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Efficient Human to Human H5N1 Transmission in Indonesia

Recombinomics Commentary
December 6, 2005

LEAVITT: Yes, millions of people. This is a very serious, world-changing event if it occurs.

Now, there's no certainty that it will occur as the H5N1 virus, but there is a high degree of probability that some pandemic will occur at some point, and we need to be better prepared than we are today.

The above comments on the effects of efficient human-to-human transmission of avian influenza with a case fatality rate of 2-3% accurately predicts some of the consequences, but fails to acknowledge the fact that H5N1 is clearly gaining in efficiency for human-to-human transmission.  This increased efficiency is being seen in Vietnam, Thailand, and China, but the clearest picture is emerging in Indonesia, as the number of official WHO confirmed cases continues to rise.

WHO's list of confirmed cases in Indonesia recently rose to 12 with the confirmation of H5N1 in a 16 year old boy.  However, the WHO report acknowledges that two brothers of the latest case recently died with bird flu symptoms, but samples for testing were not collected, so the two siblings were not included in the WHO totals.  The exclusion due to lack of samples, or inappropriately collected samples, is similar to the first fatalities reported in Indonesia over the summer.

That cluster included 3 fatalities, but again only one of the three is in the list of WHO confirmed cases.  The index case, an 8 year-old girl, was admitted, but samples were not collected.  He admission was followed by her 1 year-old sister, but again samples were not collected.  Samples were collected when the father of the index case was admitted.  He tested positive for H5N1 and subsequently became Indonesia's first confirmed H5N1 fatality.  Two serum samples were collected from the index case and both were strongly positive for H5N1 antibodies as determined by WHO reference labs in Hong Kong and Atlanta.  However, since the samples were collected just 3 days apart, the increased titer in the second collection was not four fold higher than the earlier collection, so the case was excluded from the list of confirmed cases.  The 1 year old was also excluded because the proper samples were not collected.

Thus, in the first and most recent cluster there were five H5N1 fatalities, but only one of the five fatalities is on the confirmed list from WHO, which today has 13 cases including 8 fatalities.

The collection procedure plays are large role in the creation of lab confirmed cases.  Indonesia, like most countries in Asia collects samples for testing at an infectious diseases hospital.  Cases initially go to primary care facilities were samples are not collected for H5N1 testing.  By the time the patient is transferred to the infectious disease hospital, the H5N1 has been cleared from the nose and throat, so the swabs are collected too late.  Similarly, antibody levels peak at around 30 days post symptoms, so serum collections at 1-3 weeks are too early for antibody collection.  Instead the samples are too late for PCR but too early for antibody.  The samples  are however "Goldilocks" collections which are just right for false negatives.

When a patient does test positive, relatives are tested and this has led to several positives because the samples are collected when the patient first begins to develop symptoms.  In many instances, these cases are mild.  This was seen in the nephew of the second confirmed case in Indonesia.  He had mild symptoms, but a throat swab was collected because is aunt was H5N1 positive.  The nephew was tested prior to hospitalization and he subsequently had a fever for 3 days, recovered, and returned to school.  This mild case was detected because his aunt was positive.  If there was not familial connection, he would have just had a case of the flu that was not identified as being caused by H5N1.

The same situation developed in a 4 year old who had two older siblings hospitalized.  The 4 year old was tested when he just had a sore throat and he too was H5N1 positive.  The case was mild and the younger brother was discharged.  One of the older siblings was positive for H5N1 while the other was negative, but again because of untimely sample collection.  Both older brothers recovered.

Thus, collection samples at an nearly stage, when H5N1 is still present in the nose and throat, leads to lab confirmation of H5N1 cases.  However. Most mild cases are missed because of Goldilocks testing.

The effects of these policies can be seen in the official cases.  Of the 13 confirmed cases, 8 are from familial clusters.  Of the five cases not linked to clusters, all five have died because the detection of H5N1 in nose or throat swabs signaled a massive infection where sufficient H5N1 remained in the nose and throat to produce a positive result.  Of the 8 confirmed cases in family clusters, only 3 were fatal because many of the positive cases were mild and detected because testing was shortly after onset of symptoms.

In addition to the 8 confirmed cases, 5 other family members were excluded because of improper samples.  Thus, of the 13 confirmed and 5 excluded cases, 13 or over 72% of these cases were in familial clusters.

In contrast, only about 1/3 of the cases in southeast Asia were from familial clusters through the spring of this year.  This dramatic increase in cases from clusters shows that H5N1 is being more efficiently transmitted and this efficiency can also be seen in recent cases from China, Thailand, and Vietnam.

Thus, suggestions that the next pandemic may not involve H5N1 or that the pandemic is years away, fails to address the dramatic increase in efficiency of human-to-human transmission of H5n1, especially in milder cases such as those in Indonesia.


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