eMedicine Specialties > Emergency Medicine > Infectious Diseases

Avian Flu

Author: Ethan E Bodle, MD, MPH, Associate Physician, Department of Emergency Medicine, Kaiser Permanente East Bay Medical Center
Coauthor(s): David Yew, MD, Assistant Clinical Professor, Department of Surgery, University of Hawaii; Medical Director and Flight Physician, AirMed Hawaii/AirMed International
Contributor Information and Disclosures

Updated: Aug 10, 2009

Introduction

Background

Influenza viruses rank among the most common causes of respiratory tract infection worldwide, causing an average of 36,000 deaths in the United States each year. Although the usual strains of influenza that circulate in the annual influenza cycle constitute a substantial public health concern, far more lethal influenza strains than these have emerged 3 times in the last century. These deadly strains have produced global pandemics, the worst of which occurred in 1918. Called the Spanish flu, this event killed an estimated 500,000 people in the United States and 30-40 million people worldwide.

H5N1, a new avian influenza strain ("bird flu") discovered in 1997, likely emerged as a result of a reassortment of avian influenza genes. In addition to infecting birds, this new strain is highly virulent in humans. The first cases of human infection were observed during an outbreak of severe respiratory disease in Hong Kong in 1997, when a mortality rate of 30% was observed among 18 cases. Prompt and aggressive culling of poultry by the local government may have reduced the extent of the initial outbreak. However, after 1997, avian H5N1 influenza has spread throughout Asia and beyond and caused a growing number and wider distribution of human disease and deaths.

Pathophysiology

Types and strains of influenza viruses

Influenza viruses are encapsulated, negative-sense, single-stranded RNA viruses of the family Orthomyxoviridae. The core nucleoproteins are used to distinguish the 3 types of influenza viruses: A, B, and C. Influenza A viruses cause most human and all avian influenza infections.

Individual strains of influenza A are further identified on the basis of their location, species, and serial numbers. The species specificity of the influenza strains is partly due to the ability of a given hemagglutinin to bind to different sialic acid receptors on respiratory tract epithelial cells. Avian influenza viruses generally bind to alpha-2,3-sialic acid receptors, whereas human influenza viruses bind to alpha-2,6-sialic acid receptors. The current H5N1 strain of avian influenza is remarkable for also binding to human epithelium in vitro.

Since 1959 and prior to the current H5N1 epidemic, 10 incidents of human infection with avian influenza had been reported. However, all but the current H5N1 strain have caused minimal symptoms in humans.⁴ It is easily conceivable that additional point mutations in this strain could increase the efficiency of binding, uptake, and transmission in humans and result in a pandemic similar to the 1918 Spanish flu.

Reservoirs for avian influenza A

Natural reservoirs for avian influenza A are considered to be the waterfowl, including ducks and geese, in which most infections are believed to be asymptomatic. However, because these viruses can also infect and cause disease in domestic poultry and because of the potential economic implications, substantial attention has been given to avian influenza.

Most strains that infect poultry cause only minor illness. These strains are collectively called low pathogenic avian influenza virus (LPAIV). However, after infecting domestic poultry, some strains of LPAIV have become highly virulent and caused death in nearly all infected chickens. These emergent strains are referred to as highly pathogenic avian influenza virus (HPAIV), where highly pathogenic refers to the nature of the disease in birds. To date, HPAIV strains have occurred in only the H5 and H7 subtypes. Such HPAIV outbreaks required aggressive quarantining and culling measures to prevent major setbacks to poultry farming. The current highly pathogenic H5N1 strain is unique and alarming in that it is the only HPAIV known to cause clinically significant disease in humans.⁴

Antigenic drift and shift

Influenza A is a genetically labile virus, with mutation rates as high as 300 times that of other microbes.⁵ Changes in its major functional and antigenic proteins occur by means of 2 well-described mechanisms: antigenic drift and shift.

Antigenic drift is the process by which inaccurate viral RNA polymerase frequently produces point mutations in certain error-prone regions in the genes. These mutations are ongoing and are responsible for the ability of the virus to evade annually acquired immunity in humans. Drift can also alter the virulence of the strain.

Antigenic shift is less frequent than antigenic drift. In a shift event, influenza genes between 2 strains are reassorted, presumably during co-infection in a single host. Segmentation of the viral genome, which consisting of 10 genes on 8 RNA molecules, facilitates genetic reassortment. Antigenic shifts created the pandemic influenzas of 1957 due to H2N2 and of 1968 due to H3N2, and they produced the current avian influenza H5N1.

Because pigs have been susceptible to both human and avian influenza strains, many believe that combined swine and duck farms in some parts of Asia may have facilitated antigenic shifts and the evolution of previous pandemic influenza strains.

Transmission of H5N1

Avian influenza transmission to humans appears to occur predominantly as a result of direct contact with infected poultry. The risk is especially high during the slaughter, defeathering, and preparation of the birds for consumption. People at risk include those who are exposed to water and surfaces contamination by bird droppings.⁴

Frequency

United States

No cases of highly pathogenic H5N1 influenza have been reported in humans or birds in the United States. Frequently updated information on H5N1 avian influenza cases and pandemic flu preparedness can be found on the Centers for Disease Control and Prevention online resources (Avian Influenza [Bird Flu]).

Two case reports describe humans infected with another avian influenza virus, H7N2, in Virginia (in 2002) and in New York (in 2003); the patients had no symptoms but positive serologic results and mild respiratory symptoms, respectively.

The 1918 H1N1 influenza pandemic (Spanish flu) affected approximately 25% of people in the United States. (The avian origin of the 1918 influenza virus is the subject of ongoing investigation and debate.)

International

Between December 1, 2003, and July 1 2009, the World Health Organization (WHO) reported 436 laboratory-confirmed cases of avian H5N1 disease in humans. Documented cases have occurred in Azerbaijan, Cambodia, China, Djibouti, Egypt, Laos, Indonesia, Iraq, Nigeria, Pakistan, Thailand, Turkey, and Vietnam. Additional countries have identified the virus in wild birds and poultry.

Several hundred human cases are estimated to have occurred in the 1997 outbreak of avian H5N1 influenza in Hong Kong, including 18 laboratory-confirmed cases and 6 deaths.

The most current data on case counts and global distribution can be found in the WHO Web site (Avian influenza).

Mortality/Morbidity

According to WHO records, laboratory-confirmed avian H5N1 caused 262 human deaths worldwide (61% case-mortality rate) between December 1, 2003, and July 1, 2009. The mortality rate among those cared for in the most developed nations is significantly lower.

The following facts are offered for comparison:

• The 1918 H1N1 influenza pandemic caused 500,000-700,000 deaths in the United States. Almost 200,000 deaths of these deaths were recorded in October 1918 alone. Worldwide, an estimated 30-40 million deaths occurred. Although most people who die from other influenzas are young or elderly, most of those dying in this pandemic were aged 15-35 years.
• The 1957 H2N2 influenza pandemic (Asian flu) caused an estimated 70,000 deaths in the United States and 1-2 million fatalities worldwide.
• The 1968 H3N2 influenza pandemic (Hong Kong flu) caused an estimated 34,000 deaths in the United States and 700,000 to 1 million fatalities worldwide.
• According to the CDC, the annual human influenza A strains H1N1 and H3N2 cause a mean of 36,000 deaths and symptomatic cases in about 10-20% of the total US population.

Race

At present, the race of affected individuals is presumed to reflect only the geography of exposure.

Sex

Among WHO-confirmed cases to date, the male-to-female ratio is 0.9.

Age

• Cases have been reported in all age groups (range, 3 mo to 75 y), with a median age of 20 years.
• Most cases and the highest mortality rate (79%) have been observed in individuals aged 10-19 years.⁶  
• The age range affected resembles the epidemiologic age distribution of the 1918 influenza epidemic more than that of seasonal human influenza.

Clinical

History

• Human cases have had a mean incubation period (interval between exposure and the onset of symptoms) of 2-4 days, but it can be as long as 8 days.⁷
• Median interval between the onset of symptoms and hospitalization or death is 4 and 9 days, respectively.⁶
• About 94-100% of cases begin with a typical influenza syndrome, including high fever (temperature >38°C) and lower respiratory tract symptoms (cough and pleuritic pain). Headache, myalgia, and fatigue are also common.^8,7
• Dyspnea is reported in 76-100% of cases.⁷ Lower respiratory tract involvement appears to occur earlier with avian flu than with seasonal influenza. Dyspnea, shortness of breath, hoarseness, and copious sputum production may be presenting complaints.⁴
• Upper respiratory findings of sore throat or rhinorrhea occurred in only about half of confirmed cases.⁷
• GI symptoms, including diarrhea, nausea, and abdominal pain, are common early complaints occurring in 10-50% of patients.⁷ Nonbloody, watery diarrhea appears to be more common with avian flu than with human seasonal influenza.⁴
• Fatal encephalitis has been reported in at least 1 patient.⁹
• The incidence of asymptomatic or mild cases is uncertain. Seroprevalence studies demonstrated exposure in poultry workers but little exposure to health care workers caring for patients with avian flu.⁸

Physical

• High fever (temperature >38°C), tachypnea, and hypoxia may be noted at presentation.
• Signs of upper respiratory tract infection, including coryza, conjunctivitis, and pharyngitis, may be noted, but these findings are not necessarily present. Conjunctivitis appears to be less common with H5N1 infection than with seasonal influenza or with infection due to other strains of avian influenza in humans.
• Pulmonary rales may be heard early. Patients typically have a productive cough, occasionally with blood-tinged sputum.
• Diarrhea is relatively common. Abdominal pain and vomiting are relatively infrequent.
• From a review of cases in 4 countries, the clinical course progressed to acute respiratory distress syndrome (ARDS) and respiratory failure in 70-100% of patients.⁸  The mean time to the development of ARDS was 6 days. Lymphopenia at presentation is a significant predictor of the progression to ARDS and death (see Lab Studies).
• Severe cases may progress to multiorgan failure. In a study of 12 hospitalized patients with confirmed H5N1 influenza, 75% had respiratory failure, 42% had cardiac failure, and 33% had renal failure.⁸

Causes

The primary risk factor for human infection with avian H5N1 influenza virus is direct contact with diseased or deceased birds infected with it. Contact with excrement from infected birds or contaminated surfaces or water are also considered mechanisms of infection. Close and prolonged contact of a caregiver with an infected person is believed to have resulted in at least 1 case. Other specific risk factors are not apparent given the few cases to date.

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