Pandemic Influenza - Last updated September 10, 2006

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Pandemic Influenza

Last updated September 10, 2006

http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/biofacts/panflu.html​

http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/biofacts/panflu.html#_References_3
Note: Information on avian influenza is available in the overviews "Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations" and "Avian Influenza (Bird Flu): Implications for Human Disease."
Agent

All past influenza pandemics in humans have been caused by influenza A viruses. General information about influenza A viruses (not specific to pandemic strains) is presented in the bullets below.

• Family: Orthomyxoviridae
  • Enveloped virions are 80 to 120 nm in diameter, are 200 to 300 nm long, and may be filamentous.
  • They consist of spike-shaped surface proteins, a partially host-derived lipid-rich envelope, and matrix (M) proteins surrounding a helical segmented nucleocapsid (6 to 8 segments).
  • The family contains five genera, classified by variations in nucleoprotein (NP and M) antigens: influenza A, influenza B, influenza C, thogotovirus, and isavirus.
• Genus: Influenzavirus A
  • Consists of a single species: influenzaA virus.
  • Influenza A viruses are a major cause of influenza in humans.
  • The multipartite genome is encapsidated, with each segment in a separate nucleocapsid. Eight different segments of negative-sense single-stranded RNA are present; this allows for genetic reassortment in single cells infected with more than one virus and may result in multiple strains that are different from the initial ones (see References: Voyles 2002).
  • The genome consists of 10 genes encoding for different proteins (eight structural proteins and two nonstructural proteins). These include the following: three transcriptases (PB2, PB1, and PA), two surface glycoproteins (hemagglutinin [HA] and neuraminidase [NA]), two matrix proteins (M1 and M2), one nucleocapsid protein (NP), and two nonstructural proteins (NS1 and NS2).
  • The virus envelope glycoproteins (HA and NA) are distributed evenly over the virion surface, forming characteristic spike-shaped structures. Antigenic variation in these proteins is used as part of the influenza A virus subtype definition (but not used for influenza B or C viruses).
• Influenza A virus subtypes:
  • There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A. Until recently, 15 HA types had been recognized, but a new type (H16) was isolated from black-headed gulls caught in Sweden and the Netherlands in 1999 and reported in the literature in 2005 (see References: Fouchier 2005).
  • Human disease historically has been caused by three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2).
  • More recently, human disease has been recognized to be caused by additional HA subtypes, including H5, H7, and H9 (all from avian origin).
  • All known subtypes of influenza A can be found in birds, and feral aquatic birds are the major reservoir for influenza A viruses. Feral birds generally do not develop severe disease from influenza; however, domestic chickens and turkeys are susceptible to severe and potentially fatal influenza.
  • Certain mammals also are susceptible to influenza. Influenza A viruses have traditionally been known to cause disease in horses, pigs, whales, and seals; however, the range of several influenza A subtypes is expanding to further mammalian species. H5N1 influenza A recently has been shown to infect cats, leopards, and tigers (see References: Keawcharoen 2004; Webster 2006).Cases of canine influenza have been recognized in the United States and are being caused byH3N8 influenza A, a subtype traditionally found in horses (see References: Crawford 2005).
• Influenza A virus subtype strains
  • Antigenic strain nomenclature is based on: (1) host of origin (if other than human), (2) geographic origin, (3) strain number, (4) year of isolation, and (5) HA and NA type. (Examples are as follows: A/Hong Kong/03/68[H3N2], A/swine/Iowa/15/30[H1N1].)
