Highlights & Basics
- Avian influenza A(H5N1) virus infection is a notifiable condition. Infection prevention and control measures such as patient isolation and standard, contact, and airborne (including eye protection) precautions are recommended.
- High case-fatality proportion of approximately 52% among patients with laboratory-confirmed infection.
- Most patients present with fever and features of lower respiratory tract infection on admission. Molecular testing is recommended to confirm diagnosis; however, it is usually not available in most clinical settings.
- Antiviral therapy is recommended as soon as possible in symptomatic patients with suspected or confirmed infection. Supportive care and specialized intensive care management are indicated for respiratory failure and other severe complications.
- Postexposure antiviral chemoprophylaxis and monitoring of close contacts of a confirmed or probable case are recommended.
Quick Reference
History & Exam
Key Factors
cough
influenza-like illness
dyspnea
fever
rales, rhonchi
wheeze
decreased breath sounds
tachypnea
Other Factors
abdominal pain, vomiting, diarrhea
altered mental status
seizures
Diagnostics Tests
1st Tests to Order
CBC with differential
LFTs
chest x-ray
pulse oximetry
sputum Gram stain
sputum and blood bacterial culture
real-time reverse transcription polymerase chain reaction (rtRT-PCR)
Other Tests to consider
viral culture
Treatment Options
presumptive
close contact of confirmed or probable case
observation ± postexposure neuraminidase inhibitor
acute
suspected or probable or confirmed infection
infection prevention and control
antiviral treatment
supportive care
Definition
Classifications
Pathogenicity
- Most strains are LPAI viruses and cause asymptomatic infection or mild disease in infected poultry. LPAI H3N8, H6N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N3, H10N7, and H10N8 virus strains have infected humans causing disease ranging from conjunctivitis to nonfatal upper respiratory and lower respiratory tract disease, to severe lower respiratory tract disease and death (H3N8, H7N9, H9N2, H10N8).[4] [5] [6] [7] [8] [9] [10] [11]
- HPAI strains identified to date are of the H5 and H7 subtypes and can cause severe illness in poultry. HPAI A virus infections in humans have ranged from asymptomatic to severe or fatal disease. Rare, sporadic human cases of HPAI A virus infection have been detected with H5N1, H5N6, H7N3, H7N7, and H7N9 viruses and have caused a wide spectrum of illness from conjunctivitis (H7N3, H7N7) to severe pneumonia, acute respiratory distress syndrome, and fatal outcomes (H5N1, H5N6, H7N7, H7N9).[12] [13] [14] [15] Asian lineage HPAI H7N9 viruses were detected and reported in the People's Republic of China for the first time in February 2017.
Antigenic structure (clades)
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
- April 2024: One HPAI A(H5N1) case was reported in Texas, US. The person developed eye redness as their only symptom, and they had exposure to dairy cattle presumed to be infected with HPAI A(H5N1) virus.[34]
- March 2024: One HPAI A(H5N1) case was reported in a 21-year old man in Khanh Hoa Province, Vietnam. He developed fever and cough before being admitted to hospital with persistent abdominal pain and diarrhea. He then developed severe pneumonia, sepsis, and acute respiratory distress syndrome, and died 12 days after initial symptom onset. The man went bird hunting in February 2024 and did not have contact with dead or sick poultry since then. No evidence of human-to-human transmission was identified.[35]
- February 2024: Two HPAI A(H5N1) cases were reported in epidemiologically-unrelated people in different provinces in Cambodia. A 3-year old child exposed to dead backyard poultry was hospitalized with mild uncomplicated upper respiratory tract illness, and a 69-year old patient who raised domestic poultry and fighting roosters was hospitalized with difficulty breathing. Both patients recovered, and no evidence of human-to-human transmission was identified.[36]
- November 2023: Two HPAI A(H5N1) cases were reported in people living in different households in the same rural village in Cambodia. After exposure to sick or dead backyard poultry, a young girl experienced mild uncomplicated upper respiratory tract illness and survived, and a previously healthy young woman developed severe pneumonia and died. No evidence of human-to-human transmission was identified.[37]
- October 2023: Two HPAI A(H5N1) cases were reported in epidemiologically-unrelated people in different provinces in Cambodia. A young child and a middle-aged adult both died of severe pneumonia after close exposure to sick and dead poultry in rural villages. No evidence of human-to-human transmission was identified.[33]
- May 2023: Two HPAI A(H5N1) cases were identified in poultry farm workers in the United Kingdom. Both cases were asymptomatic and were detected through a surveillance study of asymptomatic workers exposed to infected poultry. Both people have since tested negative, and work to determine whether these are false positives (rather than mucosal contamination of the nose with virus particles) is ongoing. No evidence of human-to-human transmission was identified.[38]
- March 2023: The first case of HPAI A(H5N1) virus infection in Chile was identified in a middle-aged man who developed severe pneumonia and respiratory failure. The man lived in an area where H5N1 virus was detected in wild birds and sea lions in northern Chile, but the source of his infection was unknown.[39] [40] [41]
- February 2023: Two HPAI A(H5N1) cases were reported in family members, an 11-year-old girl and her father, in a rural Cambodian village after exposure to sick and dead infected poultry. The girl died of respiratory failure while her father only experienced mild upper respiratory tract illness. No evidence of human-to-human transmission was identified.[42]
- January 2023: One HPAI A(H5N1) case was reported in a 9-year-old girl who was admitted to hospital on December 30, 2022 for respiratory illness after exposure to sick and dead backyard poultry in a rural area of Ecuador. She was transferred to an intensive care unit of a pediatric hospital for septic shock and pneumonia, and survived. This was the first human case of HPAI A(H5N1) virus infection ever reported in South America.[43] [44]
Etiology
Pathophysiology
- Direct contact (touching) or close exposure to infected sick or dead poultry or poultry products is thought to be the major risk for transmission of avian influenza A viruses to humans.
