Avian influenza A viruses occur in multiple subtypes based on the hemagglutinin proteins on their surfaces. To date, three subtypes have been associated with infections in humans: H5, H7, and H9. In addition, these viruses can occur in “low pathogenic avian influenza (LPAI)” and “high pathogenic avian influenza (HPAI)” forms, depending on the severity of disease they cause in birds. Typically wild birds may not become ill when infected, however domestic poultry, such as chickens and turkeys, may become sick and die, especially with “high pathogenic” forms of the viruses. It is known that low pathogenicity avian viruses can evolve into high pathogenicity viruses, and the relationship of avian pathogenicity to disease potentially caused by these viruses in humans is unclear; thus both LPAI and HPAI outbreaks in birds are of concern.

Epidemiology:

Events in recent years have substantially increased concerns regarding avian influenza outbreaks in humans. Almost all human cases to date have occurred following bird or animal cases, and result primarily from animal to human spread. A large and widespread epizootic of H5N1 avian influenza occurred in poultry across Southeast Asia, China, Korea, and Japan in early 2004 - 35 associated human cases occurred in Thailand and Vietnam, with 24 deaths. New outbreaks of H5N1 influenza in bird populations began again in late June 2004 in China, Indonesia, Thailand and Vietnam; sporadic human cases of H5N1 infection occurred in Thailand and Vietnam subsequently, with 4 reported human deaths each in Vietnam and Thailand through October, 2004. In this second wave, one instance of confirmed human to human transmission of avian influenza was reported in Thailand in September, 2004. A third wave of cases began in December, 2004, with outbreaks in bird populations. Since then, 89 confirmed cases with 39 deaths have been reported to WHO (as of November 29, 2005). Cases have occurred in 5 countries: Cambodia, China, Indonesia, Thailand, and Vietnam.

Avian strains have been shown to cause influenza in humans in a number of other prior instances from 1997 through 2003:

• Hong Kong, 1997, H5N1: 18 people hospitalized, 6 deaths. First evidence of bird to human spread of disease, limited human to human transmission.
• China and Hong Kong, 1998-1999, H9N2: Disease confirmed in two children, both of whom recovered. Several other cases reported from mainland China.
• Virginia, 2002, H7N2: Poultry outbreak in the Shenandoah Valley area, with one human infection confirmed serologically.
• China and Hong Kong, 2003, H5N1: Three cases in one family from Hong Kong after travel to China, two confirmed, two deaths.
• Netherlands, H7N7, 2003: Cases in poultry, pigs, and humans. 89 confirmed human cases, with 78 having conjunctivitis only, 5 with conjunctivitis and a flu-like illness, and 2 cases with influenza symptoms only; one death.
• Hong Kong, 2003, H9N2, one patient, survived.
• New York, H7N2, 2003, one patient, survived.
• Canada, H7N3, Poultry and human cases (occupational exposure), conjunctivitis only.

The CDC case definition for avian influenza (H5N1) includes both clinical and epidemiological criteria: 1) Documented temperature of > 100.4 degrees F (38?C); AND 2) One or more of the following: cough, sore throat, shortness of breath; AND 3) A history of contact with live poultry or a known or suspected human case of H5N1 avian influenza in an affected country within 10 days of onset of symptoms.

Clinical Features:

Signs and symptoms of avian influenza in humans include the classic influenza syndrome of cough, fever, sore throat, malaise, and muscle aches. Patients may also present with conjunctivitis, acute respiratory distress and ARDS, viral pneumonia, and with other classic influenza complications such as bacterial pneumonia or cardiorespiratory compromise in individuals with underlying risk factors. Mortality rates in human cases of avian influenza may be higher (51% among the 133 confirmed cases of H5N1 to date) than in typical influenza cases caused by usual human strains.

Presenting Symptoms (Clinical Diagnosis)

• Fever
• Cough
• Sore throat
• Myalgias
• Eye pain or Irritation (conjunctivitis)
• Respiratory distress

Laboratory Clinical Diagnostic Testing:

Clinicians should contact their state public health authorities or the CDC for guidance on collection of specimens for diagnostic testing from cases meeting the clinical diagnostic criteria for avian influenza.

