WHO's case definition for H5N1

WHO has just issued case definitions for H5N1 infections. Case definitions are criteria that must be satisfied to designate a person as being "a case" of H5N1 infection. Case definitions are not clinical tools but epidemiological ones. Epidemiological measures pertain to populations and require the ability to count cases and at risk populations. For example, a case fatality ratio (sometimes incorrectly called a case fatality rate) is the percentage of people infected with H5N1 that die from the disease. A case definition is necessary to determine the denominator, those infected with H5N1. Case definitions should not be used to guide treatment, which requires clinical judgment. But they are necessary elements for understanding what is going on epidemiologically, especially monitoring and following the evolution of the disease over time and in various areas and in investigating outbreaks.

So what is the WHO case definition? It has four main categories: (1) person under investigation; (2) suspected case; (3) probable case; (4) confirmed case. Only categories (3) and (4) require formal WHO notification.

(1) Persons under investigation, are those who health authorities decide to investigate for H5N1 infection, for whatever reason. The threshold is thus very low, on the one hand, but also requires some index of suspicion on the part of health authorities. This is the place where either astute judgment or willful or ignorant blindness make a difference;

(2) A suspected H5N1 case is the category for a person with unexplained acute lower respiratory illness with fever of greater than 38 degrees C, (100.2 degrees F. ) and cough, shortness of breath or difficulty breathing. But this alone is insufficient. In Indonesia, for example, it would describe millions of people yearly, most of whom will have other diseases. So there is an additional requirement, that there is some evidence of appropriately timed exposure to a source of H5N1 infection, that is:

One or more of the following exposures in the 7 days prior to symptom onset:

• Close contact (within 1 metre) with a person (e.g. caring for, speaking with, or touching) who is a suspected, probable, or confirmed H5N1 case;
• Exposure (e.g. handling, slaughtering, defeathering, butchering, preparation for consumption) to poultry or wild birds or their remains or to environments contaminated by their faeces in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;
• Consumption of raw or undercooked poultry products in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;
• Close contact with a confirmed H5N1 infected animal other than poultry or wild birds (e.g. cat or pig);
• Handling samples (aniey armal or human) suspected of containing H5N1 virus in a laboratory or other setting.

This is an entirely reasonable way to fashion a case definition for a suspected case. However, there is the danger that the requirements for inclusion (exposure to infected poultry) will also be used as criteria for assigning the source of the infection. The exposure indications are not exclusive and there is nothing to prevent someone from being a suspected case on the basis of one exposure scenario actually to have been infected by another. It should also be obvious that there is something arbitrary about the list, but case definitions require a certain amount of arbitrariness for the overall goal of standardization (allowing comparisons to be made). The objective is to make the criteria as sensitive and specific as possible, balancing the costs of too much inclusion against the dangers of too little.

(3) Probable cases are suspected cases who have either x-ray evidence of acute pneumonia together with respiratory failure (decreased blood oxygenation and severe shortness of breath); or, laboratory evidence of influenza A infection (but insufficient evidence to specify further to the H5N1 subtype).

Also included in the "probable" category are persons who have died of an acute respiratory illness and who are linked through contact to a probable or confirmed case. A typical example would be the mother in the Karo cluster who was buried before any tests could be made to establish her diagnosis.

(4) Confirmed cases are suspected or probable cases who have positive diagnoses from a national, regional or international influenza laboratory whose H5N1 test results are accepted by WHO as confirmatory. The results are of the following forms:

• Isolation of an H5N1 virus;
• Positive H5 PCR results from tests using two different PCR targets, e.g. primers specific for influenza A and H5 HA;
• A fourfold or greater rise in neutralization antibody titer for H5N1 based on testing of an acute serum specimen (collected 7 days or less after symptom onset) and a convalescent serum specimen. The convalescent neutralizing antibody titer must also be 1:80 or higher;
• A microneutralization antibody titer for H5N1 of 1:80 or greater in a single serum specimen collected at day 14 or later after symptom onset and a positive result using a different serological assay, for example, a horse red blood cell haemagglutination inhibition titer of 1:160 or greater or an H5-specific western blot positive result.

Isolation of the virus means being able to grow it in canine, chicken or other animal host cells. PCR is a method that amplifies short stretches of viral RNA. If short stretches characteristic of the H5N1 subtype involved in the infection are present, PCR can often find them. Because use of the right recognition sequences is critical, PCR can produce false negatives on occasion, but is generally sensitive and reliable. The development of antibodies requires the patient to have survived long enough for the immune system to respond in a way that is detectable by these tests. It is a retrospective confirmation, not one useful with acutely ill patients.

These definitions seem reasonable, but we emphasize again they are for epidemiological and not clinical purposes. They are designed to get it right "most of the time," which is usually sufficient. We stress again the exposure criteria should not be used to assign source of infection for any particular case. Only detailed follow-up and investigation can establish this, except in the most obvious of circumstances. Exposure to an environment where there are likely feces from poultry and where H5N1 infection has been found is sufficient to include someone as a suspect case, but not sufficient to conclude that exposure to contaminated poultry feces was the source of infection should the diagnosis be later confirmed.