- Inhalation of aerosolized material (e.g., poultry feces) containing infectious HPAI A(H5N1) virus is a likely route of transmission from poultry to humans.
- Self-inoculation of the mucous membranes after direct contact with material containing HPAI A(H5N1) virus (touching or cleaning infected birds) or indirect (fomite) contact transmission from surfaces contaminated with poultry feces or products containing HPAI A(H5N1) virus to mucous membranes has also been hypothesized.
- Consumption of uncooked poultry products, including blood from infected birds, has been identified as a potential risk factor in field investigations, but whether transmission can occur by primary HPAI H5N1 virus infection of the human gastrointestinal tract is unknown.
Diagnostic Approach
History
Physical exam
Initial investigations
- Laboratory tests, including at least a complete blood count with differential, basic chemistries and hepatic enzymes, and a chest x-ray, should be performed. Common findings in severe cases may include leukopenia, lymphopenia, and mild to moderate thrombocytopenia, but these laboratory findings are not present in all cases and are unlikely to be useful to distinguish between infection by HPAI A(H5N1) virus and other respiratory pathogens.
- Pulse oximetry should be performed in patients with dyspnea to assess their oxygenation status, as well as arterial blood gas if considered necessary.
- Sputum Gram stain and bacterial culture, and blood culture should be performed as part of the evaluation for primary bacterial pneumonia and potential bacterial coinfection. Seasonal influenza virus A or B infection should be considered, as it is far more common than HPAI A(H5N1) virus infection.
- SARS-CoV-2 diagnostic testing should be performed, as SARS-CoV-2 infection is far more common than HPAI A(H5N1) virus infection, and a positive result can inform antiviral treatment and infection prevention and control measures.
- Other respiratory virus testing may be considered in certain circumstances (e.g., respiratory syncytial virus in young children, multiple respiratory virus etiologies in immunocompromised patients). Such testing can inform and guide appropriate treatment, including decisions on whether to initiate or discontinue antibiotic treatment, and appropriate infection prevention and control measures. Patients presenting with atypical symptoms (e.g., gastrointestinal or neurologic) should receive a suitable workup directed at alternative etiologies for those processes.
Specific viral testing
- In persons with a history of suspected recent exposure to HPAI A(H5N1) virus, the recommended and definitive diagnostic testing is real-time RT-PCR of respiratory specimens.[94] Testing for seasonal influenza A and B viruses should be performed on respiratory specimens; if influenza A is positive, then subtyping should be performed for seasonal influenza A(H1) and A(H3) viruses. If influenza A testing is positive but A(H1) and A(H3) are negative, then testing for A(H5) should be performed at a specialized public health laboratory.[95]
- RT-PCR for HPAI A(H5N1) virus is usually not available in clinical settings. Many regional public health laboratories, most national laboratories, and some private laboratories can perform testing for A(H5) virus.
- RT-PCR takes approximately 4 hours to produce preliminary results, but transport time and testing logistics may delay testing results.
- Healthcare workers should follow recommended infection control precautions and use appropriate personal protective equipment when collecting clinical specimens, including respiratory and eye protection.[96]
- The preferred specimens in nonintubated patients are upper respiratory tract specimens (e.g., oropharyngeal swab, nasopharyngeal swab, nasal aspirate or wash). Two swabs may be combined into one vial (e.g., one nasal or nasopharyngeal swab and one oropharyngeal swab. Ideally both a nasopharyngeal swab, and a combined nasal swab and oropharyngeal swab should be collected and tested separately. Oropharyngeal swabs have a higher diagnostic yield for HPAI A(H5N1) virus than other upper respiratory specimens. Nasal and nasopharyngeal swabs are preferred to detect other respiratory viruses, including seasonal influenza viruses.[94] [97] Sputum, if obtainable from a patient who is not intubated, could also be collected for testing.[98]
- Multiple respiratory specimens should be collected from different sites on at least two consecutive days for hospitalized patients, because testing single specimens may miss detection of HPAI A(H5N1) virus.[94]
- Obtain specimens as soon as possible, ideally within 7 days of symptom onset. However, if earlier specimens are not available, respiratory specimens should still be collected and tested after 7 days from symptom onset, as prolonged viral shedding has been documented for critically ill patients with HPAI A(H5N1) virus infection.[94]
- Viral culture should not be undertaken except in an experienced, biosafety level 3-enhanced laboratory or greater following recommended personal protective equipment and infection control precautions. Viral culture is important for virologic surveillance, antigenic monitoring for vaccine strain selection, and assessment and analyses of viral characteristics such as genetic reassortment, receptor binding affinity, and antiviral susceptibility.
- Serologic testing is not routinely available, cannot inform clinical management, and should not be considered for clinical diagnostic purposes. However, properly timed acute and convalescent sera tested at specialized public health laboratories for evidence of seroconversion can yield a retrospective diagnosis of HPAI A(H5N1) virus infection.
- Commercially available point-of-care rapid influenza diagnostic tests are insensitive and not specific for HPAI A(H5N1) virus and, therefore, should not be used for diagnosis of HPAI A(H5N1) virus infection.
Starting antiviral treatment
- In settings where batch RT-PCR or other rapid molecular influenza assays (with similar high sensitivity and high specificity) are available and results are expected within 24 hours, a strategy of testing for influenza, treating with oseltamivir as soon as possible, and re-evaluating treatment when the test result is available is recommended.
- In settings where batch RT-PCR or other rapid molecular influenza assays are not available to provide results within 24 hours, a strategy of not testing for influenza and empirically treating with oseltamivir as soon as possible is recommended.
Risk Factors
History & Exam
Tests
Differential Diagnosis
Coronavirus disease 2019 (COVID-19)
Differentiating Signs/Symptoms
- Important to consider the current COVID-19 epidemiologic situation and any recent outbreaks. May give history of COVID-19 exposure.
- Signs and symptoms are similar so it may be difficult to differentiate between the conditions clinically.
Differentiating Tests
- Real-time reverse transcription polymerase chain reaction (RT-PCR): positive for SARS-CoV-2 RNA.
- It is not possible to differentiate COVID-19 from other causes of pneumonia on chest imaging.
Community-acquired pneumonia
Differentiating Signs/Symptoms
- No differentiating signs/symptoms.
Differentiating Tests
- Diagnostic studies should be considered based on local guidance as well as microbial patterns in a particular community.
- Isolation of organisms such as Streptococcus pneumoniae, Staphylococcus aureus or group A Streptococcus from sputum and blood culture, and response to typical therapy confirms diagnosis.
- Chest x-ray findings for typical pneumonia are consistent with consolidation.
- Positive highly pathogenic avian influenza (HPAI) A(H5N1) virus-specific tests do not exclude coinfection, although most HPAI A(H5N1) cases have not had community-acquired bacterial coinfection identified, except in intubated patients with ventilator-associated pneumonia. Seasonal influenza virus infection with bacterial coinfection is more common.
Atypical pneumonia
Differentiating Signs/Symptoms
- No differentiating signs/symptoms.
Differentiating Tests
- Confirmation of infection by atypical pathogens (including atypical pneumonia pathogens such as Mycoplasma pneumoniae and Legionella pneumophila) by sputum culture, blood culture, or other specific tests.
- A diagnosis of atypical pneumonia does not rule out highly pathogenic avian influenza (HPAI) A(H5N1)virus infection, but coinfection with HPAI A(H5N1) virus and atypical pneumonia pathogens has not been reported.
Seasonal influenza virus infection
Differentiating Signs/Symptoms
- More common cause of severe morbidity in young children, older adults, and people with underlying chronic medical conditions (e.g., cardiopulmonary disease, immunosuppressed).
- More likely to be a self-limited condition with milder symptoms among previously healthy persons. Severe lower respiratory tract disease can occur among previously healthy children, young adults, pregnant women, and people with class III obesity.
