AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Influenza viruses rank among the most common causes of respiratory tract infection worldwide, causing a mean of 36,000 deaths in the United States each year. Although the annual influenza cycles substantially affect public health, human influenza strains far more lethal 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, since 1997, avian H5N1 influenza has spread throughout Asia and beyond, and it is causing a growing number and distribution of human disease and deaths.

At present, the poor transmissibility of the virus from human to human limits the extent of disease due to avian H5N1 influenza. However, as the virus is continuing to undergo genetic changes, the possibility of a devastating human pandemic emerging is real. In support of this concern is recent, albeit controversial, research suggesting that the great pandemic influenza of 1918 may have emerged because of processes similar to what is being observed with H5N1 now.^{1, 2} Extensive research and preparedness measures are under way at international and local levels to prevent or ameliorate the affect of a new human influenza pandemic.

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.

Subtypes of influenza A are identified by means of 2 surface glycoproteins hemagglutinin and neuraminidase. Hemagglutinin and neuraminidase are critical for virulence, and they are major targets for the neutralizing antibodies of acquired immunity. Hemagglutinin binds to respiratory epithelial cells, allowing cellular infection. Neuraminidase cleaves the bond that holds newly replicated virions to the cell surface, permitting the spread of the infection.³ Major variants of these viral glycoproteins are numbered. All 16 hemagglutinins and 9 neuraminidases infect wild waterfowl. Subtypes of human influenza virus identified to date contain only hemagglutinins 1, 2, and 3 and neuraminidases 1 and 2.

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 June 29, 2007, the World Health Organization (WHO) reported 317 laboratory-confirmed cases of avian H5N1 disease in humans. Documented cases have occurred in Azerbaijan, Cambodia, China, Djibouti, Egypt, Laos, Indonesia, Iraq, Nigeria, 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 151 human deaths worldwide (59% case-mortality rate) between December 1, 2003, and October 16, 2006. 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

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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 are 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.

DIFFERENTIALS

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Other Problems to be Considered

Severe acute respiratory syndrome (SARS)
Adenoviral infection
Parainfluenza viral infection
Arenaviral infection
Cytomegaloviral infection

WORKUP

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Lab Studies

• Hematology (CBC) may be more clinically useful in avian influenza than in seasonal influenza disease.
• • Leukopenia (white blood cell count of 454-4900/mm³), especially lymphopenia, is common and is observed in 50-80% of patients.⁷
  • In at least one study, lymphopenia at presentation (absolute lymphocyte count <1500/mm³) was a significant predictor of the progression to ARDS.⁹
  • More than half of patients will have mild-to-moderate thrombocytopenia.
• Liver function tests (LFTs) may be useful in differentiating illness from other febrile tropical diseases. Aminotransferase levels are elevated in more than half of all patients with avian influenza H5N1 infection.⁴
• In addition to thrombocytopenia, some patients with severe disease will develop disseminated intravascular coagulation (DIC), as shown on coagulation studies.⁴
• A basic metabolic panel is generally required in the care of all seriously or critically ill patients. Abnormalities in renal function may herald the progression to organ failure.
• According to a 2006 CDC Health Update, clinicians should attempt to specifically identify avian H5N1 influenza in the patients with all of the characteristics listed below. Testing may be considered in discussion with public health authorities in patients who have only some of these characteristics.
• • Severe illness requiring hospitalization
  • Temperature >38°C
  • Radiographically confirmed pneumonia, ARDS, or other severe respiratory illness for which an alternate diagnosis has not been established
  • At least 1 potential exposure in the last 10 days (including exposure to sick birds, raw poultry, or a patient potentially infected with H5N1 in an affected country), close contact with a patient with confirmed H5N1 infection, or work in a laboratory dealing with H5N1
• The best specimens are material collected with oropharyngeal swabs, material from bronchoalveolar washes, or tracheal aspirates. Specimens from nasopharyngeal swabs are acceptable, but they may contain a low quantity of the virus. Specimens should be collected in the first 3 days of illness.
• The H5N1 virus is best identified by conducting an H5N1-specific reverse-transcriptase polymerase chain reaction (RT-PCR). This assay can be performed at all state and many local public health laboratories.
• Viral culture of H5N1 should be performed only in a biosafety level 3 laboratory. Even if avian influenza is suspected, cultures should not be ordered without guidance from a public health laboratory.
• A serologic test for avian H5N1 influenza can be performed, but this is a second-line study.
• Rapid influenza tests do not detect H5N1 avian influenza.¹⁰

Imaging Studies

• Pulmonary infiltrates are seen in almost all patients.
• The wide variety of radiographic characteristics range from diffuse or patchy infiltrates to lobar multilobar consolidation.

TREATMENT

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Prehospital Care

• Prehospital care is predominantly supportive.
• Supplemental oxygenation to manage respiratory symptoms or objective hypoxia may be needed.
• Ventilatory support with a bag-valve-mask device and/or with field intubation may be required if the patient is in respiratory failure.
• Intravenous access should be obtained, and a bolus of a crystalloid can be administered to support hemodynamic stability.
• Attention should be given to the appropriate use of personal protective equipment (PPE) by the prehospital providers and advance notification should be given to the hospital regarding the potential need for patient respiratory isolation. General guidelines in low-risk areas are that patients with fever and respiratory complaints should wear a standard mask, if tolerated, to decrease airborne droplets.

Emergency Department Care

• Diagnostic considerations in the emergency department include the following.
• • Differentiate viral pneumonia from bacterial pneumonia or noninfectious causes of respiratory distress, such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary edema, and aspiration pneumonitis.
  • Assess comorbidities that might be predictive of a poor outcome in patients with seasonal influenza pneumonia.
  • Obtain a history, which may be consistent with exposure to avian influenza, and note the time of exposure and symptom onset.
• Initial interventions depend on the severity of the presenting illness.
• • Administration of neuraminidase inhibitors is currently the only specific therapy for human H5N1 disease. Early administration of this agent appears to be critical for clinical benefit.
  • Because diagnostic uncertainty is likely, management may include the administration of broad-spectrum antibiotics and aggressive fluid resuscitation to manage clinical signs of sepsis.
• If H5N1 influenza is suspected and if the patient is intubated, attend to proper precautions against infectious disease. Individuals who have close contact with the patient should wear N95 masks with ventilatory outflow.

Consultations

A pulmonary specialist, a critical care specialist, an infectious disease specialist, and the staff of the local public health department may all be consulted in cases of suspected H5N1 influenza. Clinical laboratory personnel should also be informed before potential H5N1 isolates are sent to them. In addition, hospital infection-control officers should be involved early in the care of any patient who might have avian flu.

MEDICATION

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Data from tissue cultures and animal models of infection with avian H5N1 influenza suggest that treatment with neuraminidase inhibitors should be beneficial. However, human data are inadequate to determine their effectiveness at present.

Sequencing studies of H5N1 viral isolates from Thailand and Vietnam indicate resistance to treatment with the M2 ion channel inhibitors amantadine and rimantadine.

Findings from ongoing research suggest that overactivation of cytokine cascades may contribute to the severity of systemic inflammatory response syndrome (SIRS). Agents that block individual cytokines may provide future options for pharmacologic therapy.

Additional care is supportive and symptomatic.

For additional information on treatment of avian flu, see Medscape's article "World Health Organization Updates Guidelines for Avian Influenza Virus Management".

Drug Category: Antivirals

Neuraminidase inhibitors act directly on the viral proteins, decreasing the virulence of infection.

FOLLOW-UP

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Further Inpatient Care

• In the absence of clinical improvement, the current recommendation is to prolong treatment with neuraminidase inhibitors to 7-10 days and to increase the dosage. However, adverse effects of oseltamivir increase at dosages of more than 300 mg/day in adults.⁴
• If proper handling of biologic specimens can be ensured, repeat studies of the viral load, susceptibilities, and drug levels to monitor the response to therapy.

Deterrence/Prevention

• Controlling influenza in birds: At present, highly pathogenic H5N1 avian influenza is predominantly a disease of birds. However, controlling the disease in birds is important because of its potential economic effects on poultry farming. Control may also decrease the opportunity for a pandemic flu strain to emerge. In addition, control of the H5N1 strain in birds decreases the likelihood of direct human exposures to infected birds and, thus, zoonotic cases in humans.
• Culling of infected and exposed birds: In the 1997 outbreak of H5N1 disease in Hong Kong, aggressive government-ordered culling of chickens is believed to have limited the initial expansion and spread of the virus. Vietnam is similarly praised for having more success than its adjacent countries in containing the disease with aggressive testing and culling of poultry.
• Sanitation: Proper disposal of carcasses and bird excrement are critical in limiting bird-to-bird and bird-to-human spread of disease. High concentrations of virus have been demonstrated in droppings obtained from chickens infected with H5N1. Bathing in water contaminated with droppings is suspected to be one mechanism of human exposure. In economically poor, rural settings, death of individual chickens is common, and H5N1 illness may be frequently unrecognized and unreported.
• Quarantine: In the past, strict quarantining of commercial farms has limited the spread of HPAIV strains other than H5N1. Today, the importation of any bird from affected countries is prohibited. (See the CDC publication Embargo of Birds from Specified Countries.) Quarantines work relatively poorly in rural settings, where animals are allowed to run free among human living quarters and between farms. Furthermore, the presence of H5N1 in wild birds, especially migratory species, limits the extent to which quarantining can be effective over the long term.⁴
• Travelers: Because avian influenza is rare in humans, the CDC does not currently recommend against travel to any country affected by H5N1. In countries where H5N1 has been found, travelers should avoid visiting poultry farms, having contact with live animals in marketplaces, and touching any surfaces that are potentially contaminated with animal feces. For additional information, see the Avian Flu Travel Information from the CDC.
• Vaccines: The first human vaccine against H5N1 avian influenza was approved by the FDA on April 17, 2007. The vaccine has been purchased by the federal government for the National Stockpile and is not expected to become available to consumers. The CDC provides additional information about Avian Influenza Vaccines. Some data from animal studies suggest that the standard inactivated influenza vaccine may confer some partial immunity toward avian influenza. Therefore, recommendations are that poultry workers receive annual influenza vaccination to prevent illness and to prevent viral reassortment through simultaneous infection with the two types of influenza.
• Disaster medicine: Preparedness for pandemic influenza is widely considered to be grossly inadequate. Five areas important to managing a surge in severe illness are (1) surveillance and diagnostic services, (2) information sharing and dissemination, (3) community support, (4) hospital and physician capacity, and (5) the availability of vaccines and drugs.¹¹ Even in the absence of a pandemic illness, the lack of capacity in US emergency departments has been described as a crisis by the Institute of Medicine. For more information about preparedness for epidemic influenza, see the WHO Global Influenza Preparedness Plan.

MISCELLANEOUS

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Medical/Legal Pitfalls

• One pitfall is the failure to recognize potential cases in patients who had at least 1 potential exposure within 10 days of presentation. Focus on good history taking in patients who were exposed to poultry and who traveled in affected countries. Maintain a high index of suspicion and vigilance when patients with this history present with severe illness, severe fever, and radiographically confirmed pneumonia for which an alternate diagnosis has not been established.
• Attention should be given to proper infectious disease precautions, including respiratory and contact isolation. Appropriate health care provider protection, such as wearing appropriately fitted N95 masks, should occur when any case is highly suspicious.
• Early involvement of the local public health department and hospital infection control is necessary to contain any outbreaks.
• Viral cultures of H5N1 should only be ordered in conjunction with guidance from a public health laboratory as they are performed in biosafety level 3 laboratories.
• Admit severely ill patients with suspected H5N1 infection while administering broad-spectrum antibiotics. Consider early administration of neuraminidase inhibitors, though the exact duration and dosage have not been established.
• Preventive measures and disaster preparedness are necessary to contain any massive outbreaks. Cooperation on the local, national, and international levels is required. Strict sanitation measures, patient education, scientific research, and hospital preparedness are essential in limiting the spread of any epidemic.
• Commercially available rapid influenza tests do not detect H5N1 avian influenza.

MULTIMEDIA

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Media file 1:  Colorized transmission electron micrograph shows avian influenza A H5N1 viruses (gold) grown in MDCK cells (green). Image courtesy of Centers for Disease Control and Prevention.
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Media file 2:  Transmission electron micrograph (original magnification 150,000X) shows ultrastructural details of an avian influenza A (H5N1) virion, a subtype of avian influenza A. Note the stippled appearance of the roughened surface of the proteinaceous coat encasing the virion. Image courtesy of Centers for Disease Control and Prevention.
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Media file 3:  Photograph shows police officers during the 1918 Spanish flu pandemic. Image courtesy of US National Archives.
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Media file 4:  Worldwide distribution of avian H5N1 influenza virus in birds and humans. Image courtesy of Centers for Disease Control and Prevention.
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Media file 5:  Avian H5N1 influenza in humans, annual case counts from the World Health Organization.
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Media type:  Graph

REFERENCES

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1. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. Oct 6 2005;437(7060):889-93. [Medline].
2. Gibbs MJ, Gibbs AJ. Molecular virology: was the 1918 pandemic caused by a bird flu?. Nature. Apr 27 2006;440(7088):E8; discussion E9-10. [Medline].
3. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. Mar 4 2000;355(9206):827-35. [Medline].
4. Avian influenza ("bird flu"): fact sheet. February 2006. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/avian_influenza/en/print.html.
5. Drake JW. Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A. May 1 1993;90(9):4171-5. [Medline].
6. World Health Organization. Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. Wkly Epidemiol Rec. Jun 30 2006;81(26):249-57. [Medline]. [Full Text].
7. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. Sep 29 2005;353(13):1374-85. [Medline].
8. Apisarnthanarak A, Erb S, Stephenson I, Katz JM, Chittaganpitch M, Sangkitporn S, et al. Seroprevalence of anti-H5 antibody among Thai health care workers after exposure to avian influenza (H5N1) in a tertiary care center. Clin Infect Dis. Jan 15 2005;40(2):e16-8. [Medline].
9. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis. Feb 2005;11(2):201-9. [Medline]. [Full Text].
10. Oner AF, Bay A, Arslan S, Akdeniz H, Sahin HA, Cesur Y, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med. November 2006;355(21):2179-85. [Medline].
11. Gensheimer KF, Meltzer MI, Postema AS, Strikas RA. Influenza pandemic preparedness. Emerg Infect Dis. Dec 2003;9(12):1645-8. [Medline].
12. Belshe RB. The origins of pandemic influenza--lessons from the 1918 virus. N Engl J Med. Nov 24 2005;353(21):2209-11. [Medline].
13. Centers for Disease Control and Prevention. CDC Health Update. Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Avian Influenza A (H5N1) Virus in the United States. June 7, 2006. [Full Text].
14. MIST Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet. Dec 12 1998;352(9144):1877-81. [Medline].
15. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. Feb 23 2000;283(8):1016-24. [Medline].

Article Last Updated: Oct 30, 2007