Seasonal influenza in adults: Role of antiviral prophylaxis for prevention

INTRODUCTION — Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses. Vaccination is the most important intervention for prevention of influenza. Antiviral drugs may be useful adjunctive tools for patients at high risk of influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low effectiveness (eg, due to immunosuppression or mismatch between vaccine antigens and circulating virus strains); however, they should not be used as a substitute for vaccination.

Our recommendations are generally in keeping with those of the United States Centers for Disease Control and Prevention and the Infectious Diseases Society of America [1,2].

The role of antiviral drugs for prevention of seasonal influenza will be reviewed here. Issues related to treatment of seasonal influenza are discussed separately, as are the pharmacologic characteristics of the antiviral drugs and issues related to antiviral drug resistance. (See "Seasonal influenza in nonpregnant adults: Treatment" and "Antiviral drugs for influenza: Pharmacology and resistance".)

Issues related to antiviral drugs for prevention of seasonal influenza in hematopoietic cell transplant and lung transplant recipients are discussed separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Chemoprophylaxis' and "Viral infections following lung transplantation", section on 'Antiviral prophylaxis'.)

GENERAL PRINCIPLES

Definitions

High-risk individuals — Individuals at high risk for influenza complications are summarized in the table (table 1) [1]:

Close contact — A close contact is an individual who has cared for or lived with a person who has confirmed, probable, or suspected influenza infection or who has been in a setting where there was a high likelihood of contact with respiratory droplets and/or body fluids of such a person; this includes speaking face-to-face with a person with suspected or confirmed influenza infection [3]. Face masks likely mitigate this risk, though data are limited [4].

Antiviral agents

Drug classes — Classes of antiviral drugs for prevention of influenza include (table 2) [1,2]:

●Neuraminidase inhibitors − Neuraminidase inhibitors approved by the US Food and Drug Administration (FDA) for pre-exposure and postexposure prevention of influenza include oseltamivir and zanamivir.

Peramivir, an intravenous neuraminidase inhibitor, has been approved by the FDA for treatment of influenza but not for prevention of influenza.

Laninamivir, a long-acting inhaled neuraminidase inhibitor not available in the United States, has been reported to be effective for preventing infection among household contacts of patients with influenza [5]; it is approved for use in Japan but remains investigational elsewhere.

●Endonuclease inhibitor − Baloxavir is approved by the FDA for postexposure prophylaxis among nonpregnant adults, but not for pre-exposure prevention of influenza.

Due to emergence of high rates of adamantane resistance among influenza A viruses, the United States Centers for Disease Control and Prevention recommends that adamantanes (amantadine and rimantadine) not be used for the treatment of influenza in the United States [1].

Adverse effects — Oseltamivir can cause nausea and vomiting (15 percent of patients), but these effects are usually mild and do not generally result in discontinuation of therapy. Zanamivir (inhaled) can cause bronchospasm in patients with asthma and other chronic respiratory disorders; therefore, this agent is contraindicated in these patient groups. Baloxavir is generally well tolerated.

Additional issues related to adverse effects of antiviral drugs are discussed further separately. (See "Antiviral drugs for influenza: Pharmacology and resistance".)

COMMUNITY SETTINGS — General principles related to use of antiviral drugs for prevention of seasonal influenza are discussed below.

Issues related to antiviral drugs for prevention of seasonal influenza in hematopoietic cell transplant and lung transplant recipients are discussed separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Chemoprophylaxis' and "Viral infections following lung transplantation", section on 'Antiviral prophylaxis'.)

Pre-exposure antiviral prophylaxis

Clinical approach

●Recipients, timing, and duration − In community settings, there is no role for routine use of antiviral drugs for prevention of influenza. Such use may be reasonable in the following limited situations, during community influenza transmission [2]:

•Category I − Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (eg, due to immunosuppression or mismatch between vaccine antigens and circulating virus strains). United States influenza surveillance data are available at the United States Centers for Disease Control and Prevention website.  

Pre-exposure prophylaxis should be initiated as soon as influenza activity is detected in the community and continued for the duration of community influenza activity [2].

•Category II − Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is expected to be effective but has not yet been administered.

Vaccination should be administered promptly; short-term pre-exposure prophylaxis may be administered for two weeks until the immune response to the vaccine develops.