Differentiating Tests
- Diagnostic tests confirming infection by another respiratory virus does not rule out highly pathogenic avian influenza (HPAI) A(H5N1) virus infection, but coinfection with HPAI A(H5N1) virus and other respiratory viruses is uncommon.
Avian influenza A (H7N9) virus infection
Differentiating Signs/Symptoms
- Epidemic has been geographically focused in China.
- Most patients require hospitalization for management of pneumonia and/or respiratory failure and often present soon after the onset of symptoms, in contrast to the late presentation often seen with A(H5N1) virus infection.
- No differentiating signs/symptoms.
Differentiating Tests
- Reverse transcription-polymerase chain reaction (RT-PCR) is positive for H7-specific viral RNA.
Differentiating Signs/Symptoms
- Respiratory infections due to pathogens endemic to the region where infection occurred should be considered (e.g., endemic mycotic infection, melioidosis in parts of Southeast Asia).
- No differentiating signs/symptoms.
Differentiating Tests
- Diagnostic tests confirming infection by an atypical pneumonia do not rule out highly pathogenic avian influenza (HPAI) A(H5N1) virus infection, but coinfection with HPAI A(H5N1) and endemic respiratory infections has not been reported.
Respiratory syncytial virus infection
Differentiating Signs/Symptoms
- Most common cause of lower respiratory tract infection in children ages <1 year.
- Significant and often unrecognized cause of lower respiratory tract infection in both older and immunosuppressed patients.
- Gives rise to upper and lower respiratory symptoms that peak in 3 to 5 days and resolve within 7 to 10 days.
Differentiating Tests
- Rapid assays using antigen capture technology are the mainstay of the diagnostic algorithm, as the identification by culture can take from 4 days to 2 weeks.[101]
- Diagnostic tests confirming infection by another respiratory virus does not rule out highly pathogenic avian influenza (HPAI) A(H5N1) virus infection, but coinfection with HPAI A(H5N1) virus and other respiratory viruses is uncommon.
Severe acute respiratory syndrome (SARS)
Differentiating Signs/Symptoms
- No differentiating signs/symptoms.
- Both can have rapid onset of fever, cough, and pneumonia.
- The absence of confirmed cases since 2004 makes the diagnosis of SARS outside of re-emergence of the virus very unlikely.
Differentiating Tests
- The diagnosis of SARS requires high clinical suspicion and should be informed by global surveillance for infections by SARS-associated coronavirus (SARS-CoV). Tests for influenza virus are negative. Real-time reverse transcription polymerase chain reaction (RT-PCR) is positive for SARS-CoV.
Middle East respiratory syndrome (MERS)
Differentiating Signs/Symptoms
- Most cases are epidemiologically linked to the Arabian Peninsula. Many cases are associated with nosocomial transmission. Zoonotic transmission from dromedary camels and limited nonsustained human-to-human transmission have occurred.
- No differentiating signs/symptoms. Common symptoms are acute, serious respiratory illness with fever, cough, shortness of breath, and breathing difficulties. Most patients have pneumonia, respiratory failure, and acute respiratory distress syndrome. Many also have gastrointestinal symptoms (including diarrhea), while others have kidney failure.
Differentiating Tests
- Real-time reverse transcription polymerase chain reaction (RT-PCR) is positive for MERS coronavirus. The test can be found at some international public health laboratories, particularly in regions affected by MERS.
Criteria
- Highly pathogenic avian influenza (HPAI) A(H5N1) virus infection in a patient that is confirmed by the CDC's Influenza Division Laboratory or a CDC-designated laboratory using methods mutually agreed upon by the CDC and the Council of State and Territorial Epidemiologists (CSTE).
- A person meeting epidemiologic and clinical criteria for avian influenza A virus infection (below) and for whom confirmatory laboratory test results do not provide a sufficient level of detail to confirm HPAI A(H5) virus infection.
- A person meeting epidemiologic and clinical criteria for avian influenza A virus infection (below) and for whom confirmatory laboratory test results are not known or pending.
- People with recent exposure (within 10 days) to avian influenza A viruses through one of the following:
- Exposure to A(H5), A(H7), or A(H9) virus-infected birds
- Exposure to an infected person
- Laboratory exposure.
- People with signs and symptoms consistent with acute or lower respiratory tract infection or conjunctivitis, or complications of acute respiratory illness without an identified cause.
- A person whom public health authorities have decided to investigate for possible influenza A(H5N1) virus infection.
