Avian influenza is a virus originating in birds that has the capacity to infect humans. The prior influenza pandemics of the 20th century (from the devastating 1918 pandemic [H1N1], in which 40 to 100 million people died, to the lesser pandemics of 1957 [H2N2] and 1968 [H3N3], of 1 to 6 million deaths) were caused by highly virulent, efficiently transmitted influenzas that evolved from avian strains.

The highly pathogenic avian influenza A (H5N1), which emerged in 1997 in Hong Kong and is capable of only incidentally infecting humans, had threatened to bring another pandemic flu. It has infected over 850 persons worldwide and has a high case fatality rate of 55% (62 total cases in 2011) as it spread via migrating waterfowl from Asia to Europe and Africa.

However, the worldwide epidemic of a novel influenza strain in 2009 to 2010 with millions of cases was not with this virus but with the influenza A (H1N1) virus, which was a reassortment human-swine-avian virus.

In 2013, a new novel avian influenza emerged in China: H7N9, of which there were >1300 lab-confirmed cases. To date, there is no evidence of sustained transmission among humans for this virus, but there have been a few small clusters. The number of new cases was only 3 in 2017 to 2018. See related topic “Influenza.”

Bird flu

Influenza, avian

Pandemic flu

Avian influenza A H5N1 is an influenza virus related to those that bring our yearly influenzas, against which populations are routinely vaccinated. Influenza viruses are enveloped ribonucleic acid (RNA) viruses with segmented genomes and great antigenic diversity. They are categorized by their core proteins (A, B, C), species of origin (avian, swine, human), geographic site of isolation, serial number, and influenza subtypes based on the major antigenic surface glycoproteins, hemagglutinin (HA), and neuraminidase (NA). Example: H5N1 refers to hemagglutinin subtype 5 and neuraminidase subtype 1.

Often human and avian viruses meet and resort in a pig respiratory system. Southeast Asia is often the birthplace of new flu strains because birds, pigs, and people live in close proximity. It is where avian influenza A H5N1 and H7N9 emerged, first infecting domestic poultry and then wild birds that migrated across Eurasia. It is transmitted directly from birds to their keepers. Antigenic drift or shift may eventually allow avian influenza A H5N1 to gain the ability to be easily transmissible from human to human, transforming it from a highly virulent influenza strain to a pandemic flu.

• Presenting features include fever of at least 100.4° F (38° C) with leukopenia or lymphopenia nearly always followed by viral pneumonia with escalating respiratory distress.
• Ventilatory support is often required within 48 hr of hospitalization for acute respiratory distress syndrome (ARDS).
• Symptom onset is 2 to 5 days after exposure, longer than with human influenza.
• Respiratory symptoms may also be accompanied by watery diarrhea.
• Complications include respiratory failure, renal dysfunction, cardiac compromise, pulmonary hemorrhage, pneumothorax, and multiorgan failure. A common cause of death is superinfection with bacterial pneumonias.

H5N1 resists host antiviral cytokines, inducing excessive host proinflammatory responses. It may cause death by “cytokine storm” rather than by inherent pathogenicity. It attaches to sialic acid molecules via an α2-3 galactose receptor (common in birds) also found in human alveoli, leading to heavy damage to lower lungs. It causes severe pulmonary injury with diffuse alveolar damage. In the bone marrow, there is a reactive histiocytosis with hemophagocytosis that may lead to pancytopenia.

Atypical pneumonia, typical respiratory virus infections (e.g., influenza, respiratory syncytial virus), severe acute respiratory syndrome, upper respiratory infection with conjunctivitis (e.g., adenovirus). Clinical symptoms are indistinguishable from those of other illnesses.

Comprehensive travel, occupational, and epidemiologic history

• Aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, complete blood count should be performed.
• Throat swab within 3 days of onset of symptoms to be sent for viral culture and polymerase chain reaction assay for avian influenza A (H5N1) RNA with appropriate biosafety precautions. The throat swab is more effective than nasal swabs because avian influenza preferentially infects the throat and lower respiratory tract. In the U.S., the FDA has approved the release of influenza H/A5 (Asian lineage) Virus real-time reverse transcription-PCR primer and probe set for more than 140 labs in 50 states, which will return preliminary results in 4 hr. An rRT-PCR has also been developed for the influenza A H7N9 virus.
• High-risk patients who must be tested include those with history of travel within 10 days of symptom onset to a country with documented H5N1 avian flu as well as patients with radiographically confirmed pneumonia, ARDS, or severe respiratory illness without an alternate etiology.
• Low-risk patients are those who have contact with domestic poultry or contact with people who have traveled to a country with documented H5N1 avian flu who have fever >100.4° F (>38° C) and cough, sore throat, and shortness of breath.

• Chest radiography detects infiltrates a median of 7 days after onset of fever. They may be diffuse, multifocal, or patchy infiltrates, or interstitial infiltrates or segmental or lobular consolidation. Progression to respiratory failure is indicated by diffuse bilateral ground-glass infiltrates.
• See “Imaging Studies” in the “Acute Respiratory Distress Syndrome” topic.

• N95 particulate masks prevent person-to-person transmission of H5N1. Surgical masks also likely prevent transmission of the virus as was seen in the H1N1 pandemic.
• In preparation for pandemic flu, increase worldwide surveillance and disease reporting, kill infected birds, increase the numbers of available intensive care unit beds with mechanical ventilators and increase emergency capacity, educate medical personnel and the public, and produce vaccines.
• In response, use influenza surveillance, social distancing (school closures), travel restrictions, quarantine, respirator masks, communications networking, and international teamwork to cordon off affected areas.

• The neuraminidase inhibitor oseltamivir can reduce the severity and duration of symptoms if treatment is initiated in the first 48 hr after symptom onset.
  1. Treatment: Adults: 75 mg PO twice daily for 5 days
  2. Postexposure prophylaxis: 75 mg PO daily for 7 to 10 days
• H5N1 demonstrates amantadine and rimantadine resistance.
• Peramivir: An IV neuraminidase inhibitor was FDA approved in December 2014. It has a long half-life, allowing for once daily dosing. It is effective against a variety of influenza A and B subtypes.

See “NonpharmacologicTherapy.”