key: cord-0009206-pfweddqb
authors: Talan, David A.; Moran, Gregory J.; Pinner, Robert
title: Update on emerging infections: News from the Centers for Disease Control and Prevention: Outbreaks of avian influenza A (H5N1) in Asia and interim recommendations for evaluation and reporting of suspected cases—United States, 2004
date: 2004-11-19
journal: Ann Emerg Med
DOI: 10.1016/j.annemergmed.2004.10.004
sha: 076f63e1f11661e8609f7ea1c6770243c4ff8d11
doc_id: 9206
cord_uid: pfweddqb

nan

During December 2003 to February 2004, outbreaks of highly pathogenic avian influenza A (H5N1) among poultry were reported in Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand, and Vietnam. As of February 9, 2004, a total of 23 cases of laboratory-confirmed influenza A (H5N1) virus infections in humans, resulting in 18 deaths, had been reported in Thailand and Vietnam. In addition, approximately 100 suspected cases in humans are under investigation by national health authorities in Thailand and Vietnam. The Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), and national health authorities in Asian countries are working to assess and monitor the situation, provide epidemiologic and laboratory support, and assist with control efforts. This report summarizes information about the human infections and avian outbreaks in Asia and provides recommendations to guide influenza A (H5N1) surveillance, diagnosis, and testing in the United States.

On December 12, 2003, an outbreak of avian influenza A (H5N1) among poultry in South Korea was reported. Sub-sequent influenza A (H5N1) outbreaks among poultry were confirmed in Vietnam (January 8, 2004), on a single farm in Japan (January 12), in Thailand (January 23), in Cambodia (January 24), in China (January 27), in Laos (January 27), and in Indonesia (February 2). On January 19, a single peregrine falcon found dead in Hong Kong also tested positive for influenza A (H5N1) virus, but no poultry outbreak has been identified.

In Vietnam, as of February 9, a total of 18 human influenza A (H5N1) infections had been reported, resulting in 13 deaths. Patients ranged in age from 4 to 30 years; 10 patients were aged younger than 18 years. The cases included fatal infections in 2 sisters who were part of a cluster of 4 cases of severe respiratory illness in a single family.

In Thailand, influenza A (H5N1) infection was confirmed in 4 males, aged 6 to 7 years, and 1 female, aged 58 years. All 5 patients died. 1 Other cases are under investigation.

Antigenic analysis and genetic sequencing distinguish between influenza viruses that usually circulate among birds and those that usually circulate among humans. Sequencing of the H5N1 viruses obtained from 5 persons in Vietnam and Thailand, including 1 sister from the cluster in Vietnam, has indicated that all of the genes of these viruses are of avian origin. No evidence of genetic reassortment between avian and human influenza viruses has been identified. If reassortment occurs, the likelihood that the H5N1 virus can be transmitted more readily from person to person will increase. Although all the genes are of avian origin, the current H5N1 viruses are antigenically distinguishable from those isolated from humans in Hong Kong in 1997 and 2003.

Genetic sequencing of the 5 human H5N1 isolates from Thailand and Vietnam also indicates that the viruses have genetic characteristics associated with resistance to the influenza antiviral drugs amantadine and rimantadine. Antiviral susceptibility testing confirms this finding. Testing for susceptibility of the H5N1 isolates to the neuraminidase inhibitor oseltamivir has demonstrated the sensitivity of these viruses to the drug; testing to determine susceptibility to the neuraminidase inhibitor zanamavir is under way.

CDC recommends that state and local health departments, hospitals, and clinicians enhance their efforts to identify patients who could be infected by influenza A (H5N1) virus and take infection-control precautions when influenza A (H5N1) is suspected. Testing of hospitalized patients for influenza A (H5N1) infection is indicated when both of the following exist: (1) radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternative diagnosis has not been established, and (2) a history of travel within 10 days of symptom onset to a country with documented H5N1 avian influenza infections in poultry or humans. Ongoing listings of countries affected by avian influenza are available from the World Organization for Animal Health (available at http://www.oie.int/eng/en_index.htm).

