Avian influenza: Treatment and prevention

INTRODUCTION — The treatment and prevention of avian influenza infection will be reviewed here [1].

The epidemiology, clinical manifestations, and diagnosis of avian influenza infection are discussed separately, as are issues related to avian influenza vaccines. (See "Avian influenza: Epidemiology and transmission" and "Avian influenza: Clinical manifestations and diagnosis" and "Avian influenza vaccines".)

Issues related to treatment and prevention of seasonal influenza are also discussed separately. (See "Seasonal influenza in nonpregnant adults: Treatment" and "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza vaccination in adults".)

TREATMENT

Clinical approach — Our approach to treatment of avian influenza is in keeping with the guidance of the United States Centers for Disease Control and Prevention [2].

Antiviral treatment should be administered for all confirmed human cases of avian influenza, as well as probable and suspected cases. Data regarding efficacy of treatment are discussed below. Case definitions are outlined separately. (See 'Efficacy' below and "Avian influenza: Clinical manifestations and diagnosis", section on 'Case definitions'.)

Laboratory testing and initiation of antiviral treatment should occur simultaneously; treatment should not be delayed for laboratory confirmation of avian influenza virus infection. Diagnostic tools are discussed separately. (See "Avian influenza: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Site of care — Hospitalization is warranted for patients with significant dehydration and for severely ill patients, especially those with respiratory distress, hypoxemia, impaired cardiopulmonary function, or altered mental status. In the absence of these findings, admission for observation may be warranted for patients with increased risk for complications (table 1).

Infection prevention and control measures should be implemented for patients with known or suspected avian influenza. (See 'Infection control' below.)

Timing of treatment — Antiviral treatment should be administered for all confirmed, probable, and suspected cases of avian influenza. We administer antiviral treatment as early as possible; treatment should be initiated even if more than 48 hours have elapsed since illness onset. Treatment is especially important for individuals at increased risk for influenza complications (table 1).

For outpatients with uncomplicated disease in whom fever is absent and symptoms are nearly resolved, the decision to initiate antiviral treatment should be made on a case-by-case basis. Individuals who are not treated with antiviral medications should be closely monitored for progression of illness.

Data regarding timing of treatment are discussed below. (See 'Efficacy' below.)

Antiviral selection

Hospitalized patients

●Preferred regimen − Oral oseltamivir is the preferred regimen for treatment of avian influenza in hospitalized patients. Use of this agent for treatment of avian influenza is extrapolated from clinical data and experience with oseltamivir for treatment of seasonal influenza. (See "Seasonal influenza in nonpregnant adults: Treatment".)

The standard adult treatment course consists of 75 mg twice daily for five days; however, the optimal duration for patients with severe disease is uncertain. Among hospitalized patients with avian influenza virus infection, higher virus levels and longer duration of viral replication (particularly in the lower respiratory tract) have been observed compared with seasonal influenza virus infection [3-7].

Therefore, for hospitalized patients with severe and prolonged illness, reverse transcription polymerase chain reaction testing of lower respiratory tract specimens should be used in conjunction with clinical judgment to guide decisions regarding treatment duration (extension up to 10 days). In addition, an extended treatment course might be warranted in severely immunocompromised patients (such as hematopoietic stem cell transplant recipients) who may have prolonged viral replication.

There is no role for increasing the oseltamivir dose, given lack of benefit [8-10]. In addition, thus far, clinical data do not support use of combination antiviral therapy for treatment of avian influenza [11] or seasonal influenza [12].

●Alternative regimens − Alternative antiviral agents include peramivir or zanamivir (both administered parenterally):

•Peramivir − Peramivir may be used for patients who cannot tolerate oral therapy; while peramivir has been approved by the US Food and Drug Administration (FDA) for treatment of uncomplicated seasonal influenza, we think its use is reasonable for patients with severe avian influenza who cannot tolerate oral agents. In such cases, we favor adult dosing of 600 mg intravenously once daily for five days (rather than a single dose).

•Zanamivir − In regions where parenteral zanamivir is available (eg, the United Kingdom and the European Union), this agent may be used if other antiviral agents cannot be used. The usual duration of treatment for parenteral zanamivir is 5 to 10 days. Inhaled zanamivir should not be used for treatment of severe avian influenza given limited efficacy data for treatment of severe seasonal influenza.

Baloxavir is FDA approved for the treatment of uncomplicated seasonal influenza; however, given limited efficacy data for treatment of severe seasonal influenza [13,14], baloxavir is not a preferred agent for treatment of hospitalized patients with avian influenza. However, inhibitory effects of baloxavir against influenza A(H7N9) have been observed in animals and in vivo cell models [15,16].