- A person presenting with unexplained acute lower respiratory illness with fever >100.4ºF (>38ºC) and cough, shortness of breath, or difficulty breathing AND one or more of the following exposures in the 7 days prior to symptom onset:
- Close contact (within 3 feet [1 meter]) with a person (e.g., caring for, speaking with, or touching) who is a suspected, probable, or confirmed H5N1 case
- Exposure (e.g., handling, slaughtering, defeathering, butchering, preparation for consumption) to poultry or wild birds or their remains or to environments contaminated by their feces in an area where influenza A(H5N1) virus infections in animals or humans have been suspected or confirmed in the last month
- Consumption of raw or undercooked poultry products in an area where influenza A(H5N1) virus infections in animals or humans have been suspected or confirmed in the last month
- Close contact with a confirmed influenza A(H5N1) virus-infected animal other than poultry or wild birds (e.g., cat or pig)
- Handling samples (animal or human) suspected of containing H5N1 virus in a laboratory or other setting.
- Probable definition 1: a person meeting the criteria for a suspected case AND one of the following additional criteria:
- Infiltrates or evidence of an acute pneumonia on chest radiograph plus evidence of respiratory failure (hypoxemia, severe tachypnea); or
- Positive laboratory confirmation of an influenza A infection but insufficient laboratory evidence for influenza A(H5N1) virus infection.
- Probable definition 2: a person dying of an unexplained acute respiratory illness who is considered to be epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1 case.
- A person meeting the criteria for a suspected or probable case AND one of the following positive results conducted in a national, regional, or international influenza laboratory whose H5N1 test results are accepted by WHO as confirmatory:
- Isolation of an influenza A(H5N1) virus
- Positive influenza A(H5) PCR results from tests using two different PCR targets (e.g., primers specific for influenza A and H5 hemagglutinin)
- A fourfold or greater rise in neutralization antibody titer for influenza A(H5N1) virus based on testing of an acute serum specimen (collected 7 days or less after symptom onset) and a convalescent serum specimen. The convalescent neutralizing antibody titer must also be 1:80 or higher
- A microneutralization antibody titer for influenza A(H5N1) virus of 1:80 or greater in a single serum specimen collected at day 14 or later after symptom onset and a positive result using a different serologic assay: for example, a horse red blood cell hemagglutination inhibition titer of 1:160 or greater or an H5-specific western blot positive result.
- Fever >100.4ºF (>38ºC); or
- Acute respiratory symptoms (e.g., cough, hoarseness, nasal discharge or congestion, shortness of breath, sore throat, wheezing, or sneezing); or
- Other severe or life-threatening illness that is suggestive of an infectious process.
- Close contact (within 3 feet [1 meter]) with live, dying, or dead domestic poultry or wild birds (including live bird markets), in an area of the world affected by avian influenza, or with any confirmed infected animal, in the 10 days before the onset of symptoms; or
- Close contact with a confirmed human case of avian influenza, or human case(s) of severe unexplained respiratory illness from avian influenza-affected areas, or human case(s) of unexplained illness resulting in death from avian influenza-infected areas, in the 10 days before the onset of symptoms.
- Close contact includes handling laboratory specimens from cases without appropriate precautions, within 3 feet distance, directly providing care, touching a case, or within close vicinity of an aerosol-generating procedure, from 1 day prior to symptom onset and for duration of symptoms or positive virologic detection.
Screening
Treatment Approach
Antiviral chemoprophylaxis for close contacts
- Household or close family member contacts with unprotected, prolonged close contact to a confirmed or probable case.
- Chemoprophylaxis is recommended.
- Healthcare workers with unprotected close contact with a confirmed or probable case, or nonhousehold members with prolonged unprotected close contact with a confirmed or probable case outside of a healthcare facility.
- Chemoprophylaxis may be considered.
- Other people who have had social contact of a short duration with a confirmed or probable case in a nonhospital setting (e.g., community or workplace environment).
- Chemoprophylaxis is not routinely recommended.
- Treatment should continue for 5 or 10 days. If exposure was time-limited and not ongoing, chemoprophylaxis 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.
- The CDC recommends that chemoprophylaxis should be given twice daily (i.e., the treatment dosing frequency) rather than once daily (i.e., the typical seasonal influenza antiviral chemoprophylaxis 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.
