WHO Update on Pakistan Cluster from November/December '07

[HenryN]

Re: WHO Update on Pakistan Cluster from November/December '07

WHO confirms two bird flu deaths in NW Pakistan
'Pakistan Times' Wire Service
PESHAWAR: World Health Organisation (WHO) confirmed two bird flu victims in NWFP province last year.

Dr Mukhtar Zaman of Khyber Teaching Hospital Peshawar said a dairy farm worker in Abbotabad area of Kakol was affected with the bird flu last year. He was shifted to a hospital on November 5.

In the meantime, his brother was also affected and he was admitted to the hospital with bird flu symptoms on November 14.

The live stock official recovered, however, his brother passed away on November 19.

Later on, two other brothers of the same dairy farm worker were brought to the Khyber Teaching Hospital Peshawar, of them, one recovered and the other died on November 28.

Dr Mukhtar Zaman said the samples from the two deceased brothers have been sent to WHO, which confirmed that both the brothers died of bird flu virus H5N1.

http://www.pakistantimes.net/2008/04/06/top14.htm

[HenryN]

Re: WHO Update on Pakistan Cluster from November/December '07

I found no quote from any statement however, where a
WHO-spokesperson even mentioned h2h2h

The latest WHO update stated

"These laboratory test results support the epidemiological findings from the outbreak investigation in December 2007, and the final risk assessment that suggested limited human to human transmission likely occurred among some of the family members "

The update included the disease onset dates. Two brothers had onset dates of November 21 indicating they were infected around November 19. The index case was infected in October , while culling. He developed symptoms on October 29 and was NOT the source of the two CONFIRMED H5N1 infections in two of his brothers, one of which died November 28. They were infected by the brother that died November 19.

WHO assumes that those reading their update also can read a calender, which in some cases may be have not have been warranted.

[gsgs]

Re: WHO Update on Pakistan Cluster from November/December '07

despite of what may or may not be obvious, it's still important
whether WHO actually sends out the message.

Those who have followed this, will remember, how long it took
until WHO admitted (likely) h2h.
Flubies knew it much earlier ...

Now we may have this with h2h2h. I assume it will still take a long time
until WHO declares likely h2h2h in Pakistan or elsewhere.

[HenryN]

Re: WHO Update on Pakistan Cluster from November/December '07

despite of what may or may not be obvious, it's still important
whether WHO actually sends out the message.

Those who have followed this, will remember, how long it took
until WHO admitted (likely) h2h.
Flubies knew it much earlier ...

Now we may have this with h2h2h. I assume it will still take a long time
until WHO declares likely h2h2h in Pakistan or elsewhere.

WHO has already addressd this. There will NOT be yet another update on H2H2H in Pakistan.

H2H2H2 is quite clear (calender required - it is the stongest metric and in the Pakistan cluster it is NOT ambiguous - there is no more data to come - sequencing doesn't prove anything, and only one isolate was obtained).

I believe you have a FUNDAMENTAL misunderstanding on how to prove H2H or H2H2H.

[HenryN]

Re: WHO Update on Pakistan Cluster from November/December '07

Commentary

http://www.recombinomics.com/News/04090801/H5N1_H2H2H_Pakistan_Proof.html

[unpathedhaunt]

Re: WHO Update on Pakistan Cluster from November/December '07

Recombinomics Commentary 12:48
April 9, 2008

This is the final installment of the rather tortuous and conflicting story
laid out in the ProMED-mail posts listed below, which is best forgotten.
The final analysis summarized in the table above now indicates clearly that
person-to-person transmission of avian influenza virus infection occurred
within a family of brothers in Peshawar, Pakistan.

The above comments from a ProMed commentary acknowledge the obvious human to human transmission of H5N1 in Pakistan, but since it is one of the longest transmissions for confirmed H5N1 reported to date, it is not "best forgotten." ProMed would probably like to forget about the number of times their commentaries, linked below, suggested that the human to human to human (H2H2H) transmission was not an example of H2H transmission, and current media reports and blogs are still suggesting that the H2H2H was just H2H, involving the index case infecting three of his brothers.

However, it was the length of the chain which lasted for more than a month that created much of the confusion in media reports, coupled with the delay in reporting the outbreak and the degradation or absence of samples, which created more confusion. The latest report raises the number of confirmed cases to three, which more accurately reflect the H2H2H transmission, which was confusing earlier, when there was only one confirmed case in Pakistan.