  • H5N1 strains have been differentiated into genetic clades, with nonoverlapping case distributions. All human H5N1 strains are grouped in clade 1 (see References: WHO Global Influenza Program Surveillance Network).
• Classification of influenza A strains by pandemic potential
  • Strains from past pandemics: "Noncontemporary" strains are those from previous pandemics that pose some degree of risk to the public owing to decreased immunity in the current population. The term is currently used to describe strains from the Asian flu (H2N2) but could be applied to strains from the earlier Spanish flu pandemic (H1N1) (see References: CDC: Interim CDC-NIH recommendation for raising the biosafety level for laboratory work involving noncontemporary human influenza [H2N2] viruses).
  • Nonpandemic strains: These include strains that have recently circulated or are currently circulating in the human population (ie, those belonging to H1N1, H3N2, and H1N2 subtypes).
  • Potential pandemic strains: Potential pandemic strains must have the following features: (1) have an antigenic makeup to which the population is immunologically naive, (2) be able to replicate in humans, and (3) efficiently transmit from human to human. Because of homosubtypic immunity (see below), new pandemic strains are most likely to be of subtypes not previously recognized in human populations. Currently, strains of H5 and H7 subtypes are of greatest concern.
  • Animal pandemic strains (including avian influenza strains): Animal strains such as H5N1 avian influenza are not considered human pandemic strains unless the above criteria are met, but they have significant potential to evolve into new human pandemic strains through the process of genetic reassortment (see below) or through gradual adaptation to the human host. Most avian strains are not of concern as potential pandemic strains.
• Avian influenza
  • The term "avian influenza" is used to describe influenza A subtypes that primarily affect chickens, turkeys, guinea fowls, migratory waterfowl, and other avian species.
  • "Avian influenza" is an ecological classification that does not correspond exactly to other classification schemes.
  • As with other influenza A subtypes, standard nomenclature is used to name strains (eg, A/Chicken/HK/5/98 [H5N1]).
  • Avian influenza strains in domestic chickens and turkeys are classified according to disease severity, with two recognized forms: highly pathogenic avian influenza (HPAI), also known as fowl plague, and low-pathogenic avian influenza (LPAI). Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses are generally of lower virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for die-offs of domestic birds in Asia is an HPAI strain; other strains of H5N1 occurring elsewhere in the world are less virulent and, therefore, are classified as LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes.
  • Human infections have been associated with both HPAI and LPAI strains (see References: HHS: Pandemic influenza plan).
  • Evidence that HPAI strains arise from LPAI strains has led the World Organization for Animal Health to classify all H5 or H7 strains as notifiable (see References: Alexander 2003, Capua 2004, OIE 2005).
  • In the United States, currently only HPAI avian strains and reconstructed 1918 H1N1 strains are regulated as select agents (see Biosafety and Biosecurity, below).
  • The 1918 influenza pandemic strain (H1N1) appears to be of avian origin (see References: CDC: Information about pandemic influenza viruses).
• Physical characteristics of influenza A viruses
  • Strains are sensitive to lipid solvents, nonionic detergents, formaldehyde, and oxidizing agents.
  • They are inactivated by ionizing radiation, pH extremes (>9 or <5), and temperatures greater than 50?C.
  • Viruses remain infectious after 24 to 48 hours on nonporous environmental surfaces and less than 12 hours on porous surfaces (see References: Bean 1982). (Note: The importance of fomites in disease transmission has not been determined.)

