaxis with an appropriate antiviral agent active against circulating influenza strains is considered an adjunct to vaccination for the control and prevention of influenza.
Decisions regarding use of antivirals for prophylaxis of influenza should be based on the exposed person's risk for influenza complications, vaccination status, the type and duration of contact, recommendations from local or public health authorities, and clinical judgment. In general, postexposure prophylaxis should be used only if it can be initiated within 48 hours of the most recent exposure. Indiscriminate use of antivirals for prophylaxis may promote resistance or reduce availability of antiviral agents for treatment. In areas with limited availability of antiviral agents, local public health authorities might provide additional guidance about prioritizing use of antiviral prophylaxis within groups at higher risk for influenza complications. In certain situations, CDC or local public health authorities might recommend that antiviral agents be reserved for treatment and that prophylaxis be used only in certain limited situations.
When seasonal influenza viruses are circulating in the community, postexposure prophylaxis with oseltamivir or zanamivir can be considered for certain individuals, including those at high risk of developing influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals). Other possible candidates for antiviral postexposure prophylaxis include unvaccinated health care personnel, public health workers, and first responders with unprotected, close-contact exposure to a patient with confirmed, probable, or suspected influenza during the time when the patient was infectious. Antiviral prophylaxis also can be considered for controlling influenza outbreaks in nursing and long-term care facilities or other closed or semi-closed settings with large numbers of individuals at high risk for influenza complications. In individuals at high risk of influenza complications who receive influenza virus vaccine inactivated, use of prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.
(See Drug Interactions: Influenza Virus Vaccines.)
Viral surveillance data available from local and state health departments and CDC should be considered when selecting an antiviral for the prophylaxis of influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and the possibility that emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug should be considered. Although influenza A and B viruses circulating in the US during the last few years generally have been susceptible to oseltamivir
(see Resistance), clinicians should consult the most recent information.
CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at http://www.cdc.gov/flu.
Adults and Adolescents
Results of community studies in healthy, unvaccinated adults indicate that oseltamivir is about 82% effective in preventing febrile, laboratory-confirmed influenza illness. Efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in seasonal prophylaxis studies and in postexposure prophylaxis studies in households. The primary efficacy parameter for these studies was the incidence of laboratory-confirmed clinical influenza, which was defined as oral temperature exceeding 37.2°C with at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats) all occurring within a single 24-hour period and either a positive virus isolation or a fourfold increase in virus antibody titer from baseline.
In 2 seasonal prophylaxis studies in healthy, unvaccinated adults and adolescents 13-65 years of age who received oseltamivir (75 mg once daily) or placebo for 42 days during a community outbreak, pooled analysis indicates that the incidence of laboratory-confirmed clinical influenza was 1 or 5% in those receiving oseltamivir or placebo, respectively. In a seasonal prophylaxis study in geriatric residents of skilled nursing facilities (80% vaccinated, 14% with chronic airway obstructive disorders, 43% with cardiac disorders) who received oseltamivir (75 mg once daily) or placebo for 42 days, the incidence of laboratory-confirmed clinical influenza was less than 1 or 4% of those receiving oseltamivir or placebo, respectively.
In a postexposure prophylaxis study in household contacts (13 years of age or older) of influenza-infected index cases (not treated with antivirals) who received oseltamivir (75 mg once daily) or placebo for 7 days within 2 days of onset of symptoms in the index case, the incidence of laboratory-confirmed clinical influenza was 1 or 12% of those receiving oseltamivir or placebo, respectively. In another postexposure prophylaxis study, there was evidence that oseltamivir prophylaxis effectively reduced the secondary spread of influenza within households when given to household contacts of index patients who were receiving the drug for treatment.
Children 1-12 Years of Age
Efficacy of oseltamivir in preventing naturally occurring influenza illness in children 1-12 years of age was evaluated in a randomized, open-label, postexposure prophylaxis study. In this study, oseltamivir prophylaxis was used during a documented community influenza outbreak and was given to adults and children 1 year of age or older residing in households that had an index patient with an influenza-like illness who was receiving oseltamivir for treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza (defined as oral temperature 37.8°C or higher with cough and/or coryza occurring within a single 48-hour period and either a positive virus isolation or a fourfold or greater increase in virus antibody titer from baseline). In household contacts 1-12 years of age not shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was 3 or 17% in those receiving oseltamivir or placebo, respectively. The overall incidence of influenza illness in children who received oseltamivir prophylaxis was higher than that in adults and adolescents 13 years of age or older who received such prophylaxis.
Although the manufacturer states that efficacy of oseltamivir for prevention of influenza in immunocompromised patients has not been established, the drug has been used for prophylaxis of influenza in some immunocompromised individuals, including cancer patients, BMT recipients, HSCT recipients, and solid organ transplant recipients.
In a prospective, uncontrolled study, oseltamivir was used for prophylaxis of influenza in cancer patients 6.3-23.4 years of age who were immunocompromised because of current or recent chemotherapy or BMT. There were no laboratory-confirmed cases of influenza in the study participants; however, a few patients withdrew from the study because of adverse GI effects.