Outpatients

●Preferred regimen − Oseltamivir (adult dose: 75 mg orally twice daily for five days) is the preferred regimen for treatment of avian influenza in outpatients, regardless of time since symptom onset [2]. Use of this agent for treatment of avian influenza is extrapolated from clinical data and experience with oseltamivir for treatment of seasonal influenza. (See "Seasonal influenza in nonpregnant adults: Treatment".)

●Alternative regimens − Alternative antiviral agents for outpatients with uncomplicated mild-to-moderate illness presenting within 48 hours of symptom onset include zanamivir (inhaled), peramivir (parenteral), or baloxavir (oral):

•Zanamivir (for patients ≥7 years of age: 10 mg [2 inhalations] twice daily for five days); inhaled zanamivir is contraindicated in patients with asthma or chronic obstructive pulmonary disease

•Peramivir (for patients ≥13 years of age: 600 mg intravenously as a single dose; for patients 6 months to 12 years of age: 12 mg/kg intravenously as a single dose [maximum dose 600 mg])

•Baloxavir (for patients ≥12 years of age; 40 to 80 kg: 40 mg orally as a single dose; ≥80 kg: 80 mg orally as a single dose) [17]

Patients with persistent symptoms

Evaluation and treatment for bacterial infection — The approach to diagnostic evaluation for and empiric treatment of bacterial infection for patients with influenza is described separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Concomitant infection'.)

Antiviral resistance — Antiviral resistance should be considered in patients treated with oseltamivir and/or peramivir with progressive lower respiratory tract disease [5,18-21]. The emergence of oseltamivir-resistant viruses containing an H275Y mutation in viral neuraminidase has been reported during oseltamivir treatment of patients with H5N1 avian influenza infection [5,18]. Similarly, the emergence of H7N9 viruses with an R292K mutation in viral neuraminidase confers resistance to neuraminidase inhibitors [3,22-24]; this mutation confers high-level resistance to oseltamivir and moderately decreased sensitivity to peramivir and zanamivir.

In the setting of suspected oseltamivir and/or peramivir resistance, zanamivir (administered parenterally, if feasible) is the preferred treatment; baloxavir may be an acceptable alternative treatment. Consultation with United States Centers for Disease Control and Prevention (CDC) Influenza Division via the CDC Emergency Operations Center (770-488-7100) should also be pursued to arrange testing for antiviral resistance; some avian influenza viruses develop oseltamivir and peramivir resistant while retaining susceptibility to zanamivir and baloxavir.

Issued related to antiviral resistance are discussed further separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Antiviral agents

Drug classes — Classes of antiviral drugs for treatment of influenza include the neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir), a selective inhibitor of influenza cap-dependent endonuclease (baloxavir), and the adamantanes (amantadine and rimantadine, also known as M2 ion channel inhibitors).

The neuraminidase inhibitors are the mainstay of treatment. Baloxavir has activity against influenza A and B viruses and has been approved in Japan and the United States for the treatment of uncomplicated seasonal influenza; however, thus far, there is no clinical experience with use of this drug for treatment of avian influenza in humans. Adamantanes should not be used for the treatment of influenza due to emergence of high rates of resistance among influenza A viruses.

Antiviral agents are discussed further separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral agents'.)

Efficacy — The approach to antiviral selection for treatment of avian influenza described above is based largely on efficacy data for treatment of seasonal influenza, in addition to observational case series of patients with avian influenza [25-29]. (See "Seasonal influenza in nonpregnant adults: Treatment".)

●Benefit of antiviral treatment – In a 2010 registry analysis including more than 300 patients with avian influenza A(H5N1), those who were treated with oseltamivir had lower mortality than those who received no antiviral treatment (hazard ratio 0.51, 95% CI 0.34-0.77) [25]. The mortality benefit was greatest when treatment was started within the first two days following symptom onset but some benefit persisted for up to six to eight days following symptom onset.

●Timing of antiviral treatment – In a 2018 study including 160 patients hospitalized with avian influenza A(H7N9) infection, patients who received treatment with a neuraminidase inhibitor within two days of symptom onset had lower mortality compared with those who received treatment within two to five days or after five days (15, 23, and 37 percent, respectively) [30].

In a 2012 registry study including 215 patients with avian influenza A(H5N1) infection, the case-fatality rate was lower among those who received oseltamivir treatment within two days of symptom onset than among those who received treatment later (18 versus 63 percent) [29]. In another study including 193 children with avian influenza A(H5N1) infections, there was an increased risk of death for each day of delay in initiating oseltamivir (odds ratio 1.75, 95% CI 1.17-2.61) [31].

Adverse effects — Adverse effects of antiviral drugs for treatment of influenza are described separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral efficacy and adverse effects'.)

Investigational approaches

●Convalescent plasma – No conclusions can be made on the clinical benefit of convalescent plasma treatment from limited uncontrolled data [1].

●Glucocorticoids – Glucocorticoids should not be used as adjunctive therapy for treatment of patients with avian influenza in the absence of a separate indication for their use. Observational studies have suggested an increased mortality risk and increased duration of virus shedding among patients with avian influenza treated with glucocorticoids [32-34].

Outcomes — Few studies have assessed long-term clinical follow-up of survivors of severe or illness due to avian influenza A virus infection.

●In one analysis using China's national integrated database to evaluate approximately 130 cases of laboratory-confirmed avian influenza A H7N9 requiring hospitalization, the estimated fatality risk on hospital admission was 36 percent (compared with 70 percent for avian influenza A H5N1) [35,36]. The fatality risk was substantially higher for individuals ≥60 years of age compared with younger individuals (49 versus 18 percent).

●A cohort study including 56 adults with H7N9 avian influenza followed for two years reported that pulmonary function and chest computed tomography findings improved by six months after hospital discharge and most had returned to work; however, most patients had persistent abnormalities [37]. At one year after discharge, 42 percent had pulmonary fibrosis and 52 percent had parenchymal opacities, with bronchiectasis noted in 24 percent and pleural thickening reported in 22 percent.

PREVENTION — Tools for prevention of avian influenza include infection control, postexposure prophylaxis, and vaccine development. There is no role for routine pre-exposure prophylaxis.

Infection control

Health care facilities — Infection control measures to reduce the risk of nosocomial transmission include negative pressure respiratory isolation with standard, contact (including eye protection), and airborne (eg, N95 masks) precautions for health care personnel [38]. These precautions are described further separately. (See "Infection prevention: Precautions for preventing transmission of infection".)

Poultry farms and markets — The risk of exposure to avian influenza infection is increased among workers at live-bird markets and individuals involved with bird cleaning, slaughtering, defeathering, or evisceration.

Avian influenza outbreaks in poultry should prompt surveillance, quarantine, and depopulation (or culling) of affected flocks [39]. Workers involved in control of poultry outbreaks should practice frequent hand hygiene (with soap and water or alcohol-based hand rubs) and adhere to personal protective measures including use of gloves, gowns, N95 masks, and eye protection.

Measures found to be effective at reducing poultry infection and contamination at live-bird markets include market size reduction, sourcing poultry from local areas, sale of single poultry species, species separation (if multiple species are sold), and attention to sanitation practices [40]. Other proposed measures include vaccination of farm poultry and prohibiting transport of live birds [41-43].

Freezing and refrigeration do not substantially reduce the concentration or virulence of viruses in meat, so it is essential to follow safe food-handling procedures and to cook food thoroughly [39,44].

Postexposure prophylaxis — The goal of postexposure prophylaxis is to reduce the likelihood of spread of novel influenza A viruses associated with severe illness in humans. The approach outlined below is intended for circumstances in which there are sporadic human cases associated with infected domestic poultry or wild bird exposures, as well as concern for limited, nonsustained human-to-human transmission.

Recipients — We administer postexposure prophylaxis to asymptomatic individuals in the following categories [45]:

●Exposure to an infected person − A person with close (within 2 meters), unprotected (without use of respiratory and eye protection) exposure to a person who is a confirmed, suspected, or probable case of avian influenza virus. Case definitions for confirmed, suspected, or probable cases are outlined separately. (See "Avian influenza: Clinical manifestations and diagnosis", section on 'Case definitions'.)

●Exposure to secretions of an infected person − A person with unprotected contact (without use of respiratory and eye protection) to secretions from a case patient while the case patient was likely infectious (beginning one day prior to symptom onset and continuing until symptoms resolve).

●Exposure to infected birds – A person with recent contact (within 10 days of symptom onset), unprotected (without use of respiratory and eye protection), and close exposure (within 2 meters) with sick or dead birds with confirmed avian influenza virus infection by A(H5), A(H7), or A(H9) viruses. These include poultry, wild aquatic birds, or captive birds of prey that have had contact with aquatic birds. Bird exposure includes (1) handling, slaughtering, defeathering, butchering, culling, or preparation of birds for consumption or (2) direct contact with surfaces contaminated by infected bird secretions, excretions, or remains [46].

For circumstances in which the optimal approach to postexposure prophylaxis is uncertain, consideration should be given to whether the individual is at increased risk for complications from influenza (table 1).

Clinical approach — Our approach to postexposure prophylaxis is in keeping with the guidance of the United States Centers for Disease Control and Prevention (CDC) [45]. This guidance is based on expert opinion and available data for antiviral treatment and chemoprophylaxis of seasonal, pandemic, and novel influenza A virus infections.

●Timing – Administration of postexposure prophylaxis antiviral chemoprophylaxis should begin as soon as possible (ideally within 48 hours) after the exposure.