- If a close contact becomes symptomatic during or after use of chemoprophylaxis, appropriate infection prevention and control measures should be instituted and respiratory specimens collected for testing as soon as possible.[103]
- If a close contact tests positive and has been taking oseltamivir chemoprophylaxis for ≥3 days before becoming symptomatic, oseltamivir should be stopped and inhaled zanamivir or oral baloxavir initiated, as some novel influenza A viruses may rapidly become oseltamivir-resistant.[103]
Infection prevention and control
Antiviral treatment
- Oseltamivir
- Zanamivir
- Peramivir
- Laninamivir
- The WHO recommends oseltamivir as the preferred treatment for people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on low-quality evidence.[100]
- The CDC recommends oseltamivir treatment for all hospitalized patients regardless of time since onset of illness, and all outpatients (i.e., any patient in the ambulatory care setting, including emergency departments, urgent care, and other clinics) including those with severe, progressive, or complicated illness. Oseltamivir can be administered via orogastric or nasogastric tube to ventilated patients and is well-absorbed. Oseltamivir is the only treatment recommended in outpatients if more than 48 hours have elapsed since onset of symptoms. For untreated outpatients with uncomplicated disease and no fever where symptoms are nearly resolved, the decision to start antiviral treatment should be based on clinical judgment.[99]
- Oseltamivir is recommended for people of any age, including newborn infants. It is the preferred option in pregnant women.[106]
- No completed randomized, placebo-controlled trials exist for oseltamivir in hospitalized influenza patients. However, observational uncontrolled studies have suggested a survival benefit to early oseltamivir therapy in these patients, especially when antivirals are started early in the clinical course, or before the onset of acute respiratory distress syndrome (ARDS).[19] [26] [28] [60] [80] [107] [108]
- The WHO suggests not administering inhaled zanamivir to people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence. The recommendation is based on the very low certainty of benefit on critical outcomes of mortality, hospitalization, or intensive care unit admission, rather than on evidence of harm. The WHO acknowledges that this recommendation does not apply to situations where the causative strain is known or at high risk of being resistant to oseltamivir.[100]
- The CDC recommends inhaled zanamivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population.[99]
- The WHO suggests not administering intravenous peramivir or inhaled laninamivir to patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence.[100]
- The CDC recommends intravenous peramivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population; however, it may be considered as an alternative to oseltamivir for patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding.[99]
- Intravenous zanamivir may be available in some countries for hospitalized patients with severe or critical illness, especially if oseltamivir-resistant virus infection is suspected.
- Combination therapy with more than one neuraminidase inhibitor is not recommended because of the potential for antagonism.[109]
- The WHO does not currently recommend baloxavir for patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness due to a lack of data in this population; however, the WHO acknowledges that clinical trials in this population are ongoing.[100]
- The CDC recommends baloxavir in children ages 5 years to <12 years without an underlying medical condition, and in all patients >12 years with uncomplicated mild to moderate seasonal influenza illness presenting within 2 days of onset of symptoms.[99] [110] The CDC does not recommend baloxavir in patients who are pregnant, breast-feeding, or severely immunosuppressed, outpatients with complicated or progressive illness, or hospitalized patients due to the lack of evidence in these groups.
Supportive care
Antiviral resistance
Treatment Options
close contact of confirmed or probable case
observation ± postexposure neuraminidase inhibitor
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
- oseltamivir
Secondary Options
- zanamivir inhaled
children ≥5 years of age and adults: 10 mg (2 puffs) inhaled twice daily for 5-10 days
- zanamivir inhaled
Comments
- Contacts should be monitored closely for signs of illness for up to 10 days following exposure. If the person develops a compatible illness during this time, the person should be treated as a possible case.
- The decision to use antiviral chemoprophylaxis 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 Centers for Disease Control and Prevention (CDC) recommends post-exposure antiviral chemoprophylaxis with a neuraminidase inhibitor 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 chemoprophylaxis in low or moderate risk groups should be based on clinical judgment, consideration of the type of exposure, and whether the contact is at high risk for complications.[103]
- Chemoprophylaxis may also be considered for people who are exposed to birds with avian influenza A virus infection. The decision to initiate chemoprophylaxis should be based on clinical judgment, with consideration given to the type and duration of exposure, time since exposure, known infection status of bird(s), and whether the exposed person is at higher risk for complications.[104]
- Administration should begin as soon as possible, within 48 hours after possible exposure, and continue for 5 or 10 days. If exposure was time-limited and not ongoing, chemoprophylaxis 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.[103]
- The CDC recommends that chemoprophylaxis should be given twice daily (i.e., the treatment dosing frequency) rather than once daily (i.e., the typical seasonal influenza antiviral chemoprophylaxis 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.
- Children may experience unique cutaneous, behavioral, and neurologic adverse events with neuraminidase inhibitors; therefore, extra caution should be used in this population.