In order of priority, the WHO recommends that the following specimens be collected from suspected cases of avian influenza: (1) nasopharyngeal aspirate, within 3 days of symptom onset, (2) acute serum, within 7 days of onset, and (3) convalescent serum, at 14 days after onset. Clinical diagnostic testing for avian influenza may include commercial antigen detection assays for influenza A and more specific PCR testing at large city and state public health laboratories, or at CDC.

Clinical specimens from suspected H5N1 influenza A cases may be tested by polymerase chain reaction (PCR) assays using BSL-2 safety practices in Class II biological safety cabinets; however respiratory virus isolation studies on clinical specimens from patients who meet the clinical diagnostic criteria for avian influenza should NOT be performed unless strict BSL-3+ laboratory conditions can be met. Highly pathogenic avian influenza strains are classified as select agents; laboratories performing viral isolation studies on such specimens must be certified by the USDA.

The following links provide further details regarding collection and handling of, and biological safety issues related to, clinical specimens from suspected or confirmed cases of avian influenza:

• WHO guidelines for the collection of human specimens for laboratory diagnosis of avian influenza infection (January 12, 2005). Accessed 12/12/05 from http://www.who.int/csr/disease/avian_influenza/guidelines/humanspecimens/en/index.html.


• HHS Pandemic Influenza Plan: Supplement 2 Laboratory Diagnostics. Accessed 12/12/05 from: http://www.hhs.gov/pandemicflu/plan/sup2.html

Specific Diagnostic Testing:

PCR and virus isolation are available at CDC; requests for testing should be submitted through state and local health departments. CDC will accept specimens from patients who meet clinical criteria even if commercial rapid diagnostic tests for influenza A are negative, because of issues with the sensitivity of such tests.

Differential Diagnosis:

Other typical circulating human strains of influenza A may cause an identical clinical picture during influenza seasons (H1N1, H1N2, H3N2). Differential diagnosis includes bacterial pneumonia, respiratory distress due to primary cardiac problems, ARDS, and other viral pneumonias. Autoimmune diseases and other atypical pathogens are possible other causes of similar symptoms.

Prevention:

The most common strategy for prevention of avian influenza outbreaks in humans is limiting human contact with infected birds, and culling of flocks infected with avian flu viruses. In February 2004, CDC issued an order banning the import of potentially infected birds from countries where avian influenza is prevalent.

Within the healthcare setting, the CDC recommended infection control precautions for confirmed or suspected cases of H5N1 include all of the following:

• Standard precautions
• Contact precautions
• Eye protection
• Airborne precautions (including use of airborne isolation room and use of fit-tested respirator)

Treatment:

The U.S. is stockpiling the antiviral drug Tamiflu® (oseltamivir) for treatment of avian influenza should an epidemic occur. All four drugs approved by the FDA against influenza (amantadine, rimantidine, zanamivir, and oseltamivir) have activity against influenza A viruses; however some of the H5N1 avian isolates from southeast Asia have shown resistance to amantadine and rimantidine. In addition, a recent case report from Vietnam documented resistance to oseltamivir in a pediatric patient.3 Given the evolving nature of H5N1 illness in humans, clinicians are advised to seek out the most current treatment recommendations from CDC or WHO when initiating treatment for confirmed or suspected cases.

Outlook:

Whether H5N1 or other avian viruses are likely to cause widespread or pandemic illness in humans is uncertain. Up to this point these viruses have demonstrated only limited ability to spread from human to human, and natural genetic reassortment between avian and human influenza viruses has not been observed. However, vigilence is warranted, and there are some worrisome indicators, including expansion of avian virus prevalence in the bird population as well as the increasing capability of avian viruses to infect novel species.