●Antiviral selection and dosing – We administer antiviral prophylaxis with one of the following regimens:

•Oseltamivir (adult dosing: 75 mg orally twice daily).

•Zanamivir (adult dosing: 10 mg [two 5 mg inhalations] twice daily); inhaled zanamivir is contraindicated in patients with asthma or chronic obstructive pulmonary disease.

The above regimens reflect treatment dosing (rather than prophylaxis dosing) used for seasonal influenza. This approach is based on limited data supporting higher prophylaxis dosing in animals for avian influenza A(H5N1) virus infection [47], as well as the desire to reduce the likelihood of emergence of resistance during prophylaxis [48-50].

●Antiviral duration – We administer antiviral prophylaxis for 5 or 10 days:

•In the setting of time-limited exposure, we continue antiviral prophylaxis for five days from the last known exposure.

•In the setting of ongoing exposure (such as in a household setting), we continue antiviral prophylaxis for 10 days, given the potential for prolonged viral shedding from the case patient.

●Follow-up − Close contacts should be monitored daily for 10 days after the last known exposure to a confirmed or probable case; daily assessment should include temperature measurement and evaluation for respiratory symptoms (eg, cough, sore throat, shortness of breath, difficulty breathing).

Individuals who develop symptoms — Individuals with temperature ≥38.0°C (≥100.4° F) or any new respiratory symptoms should be referred for prompt evaluation and testing for avian influenza infection. Consultation with CDC Influenza Division via the CDC Emergency Operations Center (770-488-7100) should be pursued to arrange testing for antiviral resistance. In addition, infection prevention and control measures should be implemented. (See 'Infection control' above and "Avian influenza: Clinical manifestations and diagnosis".)

For individuals who took oseltamivir prophylaxis for ≥3 days prior to onset of symptoms, oseltamivir should be discontinued as soon as treatment with inhaled zanamivir or oral baloxavir can be initiated [45]. The rationale for this approach is that novel influenza A viruses may develop oseltamivir resistance (and potentially peramivir resistance) but may remain susceptible to zanamivir and baloxavir. Dosing is outlined above. (See 'Outpatients' above.)

For individuals who took oseltamivir prophylaxis for <3 days prior to onset of symptoms, treatment with oseltamivir should be administered for five days; the duration of treatment should be restarted from the day of symptom onset. Dosing is outlined above. (See 'Outpatients' above.)

Vaccine development — Issues related to avian influenza vaccine development are discussed separately. (See "Avian influenza vaccines".)

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.)

●Basics topic (see "Patient education: Bird flu (avian influenza) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Treatment

•Site of care − Hospitalization is warranted for patients with significant dehydration and for severely ill patients, especially those with respiratory distress, hypoxemia, impaired cardiopulmonary function, or altered mental status. In the absence of these findings, admission for observation may be warranted for patients with increased risk for complications (table 1). (See 'Site of care' above.)

•Antiviral treatment − We recommend antiviral treatment for patients with confirmed, probable, or suspected avian influenza infection (Grade 1B). We suggest treatment with oseltamivir (Grade 2C); alternative agents and drug dosing are outlined above. Case definitions are outlined separately. (See 'Clinical approach' above and 'Antiviral selection' above and "Avian influenza: Clinical manifestations and diagnosis", section on 'Case definitions'.)

•Timing of treatment − We administer antiviral treatment as early as possible; treatment should be initiated even if more than 48 hours have elapsed since illness onset. For outpatients with uncomplicated disease in whom fever is absent and symptoms are nearly resolved, the decision to initiate antiviral treatment should be made on a case-by-case basis. (See 'Timing of treatment' above.)

•Persistent symptoms – Patients with persistent symptoms warrant evaluation and treatment for bacterial infection. In addition, antiviral resistance should be considered in patients with progressive lower respiratory tract disease treated with oseltamivir and/or peramivir. For patients with suspected or known infection due to oseltamivir-resistant virus, we suggest treatment with zanamivir (Grade 2C) as well as antiviral drug susceptibility testing; baloxavir is an alternative treatment. (See 'Patients with persistent symptoms' above.)

●Prevention

•Infection control (see 'Infection control' above)

-Health care workers − Infection control measures to reduce the risk of nosocomial transmission include negative pressure respiratory isolation with standard, contact (gloves, gowns, eye protection), and airborne (eg, N95 masks) precautions for health care personnel.

-Poultry workers − The risk of exposure to avian influenza infection is increased among workers at live bird markets and individuals involved with bird cleaning, slaughtering, defeathering, or evisceration. Such individuals who are involved with poultry outbreaks should adhere to the same personal protective measures used in health care facilities.

•Postexposure prophylaxis − For asymptomatic individuals with exposure to an infected person (or their secretions) or infected birds, we suggest postexposure prophylaxis with oseltamivir or zanamivir (Grade 2C).