Approach
People with infection due to highly pathogenic avian influenza (HPAI) A(H5N1) virus typically present with similar signs and symptoms of pneumonia caused by other infectious aetiologies (including seasonal influenza A or B viruses). There is a wide spectrum of disease ranging from sub-clinical or only mild symptoms (e.g., upper respiratory tract symptoms, conjunctivitis) to severe respiratory compromise and multi-organ failure, which can lead to death. However, most patients with HPAI A(H5N1) virus infection reported since 1997 and before the 2024-2025 US outbreak have been severely ill, reflecting late clinical presentation and late initiation of antiviral treatment, identified through hospital-based case-finding.
Consider the possibility of infection in anyone showing signs or symptoms of acute respiratory illness or conjunctivitis who has a relevant exposure history.[41]
Given that human infection with HPAI A(H5N1) virus is rare (even among people with high-risk exposures), diagnostic evaluation and therapy must consider alternative aetiologies. See Differential diagnosis.
If there is concern that a patient might have HPAI A(H5N1) virus infection, infection prevention and control precautions (i.e., patient isolation and standard, contact, and airborne precautions including eye protection) should be used.
Human infection with an avian influenza A virus is a notifiable disease under the World Health Organization’s (WHO) International Health Regulations. Cases are reportable to the WHO and local or national public health departments should be contacted for guidance. Many local health departments can directly assist clinicians to determine which people need testing, to facilitate testing, and to assist with case management.
History
A history of direct contact (touching) or close exposure with animals (predominantly sick or dead poultry) or people suspected or confirmed to have HPAI A(H5N1) virus infection within the prior 7-10 days by a person with febrile respiratory illness should trigger consideration of HPAI A(H5N1) virus infection.[119][120] A recent history of travel to a country or area where HPAI A(H5N1) virus has been documented in wild birds, commercial or backyard poultry, or terrestrial or marine mammals, with relevant exposures (e.g., to sick/dead animals) should also prompt consideration of HPAI A(H5N1) virus infection in the differential diagnosis of a patient presenting with fever and respiratory symptoms.
Early illness is manifested by signs and symptoms consistent with a febrile upper respiratory tract infection. A dry or productive cough and dyspnoea are common symptoms. Non-specific symptoms consistent with influenza-like illness have been reported (including conjunctivitis, rhinorrhoea, headache, sore throat, myalgia, and fatigue). Clinical progression to severe lower respiratory tract disease occurs in many patients during days 3-6.[26] Clinically mild disease (fever and symptoms of upper respiratory infection) has been documented.[30][31][32] In human cases linked to the dairy cattle outbreak in the US in 2024-2025, some dairy farm workers with evidence of recent infection reported no symptoms.[34] At hospital admission, most patients have fever and clinical findings similar to severe community-acquired pneumonia.[33] Several non-specific primary gastrointestinal symptoms (abdominal pain, vomiting, diarrhoea) have been reported in children and adults with HPAI A(H5N1) virus infection.
Most patients admitted to the hospital with HPAI A(H5N1) virus infection have severe lower respiratory tract disease, and multi-organ dysfunction or failure (renal, respiratory, hepatic, and cardiac) can occur. Other reported complications include haemophagocytosis, refractory shock requiring vasopressor support, disseminated intravascular coagulation, spontaneous abortions in pregnant women, and encephalitis.
Physical examination
Physical examination findings in severe disease usually are consistent with severe pneumonia due to other aetiologies and might include temperature ≥38°C (≥100.4°F), tachypnoea, and abnormalities on chest auscultation (including rales, wheezing, and focal decreased breath sounds). Less commonly, the examination may also show evidence of signs of atypical features (e.g., altered mental status, seizures, and febrile diarrhoeal illness initially complicated by progressing to pneumonia).
Mild illness with HPAI A(H5N1) virus infection is clinically indistinguishable from uncomplicated human influenza virus infection , especially in children. Physical examination findings include upper respiratory tract and constitutional signs and symptoms such as fever, cough, rhinorrhoea, and/or malaise.
Initial investigations
Given the rarity of HPAI H5N1 virus infection, it is critical that diagnostic evaluation also includes work-up for a broad range of more common disease processes that may also present as febrile respiratory illness, including respiratory viruses, and investigation for endemic respiratory pathogens from the region where infection may have occurred. Testing for other causes of acute respiratory illness, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), should be considered depending on the local epidemiology of circulating respiratory viruses. See Differential diagnosis.
First-line evaluation of patients suspected of having HPAI A(H5N1) virus infection should include the following.
Laboratory tests, including at least an full 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 dyspnoea 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 co-infection. Seasonal influenza A or B virus 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 aetiologies 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 neurological) should receive a suitable work-up directed at alternative aetiologies for those processes.
Clinicians should pursue alternative diagnoses whenever they encounter a patient they suspect has HPAI A(H5N1) virus infection. As always, work-up should be directed toward abnormal clinical findings.
Specific viral testing
Perform testing on people who meet epidemiological criteria and either clinical or public health response criteria.[119] For case definitions, see Criteria.
In the context of the current outbreak in the US, as of 16 January 2025, the Centers for Disease Control and Prevention (CDC) recommends routinely testing all patients with suspected influenza and to expedite the subtyping of influenza A-positive specimens from hospitalised patients, particularly those in the intensive care unit. Subtyping should be performed as soon as possible following admission, ideally within 24 hours. The goal of this approach is to prevent delays in identifying infections.[121]
Testing of symptomatic human cases of suspected novel influenza A virus infection should be referred to the nearest public health laboratory.[122] Testing of asymptomatic people is not routinely recommended, but may be considered as part of ongoing public health investigations (e.g., workers with a high risk of exposure to infected animals who do not report wearing the recommended personal protective equipment, close contacts of a confirmed case).[41]
Reverse transcription polymerase chain reaction (RT-PCR)
The recommended and definitive diagnostic testing is real-time RT-PCR of respiratory specimens.[122][123] 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 specialised public health laboratory.[124]
RT-PCR for HPAI A(H5N1) virus may not be available in some 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.
Specimen collection
Healthcare workers should follow recommended infection control precautions and use appropriate personal protective equipment when collecting clinical specimens, including respiratory and eye protection.[125]
The preferred specimens in non-intubated 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.[122][126] A conjunctival swab (with a nasopharyngeal swab) and/or nasal swab combined with an oropharyngeal swab should be collected if the person has conjunctivitis (with or without respiratory symptoms). Sputum, if obtainable from a patient who is not intubated, could also be collected for testing.[41][122]
The preferred specimens in intubated patients or patients with severe lower respiratory tract illness are lower respiratory tract specimens (e.g., endotracheal aspirate, bronchoalveolar lavage fluid). These specimens have a higher yield for detecting HPAI A(H5N1) virus.[122][126]
Multiple respiratory specimens should be collected from different sites on at least two consecutive days for hospitalised patients, because testing single specimens may miss detection of HPAI A(H5N1) virus.[122]
Swabs with a synthetic tip (e.g., Dacron®, polyester) and an aluminum or plastic shaft should be used. Swabs with cotton tips or wooden shafts, and calcium alginate swabs are not recommended because they may interfere with the test.[122][126]
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.[122]
Other investigations
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 virological surveillance, antigenic monitoring for vaccine strain selection, and assessment and analyses of viral characteristics such as genetic re-assortment, receptor binding affinity, and antiviral susceptibility.
Serological 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 specialised 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.
Commercially available influenza molecular assays available in clinical settings are not specific and do not differentiate between seasonal, avian, or swine influenza A viruses.
All positive tests on human clinical specimens for influenza A(H5) virus should be confirmed at a WHO H5 reference laboratory; the WHO also accepts positive A(H5) results from a limited number of WHO-designated national laboratories. Positive laboratory results for human infection with avian influenza A viruses, including HPAI A(H5N1) virus, should be reported to the WHO under the International Health Regulations.[126]
Government public health organisations have many useful online resources to assist clinicians to determine whether a particular patient should have clinical specimens tested for HPAI A(H5N1) virus, and they have health officers available to consult and assist clinicians in the evaluation, testing, and case management of suspected or confirmed human HPAI A(H5N1) virus infection.
Starting empirical antiviral treatment
The CDC recommends starting empirical antiviral treatment immediately for patients with suspected HPAI A(H5N1) virus infection. Antiviral treatment should not be delayed by diagnostic specimen collection or pending laboratory testing results.[112]
However, the WHO recommends starting antiviral treatment prior to receiving test results only if results will be delayed for more than 24 hours (antiviral treatment can be stopped if the test is negative).[123]
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