A fascinating dispatch appears today in the CDC’s EID Journal that gives us new insight into Pakistan’s H5N1 human cluster of 2007, and suggests that the outbreak may have been larger than previously acknowledged.
First, a bit of history of this outbreak (if you remember it well, you can always skip it).
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On December 11th, 2007 in A Strange Story Out Of Pakistan I wrote of the first media reports of a possible bird flu outbreak in the North West Frontier Province (NWFP) of Pakistan.
Over the next few days we saw a procession of confused and often contradictory media reports at first suggesting that there were 8 cases, and 2 fatalities – but which would eventually be reduced to 4 `officially confirmed’ cases and 1 fatality (see They Apparently Can't Find A Number They Like).
On December 15th, 2007 the World Health Organization released the following statement:
15 December 2007
The Ministry of Health in Pakistan has informed WHO of 8 suspected human cases of H5N1 avian influenza infection in the Peshawar area of the country. These cases were detected following a series of culling operations in response to outbreaks of H5N1 in poultry. One of the cases has now recovered and a further two suspected cases have since died.
On April 3rd, 2008 the WHO released an update where they identified a total of 4 cases in this outbreak - Avian influenza – situation in Pakistan - update 2.
Some of the discrepancies in the case counts and death totals comes about due to the the first fatality – Case #2 – having been buried without actually being tested for the virus.
Although the circumstantial evidence for his being infected is very strong, he isn’t `officially counted’ in the totals.
Eventually the initial media furor, and concerns over extended H-2-H (human-to-human) transmission, faded away. No new cases were detected in Pakistan, and the focus moved back to fresh cases in Indonesia, Egypt, and China.
In October of 2008 – nearly a year after the outbreak began - we got a detailed recap of the outbreak from the WHO’s Weekly Epidemiological Record (see WHO: Unraveling the 2007 Pakistan H5N1 Cluster).
The only big revelation in this wrap up was the confirmation of a 5th – asymptomatic case; the 33 year-old brother of Case #1 whose displayed an H5 antibody titre of 1:320 and a positive western blot assay.
And that is pretty much where this story has laid since that time. The official WHO count remains at 4 cases and 1 fatality (case #2 not being officially counted).
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Officially, as of May 13th, the World Health Organization has documented 553 human infections with the H5N1 virus, with 323 fatalities. Along the way, there have been only a handful of confirmed H-2-H transmissions of the virus.
Unofficially, most observers grant that our surveillance methods are incapable of detecting all of the H1N1 cases out there, and that we are probably missing a significant number of them.
All of which serves as prelude to today’s EID Journal article called:
Volume 17, Number 6–June 2011
Mukhtiar Zaman, Saadia Ashraf, Nancy A. Dreyer, and Stephen Toovey
A few excerpts (bolding mine):
Human infection with avian influenza (H5N1) virus raises concern for the possibility of a pