Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

close contact of confirmed or probable case

1st line – observation ± post-exposure prophylaxis

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INITIAL
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close contact of confirmed or probable case
1st line – 

observation ± post-exposure prophylaxis

Contacts of symptomatic confirmed or probable cases should be monitored closely for signs of illness for up to 10 days following the date of last exposure. This includes daily assessment for acute respiratory symptoms and temperature measurement. If the person develops a compatible illness during this time, the person should be referred for prompt medical evaluation and testing, and treated as a suspected case (including isolation and starting antiviral post-exposure prophylaxis if not already on it).[130]

Post-exposure prophylaxis can be considered for any person who meets epidemiological exposure criteria. The decision to start antiviral post-exposure prophylaxis should be considered on a case-by-case basis and guided by assessment of highly pathogenic avian influenza (HPAI) A(H5N1) virus exposure and subsequent risk of developing infection. Local or national public health departments should be contacted for guidance.

The US Centers for Disease Control and Prevention (CDC) recommends post-exposure prophylaxis in highest-risk exposure groups. It may be considered in moderate-risk exposure groups, and is not routinely recommended in low-risk exposure groups. The decision to start post-exposure prophylaxis in low or moderate risk groups should be based on clinical judgement, consideration of the type of exposure, and whether the contact is at high risk for complications.[130] 

Post-exposure prophylaxis may also be considered for people with recent close exposure (within approximately 2 meters [6 feet]) to A(H5) virus-infected animals. The decision to initiate post-exposure prophylaxis in these people should be based on clinical judgement, with consideration given to the type (e.g., without use or personal protective equipment) and duration of exposure, time since exposure, known infection status of bird(s), and whether the exposed person is at higher risk for complications.[142]  

The CDC does not routinely recommend post-exposure prophylaxis for people handling sick or potentially infected birds or other sick or dead animals or decontaminating infected environments who properly use (including removing) the recommended personal protective equipment, provided there are no breaches. However, post-exposure prophylaxis and influenza A(H5) testing can be offered to asymptomatic people who experience a high risk of exposure to animals confirmed or highly suspected to be infected with HPAI A(H5N1) virus without using the recommended personal protective equipment (or if there are breaches in or failures of the recommended personal protective equipment).[41]

The CDC recommends oral oseltamivir for post-exposure prophylaxis. Administration should begin as soon as possible, ideally within 48 hours after first exposure, and continue for 5 or 10 days. If exposure was time-limited and not ongoing, post-exposure prophylaxis is recommended for 5 days from the last known exposure. If exposure is likely to be ongoing (e.g., household setting), 10 days is recommended.[130]

Oseltamivir is recommended for people of any age, including newborn infants, and pregnant women.[130][132] 

The CDC recommends that post-exposure prophylaxis should be given twice daily (i.e., the treatment dosing frequency) rather than once daily (i.e., the typical seasonal influenza antiviral post-exposure prophylaxis dose) because of the potential that HPAI A(H5N1) virus infection may have already occurred. However, the dose may vary depending on location, and local guidelines should be consulted.

The World Health Organization (WHO) conditionally recommends using oseltamivir for asymptomatic people exposed to zoonotic influenza viruses associated with high mortality in humans or with an unknown risk of causing severe disease in the prior 2 days (based on low-quality evidence).[123] The WHO also conditionally recommends zanamivir, baloxavir, or laninamivir as other options, but the CDC does not currently recommend these agents.[123][130]

Children may experience unique cutaneous, behavioural, and neurological adverse events with neuraminidase inhibitors; therefore, extra caution should be used in this population.

Recommended doses are based on guidelines from the CDC.[132]

Primary options

oseltamivir: children ≥3 months of age: 3 mg/kg orally twice daily for 5-10 days; children ≥1 year of age and ≤15 kg body weight: 30 mg orally twice daily for 5-10 days; children ≥1 year of age and >15-23 kg body weight: 45 mg orally twice daily for 5-10 days; children ≥1 year of age and >23-40 kg body weight: 60 mg orally twice daily for 5-10 days; children ≥1 year of age and >40 kg body weight and adults: 75 mg orally twice daily for 5-10 days

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ACUTE

suspected or probable or confirmed infection

1st line – infection prevention and control

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ACUTE
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suspected or probable or confirmed infection
1st line – 

infection prevention and control

Patients with suspected, probable, or confirmed highly pathogenic avian influenza (HPAI) A(H5N1) virus infection should be isolated and local infection control recommendations should be followed. Given the potential infectiousness and virulence of HPAI A(H5N1) virus, enhanced infection control precautions are recommended, including airborne and contact precautions (with the use of eye protection), in addition to standard precautions.[125] 

There may be slight infection control recommendation differences between national public health organisations; therefore, if HPAI A(H5N1) virus infection is considered in a patient, it is recommended that clinicians consult national infection control guidelines.

Patients may be treated as outpatients or in hospital depending on disease severity and clinical presentation.

Plus – antiviral treatment

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ACUTE
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suspected or probable or confirmed infection
Plus – 

antiviral treatment

Treatment recommended for ALL patients in selected patient group

Antiviral treatment is recommended as soon as possible for outpatients and hospitalised patients who are suspected, probable, or confirmed cases of highly pathogenic avian influenza (HPAI) A(H5N1) virus infection. Antiviral treatment should not be delayed by diagnostic specimen collection or laboratory testing.[112] Antiviral therapy can be discontinued in patients who are not hospitalised and who test negative for HPAI A(H5N1) virus infection (or other influenza viruses).

