Influenza Treatment & Management

Prevention is the most effective management strategy for influenza. To prevent seasonal flu, the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) recommend routine annual influenza vaccination for all persons aged 6 months or older, preferably before the onset of influenza activity in the community. ^{[45, 46]} The ACIP also publishes recommendations on the use of antiviral agents for prevention and treatment of influenza. ^[8]

The ACIP's Adult Immunization Schedule for influenza vaccine includes information about the recombinant influenza vaccine and addresses the use of this vaccine and the inactivated influenza vaccine in patients with egg allergy. ^[47]

Public health measures are effective in limiting influenza transmission in closed environments. ^[48] Enhanced surveillance with daily temperature taking and prompt reporting with isolation through home medical leave and segregation of smaller subgroups decrease the spread of influenza. In one study, symptomatic illness attributable to influenza decreased from 12% to about 4% with the use of these measures. ^[48]

Patients with influenza generally benefit from bed rest. Most patients with influenza recover in 3 days; however, malaise may persist for weeks.

Patients most often require hospitalization when influenza exacerbates underlying chronic diseases. Some patients, especially elderly individuals, may be too weak to care for themselves alone at home. On occasion, the direct pathologic effects of influenza may necessitate hospitalization. Most commonly, this is influenza pneumonia.

Influenza vaccine provides reasonable protection against immunized strains. The vaccination becomes effective 10-14 days after administration. Specific recommendations for individuals who should be immunized can be obtained from the CDC, which publishes regular updates of this information (see Seasonal Influenza Vaccination Resources for Health Professionals).

Historically, influenza vaccine has had 50-60% efficacy against infection with influenza A viruses and 70% efficacy against influenza B viruses. Influenza vaccine component recommendations are based on numerous factors, including global influenza virologic and epidemiologic surveillance, genetic and antigenic characterization, antiviral susceptibility, and the availability of candidate vaccine viruses for production. ^[8]

Seasonal Influenza Vaccines

Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during the winter flu season is produced; 2 strains of influenza A and 2 of influenza B are included for the quadrivalent flu vaccines. All vaccines distributed in the United States are quadrivalent. ^[8]   

The following are influenza vaccine recommendations by the ACIP:

• In the Northern Hemisphere, all persons aged 6 months or older should receive influenza vaccine annually, by the end of October, if possible. Influenza vaccination should not be delayed to procure a specific vaccine preparation if an appropriate one is already available.
• For healthy children aged 2-8 years who have no contraindications or precautions, inactivated influenza vaccine (IIV) is an appropriate option. An age-appropriate formulation of vaccine should be used.

Regardless of allergy history, all vaccines should be administered in settings in which personnel and equipment for rapid recognition and treatment of anaphylaxis are available.

Vaccines against seasonal influenza are reformulated annually to contain the most recently circulating strains. The vaccine viral strains recommended by the World Health Organization and the Centers for Disease Control and Prevention (CDC) for the 2023-2024 Northern Hemisphere influenza season differ from those from the previous influenza season. Additionally, the specific composition also differs between vaccines that are manufactured using an egg-based culture and those that utilize recombinant or cell culture technologies. All vaccines in the United States for the 2023-2024 influenza season are expected to be quadrivalent vaccines. ^[8]

The egg-based vaccines for the 2023-2024 Northern Hemisphere vaccine season contain the following components:

• A/Victoria/4897/2022 (H1N1)pdm09-like virus (new for 2023-2024) 
• A/Darwin/9/2021 (H3N2)-like virus (no change from last season) 
• B/Austria/1359417/2021 (B/Victoria lineage)-like virus (no change from last season) 
• B/Phuket/3073/2013-like virus (B/Yamagata lineage) (no change from last season) 

The recombinant or cell-culture quadrivalent vaccine composition is as follows:

• A/Wisconsin/67/2022 (H1N1)pdm09-like virus (new for 2023-2024) 
• A/Darwin/6/2021 (H3N2)-like virus (no change from last season) 
• B/Austria/1359417/2021 (B/Victoria lineage)–like virus (no change from last season) 
• B/Phuket/3073/2013–like (Yamagata lineage) virus (no change from last season) 