- Recommended doses are based on guidelines from the CDC.[106]
suspected or probable or confirmed infection
infection prevention and control
Comments
- 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.[96]
- There may be slight infection control recommendation differences between national public health organizations; 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.
antiviral treatment
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
- oseltamivir
Secondary Options
- zanamivir inhaled
children ≥7 years of age and adults: 10 mg (2 puffs) inhaled twice daily for 5 days
- zanamivir inhaled
Tertiary Options
- peramivir
children 6 months to 12 years of age: 12 mg/kg intravenously as a single dose, maximum 600 mg/dose; children ≥13 years of age and adults: 600 mg intravenously as a single dose
- peramivir
- baloxavir marboxil
children ≥5 years of age (body weight <20 kg): 2 mg/kg orally as a single dose; children ≥5 years of age and adults (body weight 20-79 kg): 40 mg orally as a single dose; children ≥5 years of age and adults (body weight ≥80 kg): 80 mg orally as a single dose
- baloxavir marboxil
Comments
- Antiviral treatment is recommended as soon as possible for suspected, probable, or confirmed cases of highly pathogenic avian influenza (HPAI) A(H5N1) virus infection, even if more than 48 hours has elapsed since onset of symptoms, and regardless of disease severity. Antiviral treatment should not be delayed by diagnostic specimen collection or laboratory testing.[99] Antiviral therapy can be discontinued in patients who are not hospitalized and who test negative for HPAI A(H5N1) virus infection (or other influenza viruses).
- Oral oseltamivir is the most widely studied and available. The World Health Organization (WHO) recommends oseltamivir as the preferred treatment for people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on low-quality evidence.[100] The Centers for Disease Control and Prevention (CDC) recommends oseltamivir for all hospitalized patients regardless of time since onset of illness, and all outpatients (i.e., any patient in the ambulatory care setting, including emergency departments, urgent care, and other clinics) including those with severe, progressive, or complicated illness. Oseltamivir can be administered enterically via nasogastric or orogastric tube in ventilated patients. Oseltamivir is the only treatment recommended in outpatients if more than 48 hours have elapsed since onset of symptoms. For untreated outpatients with uncomplicated disease and no fever where symptoms are nearly resolved, the decision to start antiviral treatment should be based on clinical judgment.[99] Oseltamivir is recommended for people of any age, including newborn infants. It is the preferred option in pregnant women.[106]
- Inhaled zanamivir may be an alternative option in nonintubated patients who do not have underlying airway disease (e.g., COPD, asthma). The WHO suggests not administering zanamivir to people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence.[100] The CDC recommends zanamivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population.[99]
- Other neuraminidase inhibitors may be available in certain jurisdictions. The WHO suggests not administering intravenous peramivir or inhaled laninamivir to patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence.[100] The CDC recommends intravenous peramivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population; however, it may be considered as an alternative to oseltamivir for patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding.[99]
- Oral baloxavir is a newer antiviral agent with a different mechanism of action to neuraminidase inhibitors. The WHO does not currently recommend baloxavir for patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness due to a lack of data in this population.[100] The CDC recommends baloxavir in children ages 5 years to <12 years without an underlying medical condition, and in all patients >12 years with uncomplicated mild to moderate seasonal influenza illness presenting within 2 days of onset of symptoms.[99] [110] The CDC does not recommend baloxavir in patients who are pregnant, breast-feeding, or severely immunosuppressed, outpatients with complicated or progressive illness, or hospitalized patients due to the lack of evidence in these groups.
- Children may experience unique cutaneous, behavioral, and neurologic adverse events with neuraminidase inhibitors; therefore, extra caution should be used in this population.
- 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. Consult an infectious disease specialist for guidance.
- Oral oseltamivir may be given enterically/nasogastrically. Oseltamivir has been shown to be adequately absorbed following nasogastric administration to mechanically ventilated adults with disease caused by HPAI A(H5N1) virus infection.[117]
- 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.
- Recommended doses are based on guidelines from the CDC.[106]
supportive care
Comments
- 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.[19] Patients with early recognition of disease and initiation of antiviral and supportive therapies may have improved clinical outcomes.[111] [112]
- While there is no standardized 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).[19] [113]
- The WHO suggests not administering corticosteroids to patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence. This recommendation is based on observational studies, and acknowledges the signal for increased risk of mortality with corticosteroids (although this finding is confounded by indication and time-dependent biases). However, corticosteroids should still be considered for other concurrent indications, when consistent with other recommendations (e.g., septic shock, asthma exacerbations, COPD).[100]
Emerging Tx
Convalescent plasma
Prevention
Primary Prevention
- Various H5N1 vaccines are licensed around the world, including the US and Europe, for use in children and adults in pandemic situations. The US has a national stockpile that includes H5 vaccines that could be used if the virus begins transmitting easily from person to person.[90]
- Information on the development and availability status of candidate vaccines is available from the WHO.WHO: zoonotic influenza - candidate vaccine viruses and potency testing reagents
- Healthcare workers worldwide are recommended to receive an annual seasonal influenza vaccine to decrease their risk of seasonal influenza and also to reduce the potential for nosocomial transmission of seasonal influenza viruses in the healthcare setting. Preventing seasonal influenza among people exposed to or infected with HPAI A(H5N1) virus may also decrease the theoretical risk of human coinfection with seasonal influenza A viruses and HPAI A(H5N1) virus and of viral genetic reassortment (an event that could lead to the emergence of a potential pandemic influenza virus strain).
