People with infection due to highly pathogenic avian influenza (HPAI) H5N1 virus present with similar symptoms of pneumonia caused by other infectious etiologies (including seasonal influenza A or B viruses and 2009 H1N1 virus). There is a wide spectrum of disease ranging from subclinical or only mild symptoms to severe respiratory compromise and death; however, most patients with HPAI A (H5N1) virus infection are severely ill, reflecting late clinical presentation and late antiviral treatment, identified through hospital-based case-finding.

Given that human infection with HPAI H5N1 virus is rare (even among people with high-risk exposures), diagnostic evaluation and therapy must consider alternative etiologies. If there is concern that a patient might have HPAI H5N1 virus infection, infection control precautions should be used, including face mask, goggles, disposable gown, and gloves.

Novel influenza A virus infections are a notifiable disease in the US and some other countries.


A history of direct contact or close exposure with animals (predominantly sick or dead poultry) or people suspected or confirmed to have HPAI H5N1 virus infection within the prior 7 days by a person with febrile respiratory illness should trigger consideration of HPAI H5N1 virus infection. A recent history of travel to an HPAI-H5N1 virus-affected country should also prompt consideration of HPAI H5N1 virus infection in the differential diagnosis of a patient presenting with fever and respiratory symptoms. A traveler who had returned to Canada after visiting China presented with fever, pleuritic chest pain, and abdominal pain, and progressed to lower respiratory tract disease with meningoencephalitis and died of HPAI H5N1 virus infection.[21]

Early illness is manifested by signs and symptoms consistent with a febrile upper respiratory tract infection. A dry or productive cough and dyspnea are common symptoms. Nonspecific symptoms consistent with influenza-like illness have been reported (including conjunctivitis, rhinorrhea, headache, sore throat, myalgia, and fatigue). Clinical progression to severe lower respiratory tract disease occurs in many patients during days 3 to 6. Clinically mild disease (fever and symptoms of upper respiratory infection) has been documented. At admission, most patients have fever and clinical findings similar to severe community-acquired pneumonia. Several nonspecific primary gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) have been reported in children and adults with HPAI H5N1 virus infection.

Most patients admitted to the hospital with HPAI H5N1 have severe lower-respiratory tract disease, and multiorgan dysfunction or failure (renal, respiratory, hepatic, and cardiac) can occur. Other reported complications include hemophagocytosis, refractory shock requiring vasopressor support, disseminated intravascular coagulation, spontaneous abortions in pregnant women, and encephalitis.

Physical exam

Physical exam findings in severe infection usually are consistent with severe pneumonia due to other etiologies and might include temperature ≥100.4°F (38°C), tachypnea, and abnormalities on chest auscultation (including rales, wheezing, and focal decreased breath sounds).[17] Less commonly, the exam may also show evidence of signs of atypical features (e.g., altered mental status, seizures, and febrile diarrheal illness progressing to pneumonia).

Mild illness with HPAI H5N1 virus infection may be indistinguishable from uncomplicated human influenza virus infection, especially in children. Physical exam findings include upper respiratory tract and constitutional signs and symptoms such as fever, cough, rhinorrhea, and/or malaise.

Initial investigations

Given the rarity of HPAI H5N1 virus infection, it is critical that diagnostic evaluation also includes workup for a broad range of more common disease processes that may also present as febrile respiratory illness, and investigation for endemic respiratory pathogens from the region where infection may have occurred.

First-line evaluation of patients suspected of having HPAI H5N1 virus infection should include the following.

  • Laboratory tests, including at least a complete blood count with differential, basic chemistries and hepatic enzymes, and a chest x-ray. 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 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 infection should be considered, as it is far more common than HPAI H5N1 virus infection.

  • Other respiratory virus testing may be considered in certain circumstances (e.g., respiratory syncytial virus in young children, multiple virus etiologies in immunocompromised patients). Patients presenting with atypical symptoms (e.g., gastrointestinal or neurologic) should receive a suitable workup directed at alternative etiologies for those processes.

We recommend that clinicians pursue alternative diagnoses whenever they encounter a patient they suspect has HPAI H5N1 virus infection. As always, workup should be directed toward abnormal clinical findings.

Specific viral testing

The recommended and definitive HPAI H5N1 diagnostic testing is by reverse transcription polymerase chain reaction (RT-PCR) of respiratory specimens, including real-time or conventional RT-PCR, using H5-specific primers and probes. As HPAI H5N1 virus strains continue to evolve, testing by RT-PCR using updated primers and probes is essential. However, RT-PCR for HPAI H5N1 virus is usually not available in clinical settings. Many regional public health laboratories, most national laboratories, and some private laboratories can perform RT-PCR for HPAI H5N1 virus. In nonintubated patients, the preferred respiratory specimens are oropharyngeal and nasal swabs. Oropharyngeal swabs have a higher diagnostic yield than other upper respiratory specimens. Nasal and nasopharyngeal swabs are preferred to detect other respiratory viruses, including seasonal influenza viruses. Healthcare workers collecting clinical specimens from patients with suspected HPAI H5N1 virus infection should follow recommended infection control precautions and use appropriate personal protective equipment.[76][77][78] Swabs with Dacron tips or aluminum or plastic shafts should be used. Using swabs with cotton tips or wooden shafts is not recommended because they may interfere with the RT-PCR assay. Ideally, multiple respiratory specimens for testing should be collected from multiple respiratory sites from patients with suspected HPAI H5N1 virus infection, including over multiple days because testing single specimens may miss detection of HPAI H5N1 virus. Intubated patients should also have endotracheal aspirates collected for HPAI H5N1 testing. Bronchoscopy and thoracentesis are not recommended procedures for the sole purpose of collecting clinical specimens for H5N1 testing, but if collected for other diagnostic purposes, bronchioalveolar lavage fluid specimens and pleural fluid can also be tested. Government public health organizations have many useful online resources to assist clinicians to determine whether a particular patient should have clinical specimens tested for HPAI 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 H5N1 virus infection. The RT-PCR test takes approximately 4 hours to produce preliminary results, but transport time and testing logistics may delay testing results. 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.

Commercially available, point-of-care, rapid influenza diagnostic tests are insensitive and not specific for HPAI H5N1 virus and, therefore, should not be used for diagnosis of HPAI H5N1.

Paired acute and convalescent sera, collected about 2 to 3 weeks apart and tested using specialized laboratory serologic methods, can potentially yield a retrospective diagnosis of HPAI H5N1 virus infection in a patient with clinically compatible illness, but cannot inform clinical management decisions.[76] All positive tests on human clinical specimens for HPAI H5N1 virus should be confirmed at a WHO H5 reference laboratory; the WHO also accepts positive H5 results from a limited number of WHO-designated national laboratories. Positive laboratory results for human infection with avian influenza A viruses (including HPAI H5N1 virus) should be reported to the WHO under international health regulations.

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