Proving H2H or H2H2H transmission is straightforward and is heavily dependent on disease onset dates. Although there may be extenuating circumstances to invalidate the simplest interpretation of the data, such data rarely surfaces, other than the fact that many index cases have an association with poultry, and family members, who have the closest contact with the index case, also live in proximity to poultry. Moreover, since most patients are not tested unless they have a linkage with poultry or a confirmed case, the association with the poultry is not likely to change.

However, the likelihood of a confirmed H5N1 infection by an infected family member is several orders of magnitude higher than infection by infected poultry. The number of confirmed human cases is in the hundreds, wile the number of birds culled is in the hundreds of millions. However, clusters of human cases are common, and most have a significant gap in disease onset dates, signaling H2H infections, because there is close contact.

Clusters of H5N1 infections involving the current versions of H5N1 go back to early 2004. Human clusters alone are cause for concern, because they signal a more efficient transmission of H5N1 to humans. However, most of these clusters have significant gaps in disease onset dates, implicating H2H transmission. Although the gaps in disease onset dates are obvious, such gaps were not considered as "proof" and most write-ups in the literature included epidemiological data which required that the subsequent infections were not linked to poultry.

There have been several such clusters, including the example in Thailand in 2004 involving a child living with her aunt, and her mother, an office worker in Bangkok. This was considered H2H because the mother had no poultry contact, and the cluster also involved the aunt. Clusters of 3 or more are more easily proved, because infections of humans by H5N1 is rare and sequential infections are likely to be H2H or H2H2H. However, only the lack of involvement with poultry distinguishes these clusters from the more common set of circumstances, where additional family members are physically close to poultry. However, the difficulty in infections of human by H5N1 greatly reduces the likelihood of two independent B2H transmissions.

Although unlikely, some clusters of three are not in the proven H2H category, even though the above circumstances surrounding the cluster have been met. On such cluster in early 2004 in Vietnam involved a groom and his two sisters, who cared for him. He developed bird flu symptoms and died prior to the collection of samples. However, his two sisters subsequently developed symptoms on the same day, indicating they were exposed to a common source, their brother. Testing on the sisters was initially inconclusive, but H5N1 was subsequently confirmed. They were hospitalized on the same day and both died a week later within one hour of each other. However, H5N1 sequences differed, indicating their brother was infected with multiple H5N1 strains, but these differences were used to exclude H2H, even though one of the sisters had no prior exposure to poultry.

Many other H2H clusters are excluded because samples are not collected from the index case. However, most are excluded from the proven H2H category because family members who are subsequently infected are living in areas where there is poultry.

In the case of the four brothers in Pakistan, the transmission chain was long, and the brothers were not in contact with poultry. Only the index case had a direct link to H5N1 positive birds. Moreover, the disease onset dates had large gaps. The index case developed symptoms on October 29, while one brother developed symptoms on November 12. He died on November 19 and two days later two brothers developed symptoms. The development of symptoms within a few days of the death of the index case is common. The viral load of the index case is likely to be high at the time of death, and the death creates additional transmission opportunity to family members, including hugging and kissing, preparing the body for burial, transport of the body for burial, or other close contact at the funeral. In the cases of the two brothers who developed symptoms on November 21, they were exposed to a common source, their dead or dying brother. Thus, the transmission in Pakistan was H2H2H.

Although most H5N1 clusters have a gap in disease onset dates signaling H2H, but the vast majority of such H2H transmissions are not proven because of circumstances surrounding the H2H transmission, which includes some linkage of poultry with infected family members.

Avian influenza, human (05): China, Pakistan 20080110.0134
Avian influenza, human (03): Egypt, Pakistan, WHO 20080104.0038
2007
---
Avian influenza, human (177): Pakistan, Viet Nam, Egypt 20071227.4152
Avian influenza, human (172): China, Pakistan 20071222.4110
Avian influenza, human (171): Pakistan 20071220.4089
Avian influenza, human (169): Pakistan 20071218.4072
Avian influenza, human (168): Pakistan 20071217.4059
Avian influenza, human (167): Pakistan 20071216.4049
Avian influenza, human (166): Pakistan, WHO 20071215.4038
Avian influenza, human (165): Pakistan 20071214.4023
Avian influenza, human (163): Pakistan 1st report 20071213.4008]

Media Links

[unpathedhaunt]

Re: WHO Update on Pakistan Cluster from November/December '07

Commentary

More on H2H H5N1 Transmission Media Myth

Recombinomics Commentary 14:26
April 9, 2008

The recent WHO update on the extended human to human to human (H2H2H) transmission in Pakistan, as well as the Lancet paper on H2H in China has focused media attention on H2H transmission, which has been the subject of a media myth for the past four years. This was due in part by efforts of various governments and WHO to minimize the number of examples, which is more than several dozen. A great deal of effort focuses on splitting hairs between a familial cluster due to a common source (poultry) and clusters due to H2H transmission. This distinction is not significant, since both signal a more efficient transmission, which is the key requirement for a catastrophic pandemic that could greatly exceed 1918.