Testing for influenza A (H5N1) also should be considered on a case-by-case basis in consultation with state and local health departments for hospitalized or ambulatory patients with all of the following: (1) documented temperature of greater than 100.4 F (>38 C); (2) cough, sore throat, or shortness of breath; and (3) history of contact with poultry or domestic birds (eg, visited a poultry farm, a household raising poultry, or a bird market) or a known or suspected patient with influenza A (H5N1) in an H5N1-affected country within 10 days of symptom onset.

The highly pathogenic avian influenza A (H5N1) virus requires Biosafety Level (BSL)-3C laboratory conditions for certain procedures. CDC recommends that virus isolation studies on respiratory specimens from patients who meet the testing criteria should not be performed unless all BSL-3C conditions are met. However, clinical specimens can be tested by polymerase chain reaction (PCR) assays by using standard BSL-2 work practices in a Class II biological safety cabinet. CDC has developed real-time PCR protocols for various respiratory pathogens, including severe acute respiratory syndrome (SARS) and influenza A and B viruses. In addition, commercially available antigen-detection tests can be used under BSL-2 levels to test for influenza. Although these rapid tests for human influenza also can detect avian influenza A (H5N1) viruses, the sensitivity of these tests is substantially lower than that of virus culture or PCR. 2 Specimens from persons meeting clinical and epidemiologic indications for testing should be sent to CDC if they test positive for influenza A either by PCR or antigen detection testing, or if PCR assays for influenza are not available locally. CDC also will accept, for follow-up testing, specimens from persons meeting the clinical and epidemiologic indications but testing negative on the rapid tests when PCR assay was not available. Requests for testing by CDC should come through local and state health departments, which should contact CDC's Emergency Operations Center, telephone 770-488-7100.

Since 1997, human infection with avian influenza viruses has been confirmed on 5 occasions. The ability of avian viruses to transmit from person to person appears limited. Rare person-toperson infection was noted in the A (H5N1) outbreak in Hong Kong in 1997 3, 4 and in the A (H7N7) outbreak in the Netherlands in 2003, 5 but these secondary cases did not result in sustained chains of transmission or communitywide outbreaks. These previous experiences with avian influenza viruses suggest that limited person-to-person transmission of the current H5N1 viruses could occur.

The majority of the human H5N1 cases are apparently associated with direct exposure to infected birds or to surfaces contaminated with excretions from infected birds. The family respiratory illness cluster in Vietnam suggests the possibility of limited person-to-person transmission. However, other possibilities (eg, transmission through exposure to surfaces contaminated by H5N1-infected poultry feces) cannot be ruled out. Although no evidence for sustained person-to-person transmission of influenza A (H5N1) has been identified, influenza viruses have the capacity to change quickly. Continued monitoring for new transmission patterns is an important aspect of the current investigation.

In 1997, the influenza A (H5N1) outbreak among persons in Hong Kong ended abruptly after the culling of poultry. However, the current outbreaks present challenges because of the large geographic areas and numbers of affected poultry. Asian poultry populations are maintained both on large commercial farms and in backyard flocks. In addition, infections among wild bird populations might be extensive, and the resources to address this problem are limited in certain affected countries.

Because the influenza A (H5N1) virus could develop the ability to maintain sustained person-to-person transmission, WHO collaborating centers are working to coordinate vaccine development. Efforts are under way in the United Kingdom and the United States to develop influenza A (H5N1) reference viruses for use in vaccine preparation. The minimum estimated time necessary to complete reference virus development and safety testing is 3 months. Production by vaccine manufacturers of pilot lots of vaccine for clinical testing can begin only after reference virus development and safety testing have been completed. Decisions on whether to proceed with vaccine manufacture will depend, in part, on the evolution of the current outbreaks.

CDC advises that travelers to countries in Asia with documented H5N1 outbreaks should avoid poultry farms, contact with animals in live food markets, and any surfaces that appear to be contaminated with feces from poultry or other animals. More information on travel is available from CDC at http://www.cdc.gov/travel. Additional information on influenza viruses and avian influenza is available from CDC at http:// www.cdc.gov/flu. Updated information on human infections is available from WHO at http://www.who.int/en. 

