Avian Influenza

Etiology

Avian influenza viruses (AIVs) cause disease in humans when a strain of the virus becomes adapted to a human host either by reassortment with influenza viruses from other species or by antigenic drift or both.[3] As noted previously, HPAI strains of the virus are thought to be activated in most host organ systems, while LPAI strains become activated in specific organs with appropriate protein modifying enzymes. This difference may account for some characteristic signs and symptoms of particular strains discussed below.

Epidemiology

Although other strains of avian influenza viruses (AIVs) are likely to have infected humans from time to time, the most well-known strains to cause infection are H5N1 and H7N9. To date, there have been no confirmed human cases of AIV infection in the United States, although there has been one confirmed death from AIVs in Canada.[4] H5N1 outbreaks have occurred mostly in the Middle East and Southeast Asia, although sporadic reports of infection have also come from West Africa.[4] H7N9 outbreaks have primarily occurred in the same regions. Unsurprisingly, AIV infection is most often found in people who have close contact with poultry, especially recently culled poultry. In China, H7N9 infection appears to occur more in older patients and H5N1 in younger patients, and both appear to occur more in men than in women.[5][6] While other AIVs do rarely infect humans, H5N1 and H7N9 are by far the most common, and at the moment, the others appear to be only sporadic. 

Pathophysiology

The binding of avian influenza viruses (AIVs) to human cells is mostly via specific receptors found more commonly in the respiratory tract.[7] The pathophysiology of avian influenza and that of normal influenza are different. Avian influenza involves more of the lower airways than human influenza. This involvement is probably due to differences in the hemagglutinin protein and the types of sialic acid residues to which the protein binds. Avian viruses prefer sialic acid alpha (2-3) galactose, which, in humans, is found in the terminal bronchi and alveoli. But human viruses prefer sialic acid alpha (2-6) galactose, which appears on epithelial cells in the upper respiratory tract. Interestingly, the receptors preferred by most AIVs, especially H7N9, are also found in the human eye, which may explain the conjunctival symptoms often seen with AIV infection.[8]

Once the AIV has entered the host cell, replication may be prolonged relative to endemic human influenza viruses. In the 1997 H5N1 outbreak, the median time from infection to the detection of the virus was 6.5 days, and in some patients, no virus was detectable for up to 16 days.[9]

Host immune response plays a role in pathogenicity, as inflammatory markers appear to be higher in patients who experience a more severe disease course, and the presence of inflammatory cells in damaged alveoli in post-mortem patient evaluation seems to support this suggestion.[9] The most common pathological organ failure in AIV-infected individuals is respiratory failure due to primary viral pneumonia, which appears to commonly be due to viral replication and host immune response producing diffuse alveolar damage as well as alveolar hemorrhage. There is some additional information in mouse studies that the virus may replicate and produce apoptosis in pre-Botzinger complex neurons, which are responsible for generating respiratory rhythm, and the damage caused to these neurons likely produces some of the ataxic breathing a respiratory collapse found in AIV infection.[10]

History and Physical

Clinical features of avian influenza infection are generally only known in patients requiring hospitalization. Because routine testing for avian influenza is not often necessary unless a patient presents with more severe symptoms, there is little evidence for clinical features or the prevalence of milder infections. Most patients who end up hospitalized present anywhere from 2 to 4 days after exposure but can begin over a week after transmission as well.[9]

Most patients present with symptoms consistent with a flu-like viral illness. In these patients, especially during a known avian influenza outbreak, a thorough history is necessary to evaluate for clues that the illness is due to avian influenza. Additionally, in patients with bird contact and uncharacteristically severe viral symptoms (encephalopathy or organ failure), higher suspicion should be had for avian influenza virus (AIV) infection. Patients that work in the poultry or culinary industries have frequent contact with birds and have greater opportunity to contact the active virus. Most patients with AIV infection have had contact with poultry.[11] Because environment-to-human and human-to-human transmission is theoretically possible with all AIVs and has confirmation in cases of H7N9 infection, even patients with no direct contact with birds can still acquire avian influenza.[12]

Different strains of the avian influenza virus appear to have different characteristic presentations. H5N1, for instance, usually has a presentation that includes fever and lower respiratory tract symptoms and occasionally a prodrome of non-bloody, non-inflammatory diarrhea. Other avian influenza viruses have other characteristic symptoms. H7N9 and other LPAI strains may more commonly be associated with conjunctivitis.[9]

Regardless of characteristic symptoms, if there is a current outbreak, a patient presenting with avian influenza is most likely to have the same strain as other infected patients in the area have.