- Voluntary home quarantine
- Use of face masks by people who are ill (or who are well)
- School, university, or childcare facility closures
- Social distancing measures (e.g., workplaces, mass gatherings)
- Environmental surface cleaning measures.
- Antiviral chemoprophylaxis may be recommended in close contacts.
- See Treatment algorithm .
Follow-Up Overview
Prognosis
Monitoring
Complications
Citations
Centers for Disease Control and Prevention. Interim guidance on testing and specimen collection for patients with suspected infection with novel influenza A viruses with the potential to cause severe disease in humans. Jun 2023 [internet publication].[Full Text]
Centers for Disease Control and Prevention. Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Mar 2022 [internet publication].[Full Text]
World Health Organization. Guidelines for the clinical management of severe illness from influenza virus infections. Mar 2022 [internet publication].[Full Text]
Centers for Disease Control and Prevention. Interim guidance on follow-up of close contacts of persons infected with novel influenza A viruses and use of antiviral medications for chemoprophylaxis. Mar 2022 [internet publication].[Full Text]
- BMJ talk medicine podcast: avian influenza - a guide to recognition, reporting and referral with Dr Mary-Margaret Fill
- WHO: surveillance - avian influenza
- CDC: bird flu current situation summary
- UK Health Security Agency: Avian influenza: guidance, data and analysis
- WHO: zoonotic influenza - candidate vaccine viruses and potency testing reagents
- CDC: case definitions for investigations of human infection with avian influenza A viruses in the United States
- WHO: influenza (avian and other zoonotic)
- CDC: information on bird flu
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Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
Guidance pertains to newly detected avian influenza (H5) viruses in the US including the new reassortant H5N1 virus.Published by
Centers for Disease Control and Prevention
Published
2023
Summary
Protocol for collecting, preserving, and shipping specimens for the diagnosis of H5N1 infection.Published by
World Health Organization
Published
2006
Summary
Guidelines for the diagnosis of patients infected with highly pathogenic avian influenza (HPAI) H5N1 virus. UK focus may be less relevant to H5N1-endemic regions or limited-resource countries.Published by
UK Health Security Agency
Published
2024
Treatment
Summary
Reference for health professionals providing care to international travelers.Published by
Centers for Disease Control and Prevention
Published
2024
Summary
Guidelines for the management of patients infected with H5N1 virus. UK focus may be less relevant to H5N1-endemic regions or limited-resource countries.Published by
UK Health Security Agency
Published
2023
Summary
Guidance for follow-up and antiviral chemoprophylaxis of close contacts of cases of human infection with novel influenza A viruses associated with severe human disease including H5N1 infection.Published by
Centers for Disease Control and Prevention
Published
2022
Summary
Guidance for antiviral treatment of human infection with novel influenza A viruses associated with severe human disease including H5N1 infection.Published by
Centers for Disease Control and Prevention
Published
2022
Summary
Guidance provides recommendations for initial infection control in healthcare settings for patients who may be infected with a novel influenza A virus associated with severe disease.Published by
Centers for Disease Control and Prevention
Published
2022
Summary
Guidance for antiviral chemoprophylaxis of people exposed to birds with avian influenza.Published by
Centers for Disease Control and Prevention
Published
2022
Summary
Guidance on nonpharmaceutical interventions (NPIs), or community mitigation measures, that individuals and communities can take to slow the spread of respiratory virus infections including pandemic influenza.Published by
Centers for Disease Control and Prevention
Published
2017
Summary
Guidance for people with suspected or confirmed influenza virus infection with or at risk of severe illness from influenza virus infection, including those with zoonotic influenza A viruses known to cause severe illness such as H5N1.Published by
World Health Organization
Published
2022
Summary
Guidelines for the management of patients infected with highly pathogenic avian influenza (HPAI) H5N1 virus. UK focus may be less relevant to H5N1-endemic regions or limited-resource countries.Published by
UK Health Security Agency
Published
2021