Avian influenza overview
For more information about seasonal human influenza virus that is not associated with animal exposure, see InfluenzaEditor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief:  Yazan Daaboul, M.D., Serge Korjian M.D., Gerald Chi, M.D.

# Overview
Avian influenza is caused by influenza A virus. Influenza belongs to the Orthomyxoviridae family. Influenza A is an enveloped, pleomorphic (spherical and filamentous forms) virus that contains a linear, segmented (8 segments), negative-sense, single-stranded RNA genome. The genome is composed of 8 segmented genes that encode 11 proteins. The World Health Organization (WHO) reports an incidence of 3 to 5 million cases of severe influenza disease annually, including 250,000 to 500,000 deaths every year. The majority of cases of avian influenza infection in humans have resulted from contact with infected poultry or contaminated environments. Human-to-human transmission is still rare and inefficient. Influenza virus is transmitted in aerosols of respiratory secretions. The hemagglutinin (HA) protein on the viral surface functions as a receptor binding site and binds to host receptors that contain sialic acid to allow viral fusion to the host cell in the respiratory tract, while the neuraminidase (NA) enzyme cleaves progeny virions from host cell receptors. Viral proteins are, at least in part, responsible for down-regulation of cytotoxic T-cell activity, evasion of immune responses, and activation of cytokines and pro-inflammatory mechanisms that contribute to host tissue injury. Classification of avian influenza may be based on either the pathogenicity of the virus (low pathogenicity vs. high pathogenicity) or the viral genetic subtypes (H5 vs. H7 vs. H9). Following exposure to the avian influenza virus, an incubation period of 2 to 3 days for H5N1 and 2 to 8 days for H7N9 precedes the onset of symptoms. The majority of patients present with with high-grade fever, cough, headache, sore throat, vomiting, diarrhea, and abdominal pain. Approximately 50% of patients with avian influenza develop severe complications such as acute respiratory distress syndrome, acute kidney injury, sepsis, and multiple organ dysfunction syndrome. Some strains of avian influenza virus are associated with a mortality rate as high as 60% of infected individuals. Patients without complicated disease usually recover within 3 to 5 days with no sequelae. Diagnostic tests available for avian influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR), immunofluorescence assays, or other molecular assays.  Neuraminidase inhibitors can reduce the duration of viral replication and improve survival among patients with avian influenza.  In cases of suspected avian influenza, oseltamivir, zanamivir, or peramivir should be administered as soon possible, preferably within 48 hours of symptom-onset. Seasonal influenza (human influenza) vaccination will not prevent infection with avian influenza A viruses, but can reduce the risk of co-infection with human and avian influenza A viruses. The optimal way to prevent infection with avian influenza A viruses is to avoid sources of exposure, such as infected poultry, whenever possible.

# Historical Perspective
Avian influenza was first described by Perroncito in 1878 in northern Italy following an outbreak of contagious disease of poultry. In 1918, the avian-descended influenza A H1N1 caused the first major human influenza pandemic. The first avian influenza A H5N1 virus infection in humans was described in 1997 in Hong Kong, where 18 cases were documented (including 6 deaths). The first human-to-human transmission of avian influenza infection was described in 2003 during the outbreaks in Southeast and Central Asia.

# Pathophysiology
All reported cases of avian influenza are caused by influenza A virus. The genome of influenza A consists of 8 RNA gene segments, which encode 11 proteins, including hemagglutinin, neuraminidase, non-structural proteins, matrix proteins, polymerase proteins, and nucleoprotein). Influenza virus is transmitted in aerosols of respiratory secretions. The HA protein on the viral surface functions as a receptor binding site and binds to host receptors that contain sialic acid to allow viral fusion to the host cell in the respiratory tract. Following fusion, viral replication typically takes place within 1 day, and polymerase proteins and nucleoproteins are involved in viral replication, whereas the matrix protein is responsible for viral assembly prior to viral release via cytolytic or apoptotic mechanisms. Viral proteins are, at least in part, responsible for down-regulation of cytotoxic T-cell activity, evasion of immune responses, and activation of cytokines and pro-inflammatory mechanisms that contribute to host tissue injury. Avian influenza undergoes antigenic drifts and shifts that ultimately result in genetic reassortment and capacity to reinfect the same host.