Laboratory Testing for Influenza

The following statements regarding laboratory testing apply to influenza viruses in general, not just to influenza testing in a pandemic setting. During a pandemic, recommendations for laboratory testing may change, depending on a number of factors, including availability of testing reagents and laboratory staffing/surge capacity.
General Considerations

• Tests for influenza virus include viral culture, polymerase chain reaction (PCR), rapid antigen testing, and immunofluorescence. Serologic tests are used to retrospectively diagnose infection.
• Laboratory tests do not need to be conducted on all patients with suspected influenza. Factors that influence the decision to test or not test patients with signs and symptoms of influenza include:
  • Residence in a healthcare facility: Documentation of influenza virus infection in inpatients or residents of long-term care facilities is important for detection and control of outbreaks.
  • Treatment options: Testing should be performed if laboratory results influence clinical decision making.
  • Level of influenza activity in the community: The positive predictive value of influenza tests, especially rapid assays, increases with prevalence of influenza in the community; therefore, if the prevalence of influenza is low, the utility of the tests decreases. As influenza prevalence increases, the predictive value of clinical diagnosis without laboratory testing also increases and laboratory confirmation may not be necessary (see References: CDC: Interim guidance for influenza diagnostic testing during the 2004-05 influenza season; Monto 2005).
  • Participation in a surveillance program: Sentinel surveillance can be useful to determine which strains are circulating in the community and to assess the degree of the match between circulating viruses and those used to make the vaccine for that year.
  • Patients who meet the criteria for a novel influenza virus: During a pandemic alert period, patients who meet certain criteria (such as influenza symptoms and recent travel to an area affected by a novel strain) should be considered for laboratory testing.
  • Pandemic considerations: As noted above, recommendations for testing during a pandemic may be somewhat unique and dependent upon factors such as availability of reagents and laboratory surge capacity.
• The sensitivity and specificity of laboratory tests appears to vary with the involved strain, which has implications for emerging variants (see References: Weinberg 2005).
• Laboratory tests are required for specific identification of pandemic strains. The most likely ways that a pandemic strain would be detected initially are:
  • Outbreak investigations or investigation of unexplained death in a previously healthy individual
  • Influenza surveillance with laboratory testing and characterization of unusual strains
  • Investigation of unusual laboratory findings
• State and local health departments should be prepared to process or test for the following (if they have the capability, as described below) (see References: HHS: Pandemic influenza plan).
  • Avian influenza A (H5N1) and other avian influenza viruses
  • Other animal influenza viruses
  • New or re-emergent human influenza viruses (such as H2 strains)
• Testing during a pandemic (see References: HHS: Pandemic influenza plan):
  • CDC will update protocols and distribute reagents as necessary.
  • The need for confirmatory testing will diminish as the pandemic progresses. Some level of continued monitoring will be necessary to monitor changes in antigenicity and antiviral susceptibility. CDC will provide appropriate guidance in such situations.
• Reporting and referral (see References: HHS: Pandemic influenza plan)
  • Clinical laboratories should contact their state or local health departments if they receive specimens from patients with possible novel influenza suspected on the basis of clinical and epidemiologic criteria.
  • Public health laboratories should send specimens to CDC if the patient meets clinical and epidemiologic criteria and (1) tests positive for influenza A by reverse transcriptase polymerase chain reaction (RT-PCR) or rapid testing or (2) tests negative for influenza A by rapid testing and RT-PCR is not available. Laboratories without capacity for testing avian strains by indirect immunofluorescence (IFA) or RT-PCR should send untypable influenza isolates to CDC.
  • Any unusual subtype should be reported to CDC through their emergency response hotline (770-488-7100).
• Laboratory-based influenza surveillance networks
  • WHO Global Influenza Surveillance Network (see References)
  • CDC National Respiratory and Enteric Virus Surveillance System (NREVSS) (see References)
  • State or local surveillance health department surveillance networks

Specimen Collection

• Appropriate specimens for testing include: nasal wash /aspirate, nasopharyngeal swab, throat swab, broncheoalveolar lavage, tracheal aspirate, pleural fluid tap, sputum, and autopsy specimens (see References: HHS: Pandemic influenza plan [Part 2, Supplement 2]).
• Specimens from living patients optimally should be collected within 4 days after illness onset.
• Some rapid test kits require specific specimen types and storage/transport methods.
• Nasopharyngeal swabs, nasal washes, and nasal aspirates are considered to be more sensitive than throat swabs for culture of most respiratory viruses, including convention influenza strains, and are preferred for children younger than 2 years of age.
• Pharyngeal swabs collected 4 to 8 days after onset of illness may be more sensitive for detection of influenza A (H5N1) than nasal swabs (see References: WHO: Writing Committee of WHO Consultation on Human Influenza A/H5l 2005).
• Only sterile Dacron or rayon swabs with plastic shafts should be used. Calcium alginate swabs or swabs with wooden sticks should not be used.
• Viral transport media should be used for nasopharyngeal and oropharyngeal swabs and specimens should be maintained at refrigerator temperature (4?C to 8^oC) until testing is performed. Freezing at 70?C is best for maintaining viability during extended storage
• With regard to autopsy specimens, large airways have the highest yield for immunohistochemistry (IHC) tests. Eight blocks or fixed-tissue specimens from each of the following sites should be obtained. Fixed tissue should be transported at room temperature (not frozen); fresh unfixed tissue should be frozen.
  • Central (hilar) lung with segmental bronchi
  • Right and left primary bronchi