Safety and efficacy of oseltamivir for prevention of seasonal influenza in immunocompromised patients were evaluated in a double-blind, placebo-controlled study that included 475 immunocompromised adults, adolescents, and pediatric patients 1-12 years of age who had received solid organ transplants (liver, kidney, liver and kidney) or HSCT. The median time since solid organ transplant was 1105 days in those randomized to placebo and 1379 days in those randomized to oseltamivir prophylaxis; the median time since HSCT transplant was 424 days in those randomized to placebo and 367 days in those randomized to oseltamivir. Approximately 40% of patients had received influenza vaccine prior to study entry. The primary efficacy endpoint was the incidence of confirmed clinical influenza, defined as oral temperature exceeding 37.2°C plus cough and/or coryza (all recorded within 24 hours) plus either a positive virus culture or a fourfold increase in virus antibody titers from baseline. The incidence of confirmed clinical influenza was 3% in the placebo group and 2% in the oseltamivir group; this difference was not statistically significant. The safety profile of oseltamivir reported in these immunocompromised patients (up to 12 weeks of prophylaxis) was similar to that reported in other clinical trials evaluating oseltamivir prophylaxis.
Avian Influenza A Virus Infections
Oseltamivir is used for the treatment or prevention of infections caused by susceptible avian influenza A viruses (e.g., H5N1, H7N3, H7N7, H7N9).
Risk of Exposure and Infection
Although avian influenza A viruses usually do not infect humans, infection with these viruses has been reported following exposure to infected poultry. It can be anticipated that human cases of avian influenza A will continue to be detected in countries where these viruses circulate in wild birds, outbreaks occur in poultry, and close human contact with poultry is common (e.g., backyard flocks, markets).
Since 2003, avian influenza A (H5N1) infection in poultry or wild birds has been reported in parts of Asia, Africa, the Pacific, Eastern Europe, and the Middle East. World Health Organization (WHO) data indicate that there were 668 confirmed human cases of highly pathogenic avian influenza A (H5N1) infection (including 393 fatalities) reported in 16 countries from 2003 to October 2014. These human cases occurred in Azerbaijan, Bangladesh, Cambodia, Canada, China, Djibouti, Egypt, Indonesia, Iraq, Laos, Myanmar, Nigeria, Pakistan, Thailand, Turkey, and Vietnam.
In March 2013, a novel avian influenza A (H7N9) virus causing human infection was identified in China. By June 2013, 132 human cases had been confirmed in mainland China and Taiwan. From February 2013 to February 2014, the WHO had received reports of 355 human cases of avian influenza A (H7N9) infection (including 112 fatalities). To date, no cases have been reported in animals or humans in the US. Most reported cases of avian influenza A (H7N9) infection have involved severe respiratory illness, including pneumonia and acute respiratory distress syndrome (ARDS), and approximately 27% of identified cases have been fatal. Many of the infected individuals had close contact with poultry (chickens or ducks) and the source of infection is assumed to be infected poultry or contaminated environments. Preliminary investigations of patients and close contacts have not revealed evidence of sustained human-to-human transmission of influenza A (H7N9), but limited nonsustained human-to-human transmission of the virus could not be excluded in a few family clusters.
In addition, confirmed human cases of H7N2, H7N3, H7N7, and H9N2 avian influenza A infection and illness have been reported, including a few cases in Australia, Canada, Italy, Mexico, the Netherlands, the United Kingdom, and the US. Most of these infections occurred in association with poultry outbreaks and mainly resulted in conjunctivitis and mild upper respiratory symptoms. There was a large outbreak of avian influenza A (H7N7) in commercial poultry farms in the Netherlands in 2003 that resulted in large numbers of human cases of H7N7 infection (principally conjunctivitis and influenza-like illnesses). Human infection with avian influenza A (H10N8) also has been reported rarely in China.
Experience to date indicates that human cases of avian influenza infection are rare and that these viruses do not transmit easily from poultry to humans. Most, but not all, human cases reported to date have been linked to direct contact with infected poultry, uncooked poultry products, or surfaces contaminated with infected poultry feces or respiratory secretions. Sustained person-to-person transmission of avian influenza viruses has not been reported to date, but clustering and limited person-to-person transmission of H5N1 and H7N9 viruses has been reported. Most clusters of human infection with avian influenza A (H5N1) reported to date have included documented exposure to birds. Person-to-person transmission of H7N7 has occurred among household contacts during the outbreak of that virus that occurred in the Netherlands.
In humans, avian influenza A viruses can cause typical influenza illness (fever, cough, sore throat, muscle aches), conjunctivitis, or respiratory disease; however, severe illness can occur, especially with highly pathogenic avian influenza (H5N1) and avian influenza A (H7N9). The fatality rate in patients hospitalized with H5N1 infection has been high (exceeding 50%). In one group of patients in Vietnam with severe H5N1 infections, the median time to death was 9 days (range 6-17 days) with or without treatment.