Cases of influenza A (H5N1)dThailand

Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)

Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997-1998

Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong

Influenza is one of the costliest infectious diseases worldwide. Not only do yearly endemic outbreaks lead to significant local morbidity and mortality, but less frequent pandemicsd4 in the 20th century alonedcause death tolls in the millions. The ''Spanish flu'' of 1918 to 1919 resulted in 20 to 40 million deaths worldwide. 1 In the late 1990s, after several decades of fairly stable human influenza viruses, highly pathogenic avian influenza infected humans in Southeast Asia for the first time. In the setting of the severe acute respiratory syndrome (SARS) epidemic and emerging human infections with these highly pathogenic avian influenza strains, the prospect of a pandemic looms large for public health authorities and should prompt preparative measures from emergency care providers.The ability of influenza to cause repeated outbreaks lies in its viral structure and ease of genetic reassortment. Influenza viruses belong to the Orthomyxoviridae family and contain singlestranded RNA. These enveloped viruses can be classified into A, B, and C types on the basis of their internal nucleoprotein and matrix protein identity. Only influenza A and B are associated with major outbreaks. 2 Influenza A is more diverse, associated with more outbreaks, and includes all avian influenza strains.Influenza A contains 8 distinct genes. Two surface glycoproteins, hemagglutinin and neuraminidase, account for its infectivity as well as trigger the host immune response. Hemagglutinin binds sialic acid receptors on the host cell membrane to gain access to the cell; this is the main target of antibodies and vaccines. Neuraminidase facilitates release of progeny virions from host cells after replication and is the target of antiviral therapies. These proteins are also used to identify different strains; to date, 15 hemagglutinin (H1-15) and 9 neuraminidases (N1-9) have been identified. Only 3 hemagglutinin (H1-3) and 2 neuraminidase (N1, N2) subtypes of influenza A persist in humans. Certain hemagglutinin and neuraminidases subtypes are associated with pigs (H1, H3, N1, N2) and horses (H7, N7, N8). All hemagglutinin and neuraminidase subtypes are established in aquatic birds. 2, 3 The epidemiology of influenza is closely linked with the genetics of these 2 proteins. Local epidemics, like the severe ''flu season'' of 2003 to 2004 in the United States, are caused by antigenic drift. This means that random point mutations in the genetic sequence escape repair, leading to gradual ''drift'' of the gene pool. The genes coding for hemagglutinin and neuraminidase are inherently unstable and constantly undergoing genetic drift. People are more susceptible to these slightly altered strains but also retain some degree of crossimmunity from prior influenza exposures. Thus, resultant epidemics are limited in scope and severity.Antigenic shift is potentially far more dangerous. Shift occurs when 1 of the 8 genes is exchanged in its entirety for another during replication. This requires a host cell, called a ''mixing vessel,'' to be coinfected with 2 influenza strains. Pigs are an ideal mixing vessel because they are readily infected with both human and avian forms. 4, 5 Alternatively, a person infected with a conventional human influenza virus could be coinfected with a highly pathogenic avian influenza strain. Global influenza pandemics result from such antigenic shift because there is no pre-existing immunity to the new strain.Aquatic birds serve as the primary reservoir for influenza A, carrying the viruses largely without adverse effects. 4,6 Domestic poultry, however, are highly susceptible to avian influenza. Depending on the virulence of the particular strain, poultry may manifest mild upper respiratory infections or rapidly fatal illness. 4 Formerly known as ''fowl plague,'' highly pathogenic avian influenza is now identified as strains H5 and H7, which cause severe disease in terrestrial birds. 6, 7 Since the Hong Kong pandemic of 1968, the human strains of influenza A had remained fairly stable. 5 However, in the late 1990s, new avian strains began to infect humans in relatively small numbers. Eighteen people were infected with influenza A (H5N1) in Hong Kong in 1997; 6 died. 4, 8 In 1999, H9N2 was isolated for the first time from 2 children in Hong Kong, who both recovered after mild respiratory illnesses. 4, 8 Most concerning, however, is this year's re-emergence of influenza A (H5N1)dslightly different genetically than the 1997 strain. 9-11 Affecting poultry across Southeast Asia, this is the most widespread outbreak of avian influenza in history. More than 100 million poultry have died or been killed as a result. 12 As of September 28, 2004, in Thailand and Vietnam, 42 cases were reported in healthy young adults and children, with a 71% mortality rate. 13 The H5N1 strain of influenza transmitted to humans this year has 2 of the 3 classic features of a potential pandemic: high mortality and an immunologically naive population. 14 Lacking,