People who are asymptomatic but test positive for influenza A (H5) infection after exposure to infected animals (and who report not wearing or a breach in the recommended personal protective equipment) should be offered antiviral treatment, unless they are already receiving post-exposure prophylaxis, and actively monitored for the development of signs and symptoms for 10 days after the last known exposure.[41]

Oral or enterically administered oseltamivir is the most widely studied and available antiviral agent for the treatment of HPAI A(H5N1) virus infection. It is recommended for people of any age, including newborn infants, and is the preferred option in pregnant women.[132] 

The World Health Organization (WHO) conditionally recommends oseltamivir for people with suspected or confirmed severe influenza virus infection, based on very low-quality evidence. This includes patients with novel influenza A virus infection associated with high mortality, or with an unknown risk of severe disease, even if they do not otherwise fulfill criteria for severe infection. Treatment should be administered as early as possible and within 2 days of onset of symptoms.[123] 

The US Centers for Disease Control and Prevention (CDC) recommends oseltamivir for all hospitalised patients regardless of time since onset of illness, and all symptomatic outpatients. Oseltamivir is recommended for all patients with conjunctivitis or acute respiratory illness due to the potential for progression to severe disease, but clinical judgement may be used to decide whether to initiate treatment in untreated patients with uncomplicated disease in whom symptoms are nearly resolved and there is an absence of fever.[112] 

Other neuraminidase inhibitors may be available in certain jurisdictions. The CDC recommends intravenous peramivir as an alternative to oseltamivir only in hospitalised patients who cannot tolerate or absorb oral or enterically administered oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding. If used, a minimum of 5 days treatment is recommended.[112] However, the WHO suggests not administering intravenous peramivir to patients with suspected or confirmed severe influenza virus infection, based on very low-quality evidence.[123]  

Children may experience unique cutaneous, behavioural, and neurological adverse events with neuraminidase inhibitors; therefore, extra caution should be used in this population.

The CDC does not currently recommend baloxavir (a selective inhibitor of influenza cap-dependent endonuclease) in outpatients or hospitalised patients due to a lack of data in these patients.[112] However, the WHO recommends considering baloxavir as an alternative to oseltamivir when oseltamivir is not available for patients with suspected or confirmed severe influenza virus infection. However, this recommendation is based on indirect evidence from nonsevere seasonal influenza and is of very low certainty.[123]

Combination antiviral treatment with oseltamivir plus baloxavir may be considered in immunocompromised patients and hospitalised patients due to concerns about resistance. Seek guidance from your local public health authority for antiviral treatment in patients who are immunocompromised.[112]​

Modified regimens with higher doses and longer duration of treatment (e.g., 10 days) may be considered on a case-by-case basis under specialist guidance (e.g., severely immunocompromised patients, severe or critical disease), but there are no available clinical trial data to inform recommendations.[112] Consult an infectious disease specialist for guidance.

Oral oseltamivir may be given enterically/nasogastrically. Limited data suggest that oseltamivir given orally or by orogastric/nasogastric tube is well absorbed in critically ill patients, including those in the intensive care unit, or on extracorporeal membrane oxygenation or renal replacement therapy.[112] Oseltamivir has been shown to be adequately absorbed following nasogastric administration to mechanically ventilated adults with severe disease caused by HPAI A(H5N1) virus infection.[143]

Where the clinical course remains severe or progressive, investigations for antiviral resistance should be performed, if possible. Contacting local or national public health departments for guidance is highly recommended.[112][139][140]​​​

Recommended doses are based on guidelines from the CDC.[132]

Primary options

oseltamivir: children <14 days of age: consult specialist for guidance on dose; children 14 days to 1 year of age: 3 mg/kg orally twice daily for 5 days; children ≥1 year of age and ≤15 kg body weight: 30 mg orally twice daily for 5 days; children ≥1 year of age and >15-23 kg body weight: 45 mg orally twice daily for 5 days; children ≥1 year of age and >23-40 kg body weight: 60 mg orally twice daily for 5 days; children ≥1 year of age and >40 kg body weight and adults: 75 mg orally twice daily for 5 days

Secondary options

peramivir: children and adults: consult specialist for guidance on dose

OR

baloxavir marboxil: children and adults: consult specialist for guidance on dose

Consider – supportive care

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ACUTE
|
suspected or probable or confirmed infection
Consider – 

supportive care

Additional treatment recommended for SOME patients in selected patient group

Most patients admitted to the hospital with highly pathogenic avian influenza (HPAI) A(H5N1) virus infection have had rapidly progressive pneumonia leading to acute respiratory distress syndrome (ARDS) and multi-organ failure. Patients with early recognition of disease and initiation of antiviral and supportive therapies may have improved clinical outcomes.[136][137]

While there is no standardised approach for the clinical management of humans with HPAI A(H5N1) virus infection, the World Health Organization (WHO) recommends that supportive care follow published evidence-based guidelines for the clinical syndrome present (e.g., septic shock, respiratory failure, and ARDS).​[138]

The WHO suggests not administering corticosteroids to patients with suspected or confirmed severe influenza virus infection, based on very low-quality evidence. However, there is a possibility of important benefit, especially where the clinical diagnosis overlaps with acute respiratory distress syndrome (ARDS). Corticosteroids possibly decrease mortality in the late phase of ARDS, but there was no direct evidence for patients with ARDS caused by influenza virus.[123]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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