•Category III – Individuals for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness, who are in close contact with individuals in the above categories who are unable to take chemoprophylaxis.

Pre-exposure prophylaxis should be initiated for the duration of close contact, during community influenza activity.

A reasonable alternative to pre-exposure prophylaxis is early initiation of therapy for patients who develop symptomatic illness.

●Antiviral selection – Antiviral agents for pre-exposure prophylaxis include oral oseltamivir or inhaled zanamivir; dosing is summarized in the table (table 2).

If oseltamivir-resistant influenza is suspected, zanamivir should be used. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral resistance' and "Antiviral drugs for influenza: Pharmacology and resistance".)

●If symptomatic illness develops − For individuals receiving pre-exposure prophylaxis who develop signs or symptoms of influenza, diagnostic testing should be pursued, pre-exposure prophylaxis should be discontinued, and antiviral treatment should be administered (preferably with an antiviral drug with a different resistance profile if not contraindicated). (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in nonpregnant adults: Treatment" and "Seasonal influenza and pregnancy", section on 'Antiviral treatment'.)

Patients receiving pre-exposure prophylaxis with oseltamivir may be treated with zanamivir or baloxavir. Patients receiving pre-exposure prophylaxis with zanamivir may be treated with baloxavir; case reports have described zanamivir cross-resistance to oseltamivir and peramivir [6-8].

Supporting evidence — Randomized trials evaluating pre-exposure prophylaxis include:

●A trial including more than 1550 unvaccinated healthy adults in which patients were randomly assigned to administration of oseltamivir or placebo for six weeks during a peak period of local influenza virus activity; development of symptomatic, laboratory-confirmed influenza occurred less frequently among those who received oseltamivir (13/1040 versus 25/519; protective efficacy 74 percent [95% CI 53-88 percent]) [9].

●A trial including more than 3300 adults and adolescents at high risk of influenza complications in which patients were randomly assigned to inhaled zanamivir or placebo for 28 days; development of symptomatic, laboratory-confirmed influenza occurred less frequently among those who received zanamivir (4/1678 versus 23/1685; relative risk 0.17 [95% CI 0.07-0.44]) [10].

Postexposure antiviral prophylaxis

Clinical approach

●Recipients − In community settings, there is no role for routine use of antiviral drugs for prevention of influenza. Such use may be reasonable in the following limited situations (during community influenza transmission, within 48 hours of exposure, and in the absence of symptoms) [2]:

•Category I – Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (eg, due to immunosuppression or mismatch between vaccine antigens and circulating virus strains), after household influenza exposure.

•Category II – Unvaccinated individuals who are household contacts of a person at high risk of influenza complications, after influenza exposure.

A reasonable alternative to postexposure prophylaxis is early initiation of therapy for patients who develop symptomatic illness.

●Timing and duration – Postexposure prophylaxis should be initiated as soon as possible, within 48 hours after exposure. There is no role for initiation of postexposure prophylaxis if >48 hours have elapsed since exposure.

Outside the context of an outbreak, the duration of postexposure prophylaxis is seven days [2].

In addition to administration of postexposure prophylaxis, unvaccinated individuals should be vaccinated promptly.

●Antiviral selection – Antiviral agents for postexposure prophylaxis include oseltamivir, zanamivir, and baloxavir; dosing is summarized in the table (table 2).

If oseltamivir-resistant influenza is suspected, zanamivir or baloxavir should be used. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral resistance' and "Antiviral drugs for influenza: Pharmacology and resistance".)

Caution regarding widespread use of baloxavir for prophylaxis is warranted given its vulnerability to emergence of resistance. In addition, baloxavir is not recommended for pregnant or postpartum patients given lack of safety and efficacy data [11].

●If symptomatic illness develops – For individuals receiving postexposure prophylaxis who develop signs or symptoms of influenza, diagnostic testing should be pursued, postexposure prophylaxis should be discontinued, and antiviral treatment should be administered (preferably with an antiviral drug with a different resistance profile if not contraindicated). (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in nonpregnant adults: Treatment" and "Seasonal influenza and pregnancy", section on 'Antiviral treatment'.)

For patients receiving prophylaxis with oseltamivir, treatment options include zanamivir or baloxavir. For patients receiving prophylaxis with zanamivir, treatment with baloxavir is preferred, given possible cross-resistance to other neuraminidase inhibitors. For patients receiving prophylaxis with baloxavir, treatment options include oseltamivir or zanamivir.  