Injectable vaccine, which contains inactivated virus, is available in a variety of dosage forms. The intramuscular (IM) form contains 45 µg of influenza hemagglutinin per 0.5 mL. A microinjection system for intradermal delivery (Fluzone Intradermal) is available in the United States and features an ultrafine needle that is 90% shorter than the typical 1- to 1.5-inch needle used for IM injections. The intradermal dosage form contains 27 µg of influenza hemagglutinin per 0.1 mL. The recombinant influenza vaccine (Flublok Quadrivalent) and the cell-cultured vaccine (Flucelvax Quadrivalent) contain no egg proteins, antibiotics, or preservatives. ^[47]  

Universal influenza vaccine

In April 2019, the National Institutes of Health (NIH) announced that a universal influenza vaccine has begun a trial in humans. The trial will examine the safety and tolerability of the vaccine (H1ssF_3928) as well as its immunogenicity in healthy volunteers. ^[49]

Other influenza vaccine options

In January 2013, the FDA approved Flublok (Protein Sciences), a seasonal influenza vaccine produced by means of a technique that may allow faster vaccine manufacture in influenza pandemics. ^[50] The manufacturing process for Flublok, which is indicated for adults aged 18-49 years, uses recombinant DNA technology and an insect virus expression system rather than the traditional embryonated chicken egg technique, and it does not utilize influenza viruses. The ACIP recommends FluBlok for vaccination of adults aged 18 years or older with egg allergy of any severity. It is available as a quadrivalent vaccine. The trivalent formulation has been discontinued in the United States. ^[47]

Prevention During Pregnancy

A CDC analysis stressed the importance of vaccinating pregnant people regardless of trimester and prompt treatment with a neuraminidase inhibitor (ie, within 2 days of symptom onset) if influenza occurs during pregnancy. ^[51] Vaccination of high-risk pregnant patients also provides some protective immunity for newborns and reduces subsequent hospitalizations in the infants. ^[52]

A case-control study by Thompson et al supported previous evidence that seasonal trivalent inactivated influenza vaccine reduces the risk of acute respiratory illness (ARI) by more than half in pregnant women with laboratory-confirmed influenza infection. In the study, which was conducted over 2 flu seasons (2010-2011 and 2011-2012), 42 pregnant women with influenza who had been vaccinated during flu season were compared with over 110 vaccinated control individuals with ARI but no influenza infection and 126 matched, vaccinated controls with no ARI. ^{[53, 54]}

The CDC recommends influenza vaccine be administered during pregnancy (all trimesters); vaccination during pregnancy is shown to decrease risk of illness in the mother, as well as the risk for influenza and influenza hospitalization in their infants during the first 6 months of life. ^[55]

Prevention in Geriatric Patients 

Vaccination may provide less protection against influenza in patients older than 65 years. The CDC recommends higher-dose and adjuvanted influenza vaccines (ie, Fluzone High-Dose Quadrivalent, Flublok Quadrivalent, and Fluad Quadrivalent) for individuals aged 65 years and older. 

To improve the immunogenicity of influenza virus vaccine in elderly adults, a high-dose trivalent inactivated influenza vaccine (Fluzone High-Dose) was developed. In a multicenter, randomized, double-blind controlled trial involving elderly adults (≥65 years), those who received the high-dose vaccine exhibited a statistically significantly higher seroconversion rate than those who received the standard-dose vaccine. ^[56]  The high-dose quadrivalent influenza vaccine (Fluzone High-Dose Quadrivalent) was approved by the FDA in November 2019 and has replaced the trivalent vaccine.

The high-dose vaccine met superiority criteria for both strains of influenza A, and noninferiority criteria were met for influenza B strains. ^[56] Seroprotection rates were higher for the high-dose vaccine than for the standard-dose vaccine. The authors suggest that the high-dose vaccine may provide improved immunity for elderly adults.

High-dose influenza vaccine appears to have the potential to prevent nearly one-quarter of all breakthrough influenza illnesses in elderly persons (≥65 years) compared with the standard-dose vaccine, according to results from a phase IIIb-IV double-blind, active-controlled trial. ^{[57, 58]} A total of 31,989 participants were randomly assigned to receive either a high dose (IIV3-HD) (60 μg of hemagglutinin per strain) or a standard dose (IIV3-SD) (15 μg of hemagglutinin per strain) of a trivalent, inactivated influenza vaccine. The multicenter trial was performed during the influenza seasons of 2011-2012 and 2012-2013 in Canada and the United States. ^{[57, 58]}