Currently H5N1 can grow well and produce fatal infections in a wide range of mammalian host, including humans. In humans, the case fatality rate for WHO confirmed cases exceeds 60%, which if coupled to the transmission efficiency of seasonal flu, would generate 100’s of millions of fatalities.

The media, generally does not consider a gradual change in transmission efficiency, so the mention of H5N1 and H2H in the same sentence creates concerns. However, limited H2H has been clear since the current expansion, which began in late 2003, was reported. Most of the confirmed clusters have been limited by the lack of sample collection from the index case. Those clusters which involve family members with links to poultry have been excluded from the list of proven examples, so H2H examples are usually limited to a handful of examples, when in fact the number of clusters is closer to 50 and the vast majority of such clusters involve H2H.

In fact, most initial confirmed human cases in country belong to a cluster. These cluster countries include Cambodia, Indonesia, China, Turkey, Iraq, Azerbaijan, and Nigeria. In Turkey, the number of lab confirmed cases was 21 and almost all were in clusters, although only 12 were subsequently confirmed by WHO labs because of sample degradation. Similarly, about 50% of the 2005 cases in Indonesia were in clusters, as were approximately 1/3 of the cases in Vietnam in 2005. Moreover, the discounting of clusters, due to lack of sample collection of misdiagnosis, is still ongoing, as seen in recent clusters in Indonesia.

The media myth, concerning the frequency of such clusters, continues, leading many to assume that the recent clusters in Pakistan and China are usual. Moreover, lack of human cases in India and Bangladesh remain suspect, and the clusters in Indonesia remain unconfirmed, due in part to the absence of sample testing, as well as false negatives due to collection of samples after the start of Tamiflu treatment.

Thus, the frequent and size of clusters is grossly under-estimated, and readers of the popular press remain surprised by the recent discussions of H2H transmission. Moreover, H2H transmission in families is also couched in terms of a genetic predisposition, for which there is no real data. Currently, H5N1 transmission is inefficient and requires close contact, which is most common among family members. In larger clusters there are examples of contacts who are not blood relatives, including husband / wife, friends, and patient / nurse. Moreover H5N1 is largely a avian virus at this time, but has been isolated from a wide range of mammals including domestics and wild cats, dogs, stone martens, foxes, Civet cats, swine, and mice, so the likelihood of a significant human predisposition remains remote.

However, the continued passage of H5N1 through a wide variety of mammals, including humans, increases the likelihood of the acquisition of polymorphisms via recombination, leading to more efficient transmission to humans.

http://www.recombinomics.com/News/04090802/H5N1_H2H_Media_Myth_More.html

[Sally Furniss]

Re: Pakistan: Human H5N1 Cluster December 2007

<big><big>Commentary</big></big>

Confirmed B2H2H2H2H H5N1 Transmission in Pakistan
Recombinomics Commentary 16:02
October 4, 2008

With respect to the chain of transmission, evidence gathered during the investigation supports the theory of initial transmission from poultry to humans followed by human-to-human transmission involving a third generation.

Case 5 was a 33-year-old brother of Case 1. He was asymptomatic but clinical specimens were collected from him owing to the close and prolonged contact with his ill brothers. Initial testing at the National Institute of Health yielded positive results for H5 RT?PCR on a throat swab collected on 29 November. When serum specimens were tested by microneutralization assay, a specimen collected on 8 December yielded an H5 antibody titre of 1:320 and a positive western blot assay.