Supporting evidence — Studies evaluating postexposure prophylaxis include:

●A systematic review evaluating the efficacy of postexposure prophylaxis against symptomatic laboratory-confirmed symptomatic influenza including two trials of oseltamivir and three trials of zanamivir; the pooled efficacy of these drugs was 81 percent (95% CI 55-92 percent) and 79 percent (95% CI 67-87 percent), respectively [12].

●A randomized trial including 749 household contacts of 545 index patients with influenza in Japan [13]; the risk of influenza was lower among household contacts who received postexposure prophylaxis with baloxavir than among those who received placebo (1.9 versus 13.6 percent; adjusted risk ratio 0.14, 95% CI 0.06-0.30).

No data are available on the efficacy of postexposure prophylaxis for prevention of serious complications of influenza.

INSTITUTIONAL OUTBREAK CONTROL — Influenza vaccine should be administered to all adults in institutional settings each season. Antiviral drugs may be a useful adjunctive tool but should not be used as a substitute for vaccination.

Active surveillance — The following circumstances warrant implementation of active surveillance [2]:

●In a long-term care facility − Identification of one laboratory-confirmed case of influenza

●In a hospital − Identification of one health care-associated laboratory-confirmed case of influenza

Active surveillance should consist of daily assessment for signs and symptoms of influenza among all patients in the facility; influenza testing should be pursued for those with new respiratory symptoms (increased work of breathing, coughing, or sneezing), with or without fever; in the absence of respiratory symptoms, influenza testing also should be pursued for abnormal temperature (elevation or reduction) or behavioral changes.

Use of molecular diagnostic assays is preferred for optimal sensitivity; tools for diagnosis of influenza are discussed separately. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Empiric antiviral treatment should be initiated for newly symptomatic individuals as soon as possible, while diagnostic testing is pending. Issues related to treatment of influenza are discussed separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

After treatment is completed, ongoing antiviral prophylaxis should be administered according to the protocol on the ward; the approach is discussed below. (See 'Patients' below.)

Approach to antiviral prophylaxis

Patients

●Clinical approach

•Threshold for initiating prophylaxis – The optimal threshold for initiation of antiviral prophylaxis is uncertain.

If two cases of influenza are identified within 72 hours on the same unit, we favor administration of antiviral prophylaxis to all other asymptomatic patients on the unit (in the absence of suspected or laboratory-confirmed influenza), regardless of vaccination status [2].

Influenza virus transmission to an additional unit should prompt consideration of facility-wide antiviral prophylaxis [2]. Such decisions should be guided by local circumstances including ventilation quality and whether there is mixing of staff, residents, and/or care equipment between units.

•Antiviral selection and dosing − Antiviral agents for prophylaxis include oral oseltamivir or inhaled zanamivir; dosing is summarized in the table (table 2).

If oseltamivir resistance is known or suspected, baloxavir is an acceptable alternative to zanamivir; however, baloxavir has not been studied for prophylaxis in the setting of institutional outbreaks, and caution regarding widespread use of this baloxavir for prophylaxis is warranted given its vulnerability to emergence of resistance. In addition, baloxavir is not recommended for pregnant or postpartum patients given lack of safety and efficacy data [11].

Given risk for emergence of antiviral resistance among severely immunocompromised individuals (who can have prolonged and asymptomatic influenza virus replication) [14], for such individuals administration of neuraminidase inhibitor treatment dosing rather than prophylaxis dosing (eg, twice daily rather than once daily) for five days is reasonable, followed by reduction to prophylaxis dosing for the remainder of the outbreak [2].

•Duration of prophylaxis − Prophylaxis with oseltamivir or zanamivir should be continued for at least 14 days and for at least 7 days after onset of symptoms in the last identified case [1,2]. The optimal duration of baloxavir for prophylaxis is uncertain; a single dose was found to be effective in the setting of household exposure [13].  

•Active surveillance − Individuals receiving antiviral prophylaxis who develop any signs or symptoms of influenza should be switched to receive antiviral treatment dosing. (See 'Active surveillance' above.)