These studies also measured the percentage of elderly persons with postvaccination hemagglutination-inhibition titers of 1:40 (the cut-off for seroprotection) or higher was significantly higher in the IIV3-HD group relative to the IIV3-SD group. ^{[57, 58]} Laboratory-confirmed influenza (via nasopharyngeal swabs for culture, polymerase chain reaction, or both) occurred in 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%), a relative efficacy of 24.2%. ^{[57, 58]} Although reports of at least one serious adverse event were greater in the IIV3-HD group (8.3%) than in the IIV3-SD group (9.0%) (relative risk, 0.92), all resolved by the end of the study and none required discontinuation from the study. ^[58]

Woods et al found that in sedentary elderly adults, cardiovascular exercise extends influenza vaccine seroprotection. A randomized controlled trial in 144 sedentary but healthy elderly adults showed that peak (3- and 6-week) postvaccine anti-influenza hemagglutination inhibition titers were similar in those who underwent cardiovascular exercise or flexibility and balance training, but those in the cardiovascular exercise group were significantly more likely to have seroprotective titers at 24 weeks, a period that could cover the entire influenza season. ^[59]

Avian Influenza

Prevention in poultry and swine workers

Some data from animal studies suggest that the standard inactivated influenza vaccine may confer partial immunity toward avian influenza. ^[60] Accordingly, it has been recommended that poultry workers receive annual influenza vaccinations to prevent illness and to prevent viral reassortment through simultaneous infection with the 2 types of influenza. ^[61] Similarly, vaccination of swine workers against seasonal influenza may help prevent cross-species sharing of influenza viruses and the origination of novel reassortant viruses. ^[62]

Prevention of H5N1 avian influenza

No avian influenza vaccine is available to the public, though various products are in clinical trials and appear immunogenic. One complication is that the highly pathogenic viruses cannot be easily grown by means of the traditional embryonated chicken egg method, because the embryos often die during incubation.

An H5N1 monovalent killed-virus vaccine produced by Sanofi Pasteur has been approved by the FDA in the United States but is available only to government agencies and for stockpiles. ^[7] It is derived from the influenza A/Vietnam/1203/2004 strain isolated from humans. A second H5N1 influenza vaccine was approved by the FDA in November 2013 that contains a different viral strain, A/Indonesia/05/2005. This new H5N1 vaccine also contains the ASO3 adjuvant that allows a smaller amount of antigen to simulate an immune response.

The first H5N1 vaccine was approved on the basis of a limited safety and immunogenicity study of 500 adults aged 18-64 years. ^[7] Fewer than half of those receiving the highest dose of vaccine responded and achieved antibody titers expected to be fully effective (ie, hemagglutination inhibition antibody titers >1:40) on the basis of experience with seasonal influenza. The vaccine contains thimerosal (unlike many other seasonal influenza vaccines) because of the need for multidose vials. ^[63]

In a study of vaccination against Vietnamese- and Indonesian-origin H5N1 strains using a prime-boost strategy, which included 491 subjects, optimal antibody titers required at least a 14-day interval between doses. Results were no better at 28 days. ^[64]

A newer recombinant H5N1 vaccine is also available from the WHO. The CDC provides additional information about Avian Influenza Vaccines.

Adjuvanted vaccine

In November 2013, the FDA approved the first adjuvanted vaccine for the prevention of H5N1 avian influenza. Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (ID Biomedical Corporation), is meant for use in people aged 18 years or older with a relatively greater risk of H5N1 exposure. It is not intended for commercial use but has instead been purchased by the US Department of Health and Human Services for addition to the Strategic National Stockpile (of drugs and medical supplies) and, if warranted, subsequent distribution by public health officials. ^[65]

Approval of the vaccine was based on a multicenter study in which investigators evaluated the immune response of about 2000 vaccinated adults, determining that 91% of persons aged 18 to 64 years and 74% of those aged 65 years or older achieved an antibody level that would be expected to reduce their risk of developing avian influenza. ^[65]

Avian influenza and travelers

Because avian influenza is rare in humans, the CDC does not recommend against travel to any country affected by H5N1. (See Avian Flu Travel Information.) Prophylactic antivirals are not indicated for patients who plan to travel to areas where avian influenza has been reported.

Travelers who plan to travel to areas of the world affected by avian influenza outbreaks in birds or humans are advised to avoid close contact with poultry, especially diseased or dead birds, and to consume only adequately cooked meat. If contact with birds in enclosed spaces is unavoidable, an N-95 respirator mask (or equivalent), gloves, and goggles should be used to minimize contact with droplets or particulates.