# Classification
To date, only influenza type A has been associated with avian influenza. Neither influenza B nor influenza C is associated with avian influenza. Classification of avian influenza may be based on either the pathogenicity of the virus (low pathogenicity vs. high pathogenicity) or the viral genetic subtypes (H5 vs. H7 vs. H9).

# Cause
Avian influenza is caused by influenza A virus. Neither influenza B nor influenza C causes avian influenza. Influenza belongs to the Orthomyxoviridae family. Influenza is an enveloped, pleomorphic (spherical and filamentous forms) virus that contains a linear, segmented (8 segments), negative-sense, single-stranded RNA genome. The genome is composed of 8 segmented genes that encode 11 proteins.

# Differential Diagnosis
Avian influenza should be differentiated from the following diseases or pathogens that cause upper or lower respiratory tract infection or flu-like illness, such as other influenza viruses, such as human or swine influenza, other viral, bacterial, fungal, and parasitic agents that are typically associated with nasopharyngeal and respiratory tract infections, and non-infectious causes, such as asthma, chronic obstructive pulmonary disease (COPD), drug adverse effects, and cardiac causes.

# Epidemiology and Demographics
The World Health Organization (WHO) reports an incidence of 3 to 5 million cases of severe influenza disease annually, including 250,000 to 500,000 deaths every year. The case fatality rate per outbreak is highly variable and may range from less than 1 to more than 200 per 100,000 cases. Influenza may infect patients of all age groups, but elderly patients > 65 years, young children (especially patients < 2 years of age), and adolescents are at high risk of developing complications and death. There is no racial or gender predilection for avian influenza infection.

# Risk Factors
The majority of cases of avian influenza infection in humans have resulted from contact with infected poultry, or contaminated environments. Human to human transmission is still rare and inefficient.

# Natural History, Complications, and Prognosis
Following exposure to the avian influenza virus, an incubation period of 2 to 3 days for H5N1 and 2 to 8 days for H7N9 delays the onset of symptoms. The majority of patients present with with a high grade fever, cough, headache, sore throat, vomiting, diarrhea, and abdominal pain. Approximately 50% of patients with avian influenza develop severe complications such as acute respiratory distress syndrome, renal failure, sepsis, and multiple organ dysfunction syndrome. Some strains of avian influenza virus are associated with a mortality rate as high as 60% of infected individuals. Patients without complicated disease usually recover within 3 to 5 days with no sequelae.

# Diagnosis

## History and Symptoms
Avian influenza virus infection is associated with a wide range of illness from conjunctivitis only, to influenza-like illness, to severe respiratory illness (e.g. dyspnea, pneumonia, acute respiratory distress, viral pneumonia, respiratory failure) with multi-organ disease, sometimes accompanied by nausea, abdominal pain, diarrhea, vomiting, and occasionally neurologic impairment (altered mental status or seizures).

## Physical Examination
Physical examination may reveal fever, tachycardia, tachypnea, and other findings suggestive of complications affecting multiple organ systems.

## Laboratory Findings
Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR), immunofluorescence assays, and other molecular assays. Sensitivity and specificity of any test for influenza might vary by the laboratory that performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens. As with any diagnostic test, results should be evaluated in the context of other clinical and epidemiologic information available to healthcare providers.

## Chest X-ray
Chest radiograph may demonstrate findings suggestive of acute respiratory distress syndrome or pneumonia.

## Other Diagnostic Studies
Other diagnostic test for influenza include molecular assays, such as RT-PCR. New technologies being pursued include those that examine influenza viruses at the molecular level. By examining the genetic makeup of influenza viruses, such tests could identify both the virus type and subtype simultaneously.

# Treatment

## Medical Therapy
Neuraminidase inhibitors can reduce the duration of viral replication and improve survival among patients with avian influenza. In cases of suspected avian influenza, oseltamivir, zanamivir, or peramivir should be administered as soon possible, preferably within 48 hours of symptom onset.

## Primary Prevention
Seasonal influenza vaccination will not prevent infection with avian influenza A viruses, but can reduce the risk of co-infection with human and avian influenza A viruses. The optimal way to prevent infection with avian influenza A viruses is to avoid sources of exposure whenever possible. Most human infections with avian influenza A viruses have occurred following direct close or prolonged contact with sick or dead infected poultry. Chemoprophylaxis with influenza antiviral medications can be considered for all exposed persons. Decisions to initiate antiviral chemoprophylaxis should be based on clinical judgment, with consideration given to the type of exposure and to whether the exposed person is at high risk for complications from influenza.