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January 10, 2006

Interim report of the results of A/H5N2 avian influenza ( low virulent )
serum antibody tests in Ibaraki and Saitama prefectures

National Institute of Infectious Diseases

Summary

In order to verify if A/H5N2 avian influenza virus was transmitted to humans after a series of epidemics were reported at chicken farms in Ibaraki and a farm in Saitama prefecture since June 2005, serum neutralizing antibody values were measured.  All the tests have not been completed, but the current results based on tentative criteria showed positive serological tests among people who had been in contact with infected poultry, suggesting that some people might have been infected with the A/H5N2 virus.  Further studies are required for more details.

Study method

Serum neutralizing antibody tests for avian influenza virus A/Ck/Ibaraki/1/2005(H5N2), which had been isolated in Ibaraki prefecture, were conducted on 353 samples among 385 that were first collected and 264 samples that were secondly collected in Ibaraki and Saitama prefectures since the end of June 2005, and submitted to the National Institute of Infectious Diseases for examination until the end of December.  The second blood collection was basically conducted one month after the first collection.

The serological evaluation was based on a significant increase of more than four-fold in the antibody values of paired serum samples from the first to the second collection.  On the one hand, since the virus of the epidemic has attenuated virulence, it is difficult to specify the time of the epidemic among the poultry at the chicken farms, and it is not possible to specify the time when people were exposed to the virus.  Since it could also be considered that antibody had already been produced after earlier exposure to the virus, by the time of the first collection, it is also possible that there is not a significant increase in the antibody values of the paired serum samples.  In order to evaluate a single neutralizing antibody measurement to be positive, instead of testing paired serum samples, a new criterion should be established.  Since the criteria for a positive neutralizing antibody test for the human A/H5N2 influenza virus have not been established, we established the criteria based on the measured neutralizing serum antibody values in 31 subjects who had not been in contact with infected poultry, as the control group.

Study results

A significant increase of more than four-fold in antibody values of paired serum samples from the first to the second collection, the basis for serological diagnosis, was observed in 15 cases.  No increase in antibody values was observed among subjects who were engaged in killing poultry.

In the control group, 97% of the subjects who had not had any contact with poultry showed antibody values of 10 or below, and there were no values of 40 or over.  Based on this fact, samples with an antibody value of 40 or over were tentatively defined as positive.  According to this criterion, besides the 15 whose paired serum samples showed a significant increase in antibody value, as shown in the table, 49 samples from the first collection and 24 from the second were found positive.  Of these, 11 were found to be positive both in the first and the second collections.

As a result, 77 among the 353 were found to have a positive serological test.


   Employees in chicken
farms etc.		 Health workers Total
Number of subjects with increased antibody values
(more than four-fold)		 15 0 15
Positive only in the first collection 34 4 38
Positive only in the second collection 13 0 13
Positive both in the first and second collections 10 1 11
Total number of positive cases 72 5 77
Number of subjects in the first collection 319 34 353
Number of subjects in the second collection 231 33 264


Discussion

A serological test is a method that does not detect pathogens directly, but is based on indirect speculation of infection by measuring the antibody response in a host against the infection.  When strict serum sample pairs at the time of and after exposure are not available, the study results are interpreted based on the criteria for a positive result, based on a comparison of the antibody value distribution between an infected and a non-infected group.  It is rather difficult to obtain samples from an apparently infected group and a non-infected group in human studies including the present study.  Therefore, it should be noted that some of the study results are tentative.

Based on the fact that a significant increase in paired serum samples from the first to the second blood collection was observed in 15 cases, a quarter of the 62 judged positive based on single serum values. If it is assumed that these positive cases had been infected with the virus, it seems that most had already produced antibody due to exposure to the virus by the first collection.  This is consistent with the fact that the virus infection was already terminated, since virus was not isolated, only antibody was detected in most poultry at chicken farms when avian influenza was confirmed.

Most subjects who may be infected are the employees at chicken farms.  It is considered that infection occurred due to contact with infected poultry or their feces and urine in the absence of appropriate preventive measures because infection had not been confirmed yet at the infected chicken farms.

On the other hand, for health workers, the first blood sample was collected when they started working at the farms, so it is relatively easy to detect infection due to their infection control activities.  No significant increases in paired serum samples were observed among health workers, and it is considered that there were no infection control activities, at least.  Of the 5 positive cases at the first test, 3 did not have a history of contact with poultry.  Two who had a history of contact with poultry might have been infected from poultry, before control activities started.  The other 3 with no history of contact were possibly infected by exposure to a similar virus, or by administration of anti-viral agents before control activities started, but it is not clear now.

In the current serological study based on the tentative criteria, there are 77 positive cases suggesting infection, but no influenza-like symptoms were observed.  Since avian influenza is not persistent, and the incubation period for H5N1 virus is 2 to 7 days, it is considered that these positive cases have no possibility of contracting the disease in the future.

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