The above comments are from WHO?s Oct 3 Weekly epidemiological record (WER), which includes a report entitled ?Human cases of avian influenza A(H5N1) in North-West Frontier Province, Pakistan, October-November 2007?. As indicated in the title, the report is coming out almost a full year since the start of the outbreak, and as indicated in the quotes above, includes an asymptomatic brother who was H5N1 confirmed by three different lab tests. However, these results have not been released previously, and the newly described case extends the transmission chain to B2H2H2H2H, which is the longest recorded to date for H5N1. Moreover, even though the case is acknowledged in this week's report, the case has not been added to the WHO table of confirmed H5N1 cases. These delays and omissions extend the long list of deficiencies in the detection and reporting of this historic and important H5N1 outbreak in Pakistan.

The report provides detail that was lacking for months after the outbreak began, and clears up a subset of the long list of questions raised by the outbreak. However, many important issues, including the sequence of the H5N1 isolated from the first confirmed case, which remains in WHO?s private password protected database, along with hundreds if not thousands of H5N1 sequences from infected patients or other hosts, remain unresolved.

As noted in the report, the transmission chain began when one of the cullers was infected in October (B2H) and developed symptoms on October 29, 2007. He then infected one of his brothers (B2H2H) who developed symptoms on November 12 and died a week later, but not before the brother infected two more brothers (B2H2H2H) who developed symptoms on November 21. One of these brothers died November 28 and one infected a fifth brother (B2H2H2H2H) who was asymptomatic, but as noted above, was H5N1 positive by three lab tests, including PCR on a nasal swab collected November 29.

However, none of the above was made public until there were local media reports, which were picked up by internet discussion groups in early December, 2007. The story was subsequently picked up by wire services followed by comments by agencies in Pakistan or WHO. However, the initial stories were largely confusing, in part because of the long delay between the start of the outbreak and the start of media coverage. Consequently some stories noted that the outbreak began in October, while others assumed the outbreak began in December, just prior to the media stories.

In addition to the brothers described above, other cullers and contacts were also said to be H5N1 positive based on testing done in Pakistan. However, by the time investigators from WHO regional centers in Egypt and England arrived, the samples had largely degraded and initially the only positive was a sample from the brother who died November 28. A sample from the brother who died November 19 was not tested (although at least one local media report indicated a sample had been collected), and samples from the brothers who were hospitalized and recovered tested negative. The time of the testing of the asymptomatic remains unclear, because the WER indicates the sample collected November 29 was PCR positive, yet this positive result was not disclosed prior to this week.

However, in addition to the long delay in the acknowledgment of the asymptomatic case and the failure to test the first fatal case, the two cases who recovered were not reported confirmed until April, when results from neutralizing antibody tests were reported. It is unclear if these delays were linked to the establishment of a new test using the H5N1 isolated from the second fatal case as a target, because the sequence of this isolate has been withheld. Therefore, it is unclear if there were significant differences in sequence between the human isolate and other available targets.

However, since the titer for the index case was 1:2560 and the recovered brother was 1:320, as was the asymptomatic brother, it seems likely that these high titers would have been detected when the samples were collected in late November or early December. Thus, the reasons for the four month delay in reporting the confirmation of the two recovered brothers or the 10 month delay in reporting the asymptomatic case remains unclear, as is the reason for the failure to add the asymptomatic case to the list of H5N1 confirmed cases, since the brother was H5N1 positive in three lab tests (PCR, neutralizing antibody, and Western blot).

The reporting delays associated with the longest human to human H5N1 transmission recorded to date has been followed by questionable reports by other countries. The H5N1 in Pakistan was followed by massive outbreaks in India (West Bengal) and adjacent Bangladesh. Bangladesh has acknowledged one human case, which was also reported months after the fact. The location of the reported case in the slums of Dhaka strongly suggests that the number of human cases in Bangladesh and India was markedly higher than one. India has yet to report any human cases, although the bird flu symptoms in villagers were wildly reported, as was the similarity in sequence between the H5N1 in India and Bangladesh, although neither country has released sequences from these outbreaks (and Bangladesh has not released sequences from any H5N1 outbreak).

Similarly, H5N1 clusters in Indonesia have been denied. Fatally infected index cases from clusters that involve H5N1 confirmed cases have been said to have died from respiratory disease, typhus, and dengue fever, which has raised serious credibility issues with regard to reporting from Indonesia, and WHO was stopped reporting confirmed H5N1 cases in Indonesia in a timely manner. Instead of the mandated IHR reporting time of 24-48 hours, WHO has been reporting H5N1 cases weeks or months after lab confirmation, setting the precedent for more reporting violations, including South Korea who refused to acknowledge a soldier/culler who was H5 PCR positive earlier this year.