For More Information:

The World Health Organization and CDC have extensive information available on their respective websites:

CDC - http://www.cdc.gov/flu/avian/

WHO - http://www.who.int/csr/disease/avian_influenza/en/index.html

The U.S. government has recently established a separate website for information pertaining to avian influenza and pandemic influenza. It can be accessed at: http://pandemicflu.gov/

References:

1. The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353:1374-85.
2. Hien TT, Liem NT, Dung NT, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004 Mar 18;350(12):1179-88
3. Le QM, Kiso M, Someya K, et al. Isolation of drug-resistant H5N1 virus. Nature 2005 Oct 20;437:1108

Pandemic influenza is a global outbreak of viral respiratory disease caused by the emergence of a new influenza A virus - one which has the ability to infect humans, is transmitted efficiently from person-to-person, and spreads worldwide, often in just a few months time. The risk of pandemics may be even greater today than in the past due to the speed and commonality of international travel.

Year to year, prevalent influenza A viruses undergo small genetic changes known as “antigenic drift”, producing virus strains that are somewhat different from previously circulating strains, but not radically different. A new strain may need to be added to the previous year’s vaccine, but there is still some existing immunity in the human population. However, immunity from influenza viruses is relatively short-lived, and vaccination against new strains is necessary on a yearly basis.

Occasionally, however, influenza A viruses undergo major abrupt genetic changes called “antigenic shift”, with surface protein (neuraminidase and hemagglutinin) combinations not seen in humans for many years, if ever. Some of these shifts have occurred in the past due to reassortment of human influenza viruses with animal, particularly avian, influenza viruses. Such major genetic shifts may produce viruses to which humans have little inherent immunity, increasing the possibility of worldwide pandemic disease. Pandemic mortality may range from 1% to 20%, depending on the virus, but with a worldwide distribution, even a one percent case fatality rate may produce a startling number of fatalities. Influenza B viruses have produced localized epidemics historically, but not pandemics.

Epidemiology:

Three major pandemics of influenza A have been recorded in each of the last three centuries. During the 20th century, the three pandemics occurred in 1918-1919 (the “Spanish Flu”), 1957-1958 (the “Asian Flu”), and 1968-1969 (the “Hong Kong Flu”). The 1918 pandemic, caused by an A (H1N1) virus, was the worst recorded in modern history – more than half a million deaths in the United States and up to 50 million worldwide. This outbreak killed young adults in the prime of life, unlike most influenza viruses, which typically prey on the elderly, young children, pregnant women, and the immunosuppressed. Exactly what pathogenic features caused the extreme mortality of the 1918-1919 outbreak are still unknown. The 1957 virus [A (H2N2)] originated in China in February 1957 and spread to the United States by June of 1957, killing 70,000 Americans. The 1968 virus [A (H3N2)] was first seen in early 1968 in Hong Kong and spread to the U.S. by the end of 1968, causing an estimated 34,000 deaths in this country. Death tolls from natural disasters, even the recent Asian tsunami which took over 150,000 lives very suddenly, may pale in comparison with the potential worldwide death toll from a severe pandemic influenza outbreak.

The Institute of Medicine recently estimated the possible impact of a new outbreak of pandemic influenza on the United States in a report called “The Threat of Pandemic Influenza” (http://www.nap.edu/books/0309095042/html/). Whereas a “normal” influenza season in the United States claims 36,000 lives and results in 200,000 hospitalizations, IOM experts estimate that, in a worst case scenario, a new pandemic could kill 207,000 people in the U.S., and lead to 42 million outpatient visits and nearly three quarters of a million hospitalizations.

Most physicians think of influenza as purely a human disease, when in fact it is a zoonosis of birds, horses, swine and humans. Close contact between humans and animals can allow for genetic reassortment of influenza A viruses, leading to pandemics in humans. This is why the recent spread of Avian influenza viruses to humans in Southeast Asia, and the high mortality rate associated with those cases (see UAB Web site section on avian influenza [http://www.bioterrorism.uab.edu/EI/Avian/summary.asp]) has caused such concern in the scientific and medical communities about a new influenza pandemic. Exactly when the next pandemic will occur is uncertain. In a recent USA Today interview (2004), Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Disease at NIH, was asked if it could happen next year. His answer? “Yeah. We’re due for it.”

Clinical Features:

Signs and symptoms of influenza in humans include the classic influenza syndrome of cough, fever, sore throat, malaise, and muscle aches. Patients may also present with conjunctivitis, acute respiratory distress and ARDS, viral pneumonia, and with other classic influenza complications such as bacterial pneumonia or cardio-respiratory compromise in individuals with underlying risk factors.