●Supporting evidence

•In long-term care settings, studies evaluating antiviral prophylaxis include:

-A trial including more than 480 long-term care facility residents (with 90 percent vaccination rate) in an influenza outbreak settings randomly assigned to receive zanamivir or rimantadine; symptomatic, laboratory-confirmed influenza occurred less frequently among those who received zanamivir (3 versus 8 percent) [15].

-A cluster-randomized trial including 16 long-term care facilities with influenza outbreaks in which patients received oseltamivir for treatment or treatment followed by prophylaxis for 10 days; the influenza attack rate was lower among those who received treatment and prophylaxis than among those who received treatment alone (23 versus 36 percent) [16].

No randomized trials have been conducted to assess the optimal duration of prophylaxis; the approach described above is guided by the incubation period as well as observational data [17,18].

•In hospitals, data on the effectiveness of antiviral prophylaxis for controlling influenza outbreaks are limited; use of prophylaxis has been described in conjunction with other control interventions [19].

Health care workers — Influenza vaccine should be administered to all health care personnel each season; the vaccine is more likely to be immunogenic among health care personnel than among patients. (See "Seasonal influenza vaccination in adults".)

For unvaccinated personnel, antiviral prophylaxis is reasonable for those who are household contacts of a person at high risk of influenza complications (see 'Postexposure antiviral prophylaxis' above), for the duration of the outbreak. Such individuals should be vaccinated promptly; the duration of antiviral prophylaxis for vaccinated individuals is 14 days following vaccination [2].

In settings with risk for limited clinical staffing, antiviral prophylaxis for all personnel (regardless of vaccination status) is reasonable, for the duration of the outbreak.

Antiviral agents for prophylaxis include oral oseltamivir or inhaled zanamivir; dosing for antiviral prophylaxis is summarized in the table (table 2).

Baloxavir is an acceptable alternative to zanamivir when oseltamivir resistance is known or suspected; however, baloxavir has not been studied for prophylaxis in the setting of institutional outbreaks, and caution regarding widespread use of baloxavir for prophylaxis is warranted given its vulnerability to emergence of resistance.

There are no data evaluating the effectiveness of antiviral prophylaxis for health care workers to control influenza outbreaks.

Other interventions for prevention and control — Other components of outbreak control include initiation of precautions, offering influenza vaccination to unvaccinated staff and residents, restricting contact between residents and ill staff or visitors, and restricting staff movement between sites [20]. (See "Infection control measures for prevention of seasonal influenza".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of seasonal influenza with antivirals".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Influenza prevention (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles − Vaccination is the most important tool for influenza prevention. Antiviral drugs may be useful adjunctive tools in certain circumstances but should not be used as a substitute for vaccination. There is no role for routine use of antiviral drugs for prevention of influenza. (See 'Introduction' above.)

●Role of pre-exposure prophylaxis − In community settings, we suggest pre-exposure prophylaxis in the following circumstances (Grade 2C):

•Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (due to immunosuppression or mismatch between vaccine antigens and circulating virus strains)

•Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is expected to be effective but has not yet been administered

•Individuals for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness, who are in close contact with individuals in the above categories who are unable to take chemoprophylaxis

●Role of postexposure prophylaxis − In community settings, we suggest postexposure prophylaxis (within 48 hours of exposure) in the following circumstances (Grade 2C):

•Individuals at high risk of influenza complications (table 1) for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (eg, due to immunosuppression or mismatch between vaccine antigens and circulating virus strains)

•Unvaccinated individuals who are household contacts of a person at high risk of influenza complications (table 1)

●Institutional outbreak control

•Active surveillance (daily assessment for signs and symptoms of influenza) should be implemented in the following circumstances:

-In a long-term care facility − Identification of one laboratory-confirmed case of influenza

-In a hospital − Identification of one health care-associated laboratory-confirmed case of influenza

•Influenza testing should be pursued for patients with new respiratory symptoms, abnormal temperature (elevation or reduction), or behavioral changes, followed by initiation of empiric antiviral treatment.

•For units with two influenza cases identified within 72 hours, we suggest administration of antiviral prophylaxis to all other asymptomatic patients on the unit (in the absence of suspected or laboratory-confirmed influenza) (Grade 2C).

●Antiviral selection − For antiviral prophylaxis, we suggest oseltamivir or zanamivir (Grade 2C). Baloxavir is an alternative agent for postexposure prophylaxis for nonpregnant patients. Dosing and duration of antiviral agents are summarized in the table (table 2).