In addition to the delays or lack of reports on H5N1 cases and clusters, WHO regional centers continue to hoard H5N1 sequences in the WHO private database. NAMRU-3 became a WHO regional center last year and has not released any human H5N1 sequences since, even though cases were confirmed at the end of 2007 and beginning of 2008. Sequences from West Bengal have been sequestered at Genbank for several months (see list here), and over 170 HA H5N1 sequences from Turkey have also been sequestered at Genbank for several months (see list here here here here here).

These reporting failures coupled with the hoarding of H5N1 sequence data by WHO and regional centers continue to be cause for concern and continue to be hazardous to the world?s health.

http://www.flutrackers.com/forum/sho...light=pakistan

http://www.recombinomics.com/News/10...B2H2H2H2H.html

[Laidback Al]

Re: WHO Update on Pakistan Cluster from November/December '07

It was a year ago today that that first individual in <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" /><st1:place w:st="on"><st1:country-region w:st="on">Pakistan</st1:country-region></st1:place> confirmed with H5N1 died. The most recent summary of the family cluster of those cases in <st1:place w:st="on"><st1:country-region w:st="on">Pakistan</st1:country-region></st1:place> is included in WER report: http://www.who.int/wer/2008/wer8340.pdf

Here is an updated correlation list, based on this WHO report and the threads listed below, of the names of the brothers associated with the WHO case numbers in the <st1:City w:st="on"><st1:place w:st="on">Peshawar</st1:place></st1:City> cluster.

Ishtiaq Durrani (Case 1)
Mohammad Ilyas Durrani (Case 2)
Mohammad Idrees Durrani (Case 3)
Tariq Durrani (Case 4?)<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /><o:p></o:p>
Mohammad Owais Durrani (Case 5?)
<o:p></o:p>
<o:p></o:p>
What is missing from the WHO tables and discussion are the two other human cases in <st1:place w:st="on"><st1:country-region w:st="on">Pakistan</st1:country-region></st1:place> that were confirmed by the MOH and also widely reported in the media at the time.
<o:p></o:p>

"Seven in total. One died and six other people were infected with the H5N1 virus," Federal Health Secretary Khushnood Akhtar Lashari told Reuters. "It was confirmed by blood tests."

http://www.flutrackers.com/forum/sho...&postcount=140
<o:p></o:p>
and
<o:p></o:p>

There was some confusion Saturday about how many people had tested positive for the virus, with Pakistan announcing six cases but an official of the World Health Organization suggesting as many as nine people may have tested positive for the virus in that country.
The WHO spokesperson said investigations are still underway to try to determine how the various people became infected, but some human-to-human spread is possible.

"We can't rule it out,'' WHO spokesperson Gregory Hartl said from <st1:City w:st="on"><st1:place w:st="on">Geneva</st1:place></st1:City>.

http://www.flutrackers.com/forum/showpost.php?p=118588&postcount=152

Some of the news report indicated that these two other confirmed individuals were cousins of the Durrani brothers while other reports indicate that these two were a father and a daughter cluster in Mansehra. Until the discrepancy in the test results are discussed by WHO, there will continue to be lingering questions about the extent of human H5N1 transmission in <st1:place w:st="on"><st1:country-region w:st="on">Pakistan</st1:country-region></st1:place> last November and December in 2007.
<o:p></o:p>
<o:p></o:p>
Additional FT links on the human cluster in Pakistan . . .

Pakistan: Suspected Human Cases December 10 - December 17, 2007:
http://www.flutrackers.com/forum/showthread.php?t=44767

Pakistan - BF Suspected Human Cases December 18, 2007 to Feb 2, 2008:
http://www.flutrackers.com/forum/showthread.php?t=45631

<st1:country-region w:st="on"><st1:place w:st="on">Pakistan</st1:place></st1:country-region>: Human H5N1 Cluster December 2007:
http://www.flutrackers.com/forum/showthread.php?t=46327

Human cases of avian influenza A(H5N1) in <st1:place w:st="on"><st1:City w:st="on">North-West Frontier Province</st1:City>, <st1:country-region w:st="on">Pakistan</st1:country-region></st1:place>, October?November 2007 [WHO, WER] *NEW* http://www.flutrackers.com/forum/showthread.php?t=81695
<o:p></o:p>
WHO Update on <st1:place w:st="on"><st1:country-region w:st="on">Pakistan</st1:country-region></st1:place> Cluster from November/December '07:
http://www.flutrackers.com/forum/showthread.php?t=62591