Depending on the virulence of the virus causing a pandemic outbreak, clinical features and mortality may be more or less severe. In the 1918-1919 pandemic, many young, previously healthy people presented with signs of severe primary influenzal (viral) pneumonia early in the course of disease, leading quickly to what we now know as ARDS and respiratory failure. Most influenza viruses produce primarily a tracheobronchitis – however some strains may have more of a propensity to cause a direct infection and damage to lower airways and alveolar cells, understandably leading to alveolar cell death and higher morbidity and mortality. With the 70% plus mortality seen with recent human avian influenza cases in Thailand and Vietnam, there is obviously great concern that a new pandemic strain could find its way into the human population. Less than efficient human-to-human transmission of avian viruses may be the only thing standing in the way of a major new pandemic.

• Fever
• Cough
• Sore throat
• Myalgias
• Eye pain or Irritation (conjunctivitis)
• Respiratory distress (may occur early with more virulent viruses)

Clinical diagnostic testing for influenza may include commercial antigen detection assays for influenza A and more specific PCR testing at large city and state public health laboratories, or at CDC. Clinical specimens from suspected most influenza A cases may be handled using BSL-2 safety practices in Class II biological safety cabinets.

Specific Diagnostic Testing:

PCR and virus isolation are available at CDC; requests for testing should be submitted through state and local health departments. CDC will accept specimens from patients who meet clinical criteria even if commercial rapid diagnostic tests for influenza A are negative, because of issues with the sensitivity of such tests.

Differential Diagnosis:

Differential diagnosis includes bacterial or other viral pneumonias, respiratory distress due to primary cardiac problems, ARDS from other causes such as chemicals or toxins, and emphysema from chronic smoking. Autoimmune diseases and other atypical pathogens are possible other causes of similar presenting signs and symptoms.

Prevention:

It may be almost impossible to prevent all influenza pandemics. Human influenza A viruses spread more efficiently from person to person than infections like smallpox and plague. Once a new virus starts to be transmitted within the human population, it may be very difficult to interrupt transmission. Personal and societal measures to prevent spread may include: 1) good and frequent handwashing; 2) staying home when ill so as not to spread infection in schools and workplaces; 3) school and business closings and travel restrictions when necessary to interrupt spread; 4) a more robust influenza vaccine production capability not dependent on one or two manufacturers; 5) consideration to inclusion of most likely pandemic influenza strains in current vaccines (such as A-H5N1) in order to develop some immunity against novel strains in the population; 6) stockpiling of vaccines against likely pandemic strains as well as antiviral drugs. Other measures may have to be taken as indicated when a new pandemic occurs. The NIH began clinical trials of a vaccine against H5N1 in April 2005, Vaccine development is an important preventive measure should this currently (predominately avian) virus becomes more widespread in human populations.

Treatment :

The U.S. is stockpiling the antiviral drug Tamiflu® (oseltamivir) for treatment of influenza should an epidemic or pandemic occur. All four drugs approved by the FDA against influenza (amantadine, rimantidine, zanamivir, and oseltamivir) have activity against influenza A viruses; however some of the H5N1 avian isolates from southeast Asia have shown resistance to amantadine and rimantidine, and a recent report documented a case of resistance to oseltamivir in a pediatric patient in Vietnam.¹

Outlook:

If history teaches us anything about influenza, the question we should be asking is not “if” another influenza pandemic will occur, but “when” it will occur. Prudent measures taken now to prepare the United States and other countries for this threat will likely decrease morbidity and mortality. How long we have to prepare is uncertain, thus some urgency is warranted.

For More Information:

The U.S. government has established a separate website for information pertaining to avian influenza and pandemic influenza. It can be accessed at: http://pandemicflu.gov/

The World Health Organization and CDC also have extensive information available on their respective websites:

CDC - http://www.cdc.gov/flu/pandemic/

WHO - http://www.who.int/csr/disease/influenza/en/index.html

1. Le QM, Kiso M, Someya K, et al. Isolation of drug-resistant H5N1 virus. Nature 2005 Oct 20;437:1108