Global Influenza Programme
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H5 case definitions

WHO case definition for human infections with avian influenza A(H5) virus requiring notification under IHR (2005)

4 November 2024

Background

Prompt and accurate notification of influenza A(H5) influenza cases to WHO is the cornerstone for monitoring both the evolution of these viruses and their pandemic risk. In collaboration with the WHO Collaborating Centres (WHO CCs) of the Global Influenza Surveillance and Response System (GISRS), WHO has operationalized the case definition for human infection with influenza A(H5) virus to facilitate:

1. notification of human cases of infection with influenza A(H5) viruses by State Parties;
2. standardization of language for communication; and
3. comparability of data across time and geographical areas.

Case definitions requiring notification under International Health Regulations (2005)

 

A. Human influenza caused by a new subtype Case definition for notification of human influenza caused by a new subtype under the IHR (2005) State Parties to the IHR (2005) are required to immediately notify WHO of any laboratory confirmed case of a recent human infection caused by an influenza A virus with the potential to cause a pandemic. Evidence of illness is not required for this report. An influenza A virus is considered to have the potential to cause a pandemic if the virus has demonstrated the capacity to infect a human and if the heamagglutinin gene (or protein) is not a variant or mutated form of those, i.e. A/H1 or A/H3, circulating widely in the human population. An infection is considered recent if it has been confirmed by positive results from polymerase chain reaction (PCR), virus isolation, or paired acute and convalescent serologic tests. An antibody titre in a single serum is often not enough to confirm a recent infection, and should be assessed by reference to valid WHO case definitions for human infections with specific influenza A subtypes.


WHO case definition for human infections with avian influenza A(H5) virus requiring notification under IHR (2005)

1. A person with a laboratory-confirmed infection with an avian influenza A(H5) virus.

A laboratory-confirmed infection is considered if it has been confirmed by positive results from polymerase chain reaction (PCR), virus isolation, or serological testing of paired acute and convalescent serum.  

  • The types of specimens to be collected for the diagnosis of viral infections of the upper and lower respiratory tract are described in the WHO Manual for the laboratory diagnosis and virological surveillance of influenza. In cases presenting with conjunctivitis, conjunctival specimens should also be collected.
  • WHO information for the molecular detection of influenza viruses can be found here.
  • Virus isolation from specimens suspected or confirmed to contain avian influenza A(H5) virus is not recommended, unless it is performed at a WHO influenza CC or a WHO H5 Reference Laboratory of GISRS, due to the biosafety requirements.
    • Serologic testing of paired acute and convalescent serum specimens:
      • Serological confirmation of an A(H5) case requires paired sera collection (one acute, one convalescent specimen), with a ≥ 4-fold rise in neutralizing antibody titres (or equivalent) to an influenza A(H5) virus1  that is antigenically similar to the virus the person was exposed to, with a convalescent neutralizing titre ≥ 1:40. Acute serum should be collected within 7 days of symptom onset; convalescent serum should be collected ≥ 21 days (ideally 21–28 days) after symptom onset. 

    2. A person with only a single convalescent serum specimen collected for serologic testing, when the following are met:

  • The criteria for seropositivity of an A(H5) infection using a single convalescent serum specimen, collected at ≥ 21 days after symptom onset or exposure includes a neutralizing antibody titre ≥ 1:40 to an influenza A(H5) virus; and
  • A positive result using a different serological assay such as a hemagglutination inhibition (HI) antibody titre ≥ 1:40, or an influenza A(H5)-specific positive result from another immunological assay such as an enzyme-linked immunosorbent assay (ELISA), a multiplex binding antibody assay, or similar binding antibody assay; and
  • In all assays mentioned above, sera are tested against an influenza A(H5) virus(es) or antigen(s) antigenically similar to the virus the person was exposed to; and
  • The person has an epidemiological link2 to a laboratory-confirmed human case.

    • 1. Wild type virus is preferred. 2. This may include close contact such as providing care for the patient, including as a health care worker or family member, or other similarly close physical contact, or staying at the same place (e.g. lived with, visited) as a confirmed case while the case was symptomatic.

    Operational considerations

    • All influenza A positive specimens that are not able to be subtyped should be sent immediately to a National Influenza Centre (NIC) if originally tested elsewhere, and from the NIC to a WHO Collaborating Centre of GISRS for further analysis in line with the relevant WHO operational guidance under their Terms of Reference.
    • All individuals meeting local surveillance case definition should be tested according to local protocols. 
    • Serologic testing is strongly recommended to be performed or directly supported by, or performed in collaboration with, a WHO CC or H5 Reference Laboratory of GISRS.
    • If a single serum specimen tests positive in a serology assay but does not meet the notification requirements under IHR as mentioned above, it is strongly recommended to communicate this information to a WHO CC of GISRS for surveillance and risk assessment purposes. This includes situations where a single convalescent serum specimen tests positive by microneutralization assay and another assay, such as ELISA, but the individual from whom the specimen was taken did not have an epidemiological link to a confirmed A(H5) human case, even though they may have had exposure to A(H5)-infected animals or contaminated environments.
    • Contact WHO Global Influenza Programme (GISRS-WHOhq@WHO.int) for support of serology testing for A(H5) and other help to confirm a human infection with an avian influenza A(H5) virus.

    Other considerations

    • The case definitions may change as new information about the disease, epidemiology, or the viruses become available.
    • Surveillance recommendations and guidance on the investigation of cases of human infection with influenza A(H5) viruses are currently being updated. National authorities may develop other case definitions for other objectives and testing strategies.
    • Clinical decisions concerning the treatment, care or triaging of people potentially infected with an influenza A(H5) virus should be based on clinical judgement and epidemiological reasoning. WHO clinical practice guidelines for influenza have been published separately here.
    • Other resources on influenza surveillance, preparedness and response can be found on the website of the Global Influenza Programme.