Avian influenza A virus strains isolated during the past several years (including H5N1 and H7N9 strains causing human illness) generally have been resistant to adamantanes (amantadine, rimantadine). Most avian influenza A virus strains (e.g., H5N1, H7N7, H7N9, H9N2) have been susceptible to oseltamivir and zanamivir in vitro. However, avian influenza A (H5N1) and avian influenza A (H7N9) isolates that have reduced susceptibility or are resistant to oseltamivir in vitro have been reported.
(See Spectrumand see Resistance.)
The most recent information regarding avian influenza A infections is available at the WHO website at http://www.who.int/influenza/resources/avian_influenza/en/ and the CDC website at http://www.cdc.gov/flu/avianflu/.
CDC does not currently recommend that the general public avoid travel to any of the countries that have had poultry outbreaks or human cases of highly pathogenic avian influenza A (H5N1) or avian influenza A (H7N9). However, CDC recommends that travelers to these areas take certain precautions to reduce the risks. CDC recommends that travelers to countries where highly pathogenic avian influenza A (H5N1) is endemic or countries with known poultry outbreaks of the virus avoid direct contact with all birds (poultry such as chickens and ducks, wild birds), especially contact with sick or dead poultry. Travelers also should avoid places such as poultry farms and markets where live poultry are raised, kept, or sold and avoid contact with surfaces that might be contaminated with poultry feces or secretions. Uncooked (raw) or undercooked poultry or poultry products should not be consumed, and care should be taken when preparing these foods. Because influenza viruses are destroyed by heat, all foods from poultry that comes from these areas (including eggs and poultry blood) should be thoroughly cooked; egg yolks should not be runny or liquid and poultry meat should be cooked to a temperature of 74°C.
Additional information for travelers can be obtained at the CDC website at http://wwwnc.cdc.gov/travel/content/avian-flu-asia.aspx.
Treatment and Prevention of Avian Influenza A Infections
CDC and WHO state that oseltamivir is the drug of choice for the treatment or prophylaxis of infections caused by highly pathogenic avian influenza A (H5N1). Zanamivir is considered an alternative.
Oseltamivir also is considered the drug of choice for the treatment of infections known or presumed to be caused by avian influenza A (H7N9), especially in hospitalized patients and patients with severe or complicated illness. Because of limited data, zanamivir is not recommended for the treatment of severe avian influenza A (H7N9) infections, but may be considered in those with uncomplicated infections. Either oseltamivir or zanamivir can be used for prophylaxis in close contacts of patients with confirmed or probable avian influenza A (H7N9) infections.
Only limited data are available to date regarding treatment of human cases of avian influenza A virus infections. Data from observational studies indicate that early initiation of oseltamivir therapy is associated with a reduction in mortality in influenza A (H5N1)-infected patients. Some data indicate a survival rate of 83% when oseltamivir treatment is initiated within 2 days of symptom onset compared with a survival rate of 21% if initiated 3-8 days after symptom onset. Because this virus continues to replicate for prolonged periods of time, treatment with oseltamivir is warranted even in patients who present for care in the later stages of illness. The optimum dosage and duration of oseltamivir treatment for avian influenza A (H5N1) infections are unknown, but high doses and prolonged duration of therapy may be needed in some patients. Although some individuals with avian influenza A (H5N1) infections who were treated with oseltamivir died, it is unclear whether these deaths were related to a lack of efficacy, a delay in diagnosis and initiation of oseltamivir treatment, or the dosage regimen used.
Oseltamivir is used for the treatment or prevention of pandemic influenza caused by susceptible strains of influenza virus.
Influenza viruses can cause seasonal epidemics and, occasionally, pandemics during which rates of illness and death from influenza-related complications can increase dramatically worldwide. The most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09. Influenza A strains also were involved in prior influenza pandemics occurring in 1918 (H1N1), 1957 (H2N2; originated in China), and 1968 (H3N2; originated in Hong Kong).
On June 11, 2009, the WHO declared that the first global influenza pandemic in 41 years was occurring and issued a pandemic alert regarding influenza A (H1N1)pdm09, previously referred to as the novel 2009 influenza A (H1N1) virus or swine-origin influenza A (H1N1) virus. Influenza outbreaks caused by the influenza A (H1N1)pdm09 virus were reported in several countries, including the US, beginning in March and April 2009. The virus is a triple-reassortant swine influenza virus with genes from human, swine, and avian influenza A viruses and contains a unique combination of gene segments not previously reported among human or swine influenza A in the US or elsewhere. The influenza A (H1N1)pdm09 virus is antigenically distinct from previous human influenza A (H1N1) viruses that had been in circulation since 1977, and widespread transmission of the virus occurred since most individuals had no preexisting antibody to the strain. In the US, the 2009 influenza A (H1N1)pdm09 pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010. During the pandemic, more than 99% of influenza viruses circulating in the US were the influenza A (H1N1)pdm09 virus; more than 60 million Americans become ill with the virus and more than 270,000 hospitalizations and 12,500 deaths were reported. In August 2010, the WHO declared that the world was in a post-pandemic period. Since that time, influenza A (H1N1)pdm09 has become a seasonal influenza virus and continues to circulate with other seasonal influenza viruses.
The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that has been occurring since 2003 may represent a future pandemic threat.
(See Uses: Avian Influenza A Virus Infections.)