Evaluation

Diagnosing avian influenza requires high clinical suspicion. In patients who present with viral syndromes and have risk factors such as recent live bird handling or poultry culling, there should be a high suspicion of the disease. Additional testing should evaluate for sequelae of avian influenza virus (AIV) infection, such as respiratory impairment and other organ dysfunction. As the disease can present as a severe respiratory illness, evaluation, and careful monitoring of a patient’s respiratory status should be undertaken for any patient with suspected or confirmed AIV infection. Respiratory intervention may include anywhere from supplemental oxygen to mechanical ventilation to ECMO (extracorporeal membrane oxygenation) in the most severe cases.

Rapid antigen testing for AIV does exist but is often falsely negative in confirmed cases. The preferred source of a sample for testing is a nasopharyngeal swab or aspirate, but other body fluids are usable if the nasopharyngeal swab or aspirate is not available.[13] Because the infection carries high mortality risk, a negative rapid antigen test should not rule out AIV infection when high suspicion exists. RT-PCR identification of the virus in viral cultures is the standard of care for diagnosis of AIV, and viral detection is typically possible within a few days of disease onset.[9]

Treatment / Management

Treatment of avian influenza usually consists of supportive care and antiviral medications.[2][9] The majority of care should aim at managing the sequelae of infection. For instance, patients with volume loss or possible electrolyte imbalances should receive volume resuscitation and treatment to correct imbalances. Patients with persistent fever should receive antipyretic medication. Patients with respiratory compromise should be placed on supplemental oxygen and monitored closely for signs of deterioration as these patients are at high risk of requiring intubation and mechanical ventilation.[2][9] As the severe disease can cause any range of organ dysfunction and failure, such signs should be closely monitored and aggressively treated to prevent further decompensation.(B3)

The World Health Organization released Rapid Advice Guidelines in 2007, outlining consensus treatment recommendations for H5N1 influenza outbreaks.[14] Similar recommendations can likely be used in avian influenza outbreaks due to other strains of the virus. These recommendations include neuraminidase inhibitors (especially oseltamivir) for strongly suspected or confirmed cases of H5N1. The recommendations also suggest avoiding M2 ion channel inhibitors such as amantadine and rimantadine as a single therapy unless neuraminidase inhibitors are not available or the virus is known to be resistant to neuraminidase inhibitors.(B3)

The WHO also made recommendations on chemoprophylaxis of those with possible viral exposure in the above guidelines. Of note, oseltamivir (75 mg daily) prophylaxis for 7 to 10 days after last known potential exposure for high-risk groups (household and close family contacts) receives a strong recommendation. Moderate and low-risk groups are not as strongly advised to receive chemoprophylaxis, although moderate risk groups require individual assessment.[14](B3)

Differential Diagnosis

Because avian influenza, like many viral illnesses, can present with a variety of symptoms that may be like other disease processes, a broad differential is necessary. For instance, for patients presenting with a headache with or without fever, a differential should include meningitis, intracranial bleeds, migraines, and other headache syndromes. For patients presenting with respiratory symptoms, other infectious upper and lower airway etiologies should be considered, including but not limited to:

• Bacterial pneumonia
• Streptococcal pharyngitis
• Asthma
• Chronic obstructive pulmonary disease (COPD)
• Pulmonary embolism

Additionally, in patients with shortness of breath or other possible cardiac involvement, pericarditis and myocarditis should be considered.

Pertinent Studies and Ongoing Trials

Because human cases of avian influenza are relatively rare and generally confined to individual, unique outbreaks, there has been little opportunity for research on treatment methods for infection, and most recommendations have as their basis on accepted treatment regimens for other types of influenza virus infections. There are, though, some research trials focusing on the efficacy of vaccines for AIV.[15][16][17][18][19] As real-world outcomes of vaccine trials for rare diseases are challenging to evaluate, studies generally assess the development of antibodies in humans or human cells after vaccine testing.

Prognosis

In patients requiring hospitalization for avian influenza, reported mortality is higher than 50% for all strains of avian influenza virus (AIV) infection combined, although more detailed data suggests H7N9 infection is less deadly with 35% mortality than H5N1 with a 60% mortality rate.[20][2] As noted previously, likely, not all patients affected by the virus present to a hospital, and there may be many more with milder symptoms and reduced mortality. Regardless, all current information suggests that the virus is dangerous when infecting humans, and the prognosis in hospitalized patients is generally poor.

Complications

Complications from avian influenza virus (AIV) infection result from either organ failure or damage, iatrogenic injury during treatment, or coinfection.[9] Because severe disease is common, as is widespread organ failure, long term complications should be anticipated. Long term respiratory compromise is common in patients requiring extensive mechanical ventilation, and chronic kidney disease is possible in patients with acute kidney injury from AIV. As with other viral illnesses, bacterial coinfection is possible and should merit consideration any time a patient’s condition changes during the disease course or if it worsens after an episode of improvement.