Containing pandemic influenza

Preparedness for pandemic influenza is widely considered to be grossly inadequate. The following 5 areas are important for managing a surge in severe illness ^[66] :

• Surveillance and diagnostic services
• Information sharing and dissemination
• Community support
• Hospital and physician capacity
• Supply and delivery of vaccines and drugs

Even in the absence of a pandemic illness, the lack of capacity in US emergency departments has been described as a crisis by the Institute of Medicine. (See the WHO Global Influenza Preparedness Plan.)

Prehospital care is predominantly supportive. Supplemental oxygenation to manage respiratory symptoms or objective hypoxia may be needed. Ventilatory support with a bag-valve-mask device or with field intubation may be required if the patient is in respiratory failure. Intravenous access should be obtained, and a bolus of a crystalloid can be administered to support hemodynamic stability.

Attention should be given to the appropriate use of personal protective equipment (PPE) by the prehospital providers, and advance notification should be given to the hospital regarding the potential need for patient respiratory isolation. General guidelines in low-risk areas are that patients with fever and respiratory complaints should wear a standard mask, if tolerated, to decrease airborne droplets. ^[67]

 

Antiviral Agents

In the United States, the following antiviral drugs are recommended for chemoprophylaxis and/or treatment of influenza:

• Baloxavir marboxil
• Oseltamivir
• Peramivir
• Zanamivir

The CDC and IDSA have issued guidelines regarding antiviral treatment and prophylaxis. ^{[68, 69]}

The neuraminidase inhibitors (oseltamivir, peramivir, and zanamivir) and cap-dependent endonuclease inhibitors (baloxavir marboxil) have activity against influenza A and B viruses (including H1N1), whereas the adamantanes (amantadine and rimantadine) have activity against influenza A viruses only. Since 2006, only the neuraminidase inhibitors have been recommended, because of widespread resistance to the adamantanes among influenza A (H3N2) virus strains. Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season.

Baloxavir marboxil was approved by the FDA in October 2018 for use in adults and adolescents aged 12 years or older as a single weight-based oral dose for use within 48 hours of symptom onset. It is a prodrug that inhibits cap-dependent endonuclease, an enzyme specific to influenza, resulting in inhibition of viral replication.

In clinical trials, single dose baloxavir was safe and effective in treating patients with uncomplicated influenza. It is active against influenza A and B, including strains resistant to neuraminidase inhibitors. In October 2019, the FDA expanded the baloxavir marboxil approval to include treatment in patients at high risk of developing serious influenza-related complications (eg, patients with asthma, chronic lung disease, diabetes, heart disease, morbid obesity, advanced age [≥65 years]).

Oseltamivir, peramivir, and zanamivir work by inhibiting influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus envelope; this spike is needed for successful cellular release of virus and transmission within the body.

Peramivir (Rapivab) was approved by the FDA in December 2014 for use in adults as a single 600-mg IV dose. In clinical trials, a single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, peramivir significantly reduced the time to alleviation of symptoms in comparison with placebo. ^[70] Additional data from over 2,700 subjects treated with peramivir in 27 clinical trials also supported its approval. It was available in the United States by emergency protocol during the 2009 H1N1 influenza pandemic.

To be effective as treatment, these agents must be administered within 48 hours of symptom onset. These agents are most effective if started within the first 24 hours of symptoms and less effective if begun 24-48 hours after symptoms appear. For critically ill patients with H5N1 infection, evidence suggests that initiation of oseltamivir therapy up to 6-8 days from onset of symptoms may reduce mortality. ^[71] Studies also demonstrate the efficacy of these agents in preventing influenza A and B. For acute treatment, these agents are given twice daily for 5 days. For prevention, they are given once daily for 10 days.

Prompt use of antiviral drugs during the 2009 H1N1 influenza pandemic improved survival among severely ill pregnant women. A CDC study of 347 pregnant women (including 272 who required ICU admission but survived and 75 who died) and 15 severely ill postpartum women (9 of whom died) found that 94.8% of survivors received antiviral treatment with oseltamivir or zanamivir, compared with 86.1% of those who died, a statistically significant difference. ^[51]

Time from symptom onset to initiation of treatment was significantly longer for women who died than for those who survived. Only 7% of those who died received an antiviral within 2 days of symptom onset, compared with 41% of survivors. This analysis reaffirms the importance of prevention (ie, vaccination of pregnant women regardless of trimester) and prompt treatment with a neuraminidase inhibitor (ie, within 2 days of symptom onset) if influenza occurs during pregnancy. ^[51]

A meta-analysis of outcome in patients hospitalized with H1N1 influenza during the 2009-2010 pandemic found that early treatment with neuraminidase inhibitors (ie, within 48 hours of symptom onset) reduced the death rate by 63%. Although neuraminidase treatment (early or late) during hospitalization did not produce a statistically significant reduction in severe outcomes (eg, critical care unit admission), preadmission use did. ^[72]

Lam et al suggested that cases of suspected severe influenza infection should be treated early and aggressively, even before diagnostic tests can be confirmed. ^[73] In their study, a higher dose of oseltamivir and nonconventional methods of ventilation improved outcome in patients with pandemic H1N1 2009 infection.

Advantages and disadvantages of neuraminidase inhibitors

Whether to prescribe one of the newer neuraminidase inhibitors should depend on the patient, the probable type of influenza involved (A or B), and the potential benefit. The advantages of prescribing these agents include significantly reducing illness severity and duration. In elderly and high-risk patients who receive these agents, the secondary complications of influenza are also decreased. ^[74]

The disadvantages include potential adverse effects and higher costs. In addition, they must be started within 48 hours of when the first symptoms appear. Adverse effects include potential bronchospasm with inhaled zanamivir and nausea, vomiting, and headache from oseltamivir. The bronchospasm associated with zanamivir has received attention from national media. Until more data are available, physicians should not prescribe zanamivir to patients prone to bronchospasm.

Baloxavir research

FDA initial approval of baloxavir was based on the CAPSTONE-1 trial (N=1436). Patients aged 12-64 years were randomized to receive baloxavir, oseltamivir, or placebo. Of the 1064 patients included in the intention-to-treat infected population, the median time to alleviation of symptoms was 53.7 hours in the baloxavir group compared with 80.2 hours for placebo (P < 0.001). Similar results were observed with oseltamivir compared with placebo. In addition, the baloxavir group had a significant decrease in viral load after 1 day of treatment compared with both placebo (P < 0.05) and oseltamivir (P < 0.05) groups. ^[75] It is undetermined whether the rapid drop in viral load decreases the risk of virus transmission. 

In August 2022, the indication for treatment and post-exposure prophylaxis was extended to include otherwise healthy children aged 5 years and older. The phase 3 miniStone-2 trial compared incidence and severity of adverse effects of baloxavir marboxil with oral oseltamivir in children. Single-dose baloxavir marboxil had a similar incidence of adverse effects compared with oseltamivir (46.1% vs 53.4%). The most common adverse effects in each group were vomiting and/or diarrhea. No serious adverse effects were observed. ^[76]  

The indication for post-exposure prophylaxis showed a significant prophylactic efficacy compared with placebo. A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs 13.6%; P < 0.001). ^[77]  

Oseltamivir research

Hayden et al documented the prophylactic efficacy of oseltamivir. ^[78] In this study, 1559 healthy, nonimmunized patients were treated with either placebo or oseltamivir for 6 weeks; at the end of the period, 4.8% of the placebo group had laboratory-confirmed influenza, compared with only 1.2% of the oseltamivir group.

Although oseltamivir is approved for use up to 48 hours after the onset of symptoms, one study found that earlier initiation increased the therapeutic effects of the drug: Initiation of therapy within the first 12 hours after fever onset reduced the total median illness duration by 74.6 hours (41%) more than intervention at 48 hours. ^[79]

Probenecid, a uricosuric agent, approximately doubles the effective dose of oseltamivir by disrupting renal excretion of the drug. It may have a role to play in a pandemic or in severe infections ^[80] ; however, no studies have been performed to confirm the appropriate dosing regimen in this situation.

A novel study documented the prophylactic and therapeutic effects of oseltamivir in experimentally induced influenza in humans. ^[81] In a controlled laboratory environment, volunteers were inoculated intranasally with influenza A/Texas/36/91 (H1N1). In the prophylaxis group, study participants received either oseltamivir or placebo 26 hours before virus inoculation; in the treatment arm, participants received oseltamivir or placebo 28 hours after inoculation.

In the prophylactic group, 38% of patients developed influenza, compared with 67% of patients in the placebo group. ^[81] In the treatment group, oseltamivir reduced the duration of illness from 95 to 53 hours and reduced the severity by 50%, compared with placebo.

A placebo-controlled study of oseltamivir by Treanor et al demonstrated the ability of this agent to decrease the duration and severity of influenza. ^[82] The analysis included patients with laboratory-based diagnoses of influenza and those with clinical diagnoses based on symptoms. Compared with placebo, both standard-dose and high-dose oseltamivir reduced the mean illness duration from 103 to 70 hours and reduced symptom severity by 40%.

In a randomized, double-blind, placebo-controlled trial of children aged 1-3 years with influenza A or B, Heinonen et al found that oseltamivir decreased the incidence of acute otitis media (a common bacterial complication of influenza) by 85% when treatment began within 12 hours of symptom onset. ^[83] When treatment began within 24 hours of symptom onset, no significant reduction in the incidence of acute otitis media was observed.

Heinonen et al also found that when oseltamivir treatment was started within 24 hours for children with influenza A, the median time to resolution of illness was decreased by 3.5 days in all children and parental work absenteeism was reduced by 3 days. ^[83] Efficacy was not demonstrated against influenza B infections.

A meta-analysis of available data by Jefferson et al cited a substantial risk of publication bias with oseltamivir trials, noting that 60% of patient data from phase III treatment trials of oseltamivir have never been published and that reporting bias has been documented in the published trials. ^[84] This meta-analysis concluded that alleviation of influenzalike symptoms began about 21 hours sooner in patients treated with oseltamivir compared with placebo; however, oseltamivir treatment appeared to have no effect on hospitalization. ^[84]

Zanamivir research

In a study of 837 relatives of family members infected with influenza, 20% of those treated with placebo became ill, compared with only 4% of those who received prophylactic zanamivir. ^[85] In addition, this study provided treatment to the index case family member, resulting in a 2.5-day reduction in illness as compared with placebo. Recombinant DNA viral sequences were performed in this study, and no resistant influenza strains developed.

In a placebo-controlled study of 445 patients by the Management of Influenza in the Southern Hemisphere Trialists (MIST) group 1, zanamivir reduced the duration and severity of illness. ^[86] Zanamivir was administered within 36 hours of symptom onset. The duration of influenza was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk groups. A significant decrease in the severity of illness in patients treated with zanamivir allowed them to resume normal activities much sooner.

Antiviral drug recommendations

The CDC has made the following recommendations regarding the use of antiviral drugs in influenza ^[1] :

• Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization
• Antiviral treatment is recommended as soon as possible for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions; clinical judgment should be an important component of outpatient treatment decisions
• Currently recommended antiviral medications include oseltamivir, zanamivir, peramivir, and baloxavir marboxil
• Oseltamivir may be used for treatment or chemoprophylaxis of influenza among infants younger than 1 year, when indicated
• Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset
• Because antiviral resistance patterns can change over time, clinicians should monitor local antiviral resistance surveillance data

Investigational antiviral agents

One investigational antiviral agent for influenza is laninamivir octanoate. Although not yet available in the United States, it has been approved in Japan. ^[87]

In a double-blind, randomized controlled trial, the median time to illness alleviation with a 40-mg dose of laninamivir octanoate was similar to that with oseltamivir. ^[88] A single inhalation of laninamivir octanoate proved effective for the treatment of seasonal influenza, including cases caused by oseltamivir-resistant virus, in adults.

Consultation with an infectious disease specialist is prudent in some cases of seasonal influenza. For management of severe disease, intensive care specialists must be involved.

In suspected H5N1 influenza, a pulmonary specialist, a critical care specialist, an infectious disease specialist, and the staff of the local public health department may all be consulted. Clinical laboratory personnel should be informed before potential H5N1 isolates are sent to them. In addition, hospital infection-control officers should be involved early in the care of any patient who might have avian flu. Ultimately, the WHO, the CDC, or both should be contacted; the CDC can safely perform serotyping for suspected avian influenza strains.

Early involvement of the local public health department and the hospital infection control service is necessary to contain any outbreaks.

Most patients with influenza recover in 3 days; however, malaise may persist for weeks. Patients who do not improve should return for further evaluation.

Patients diagnosed with influenza should be educated about potential complications and encouraged to return for evaluation if concerned. This is especially true of patients with underlying chronic disease or those who are immunocompromised.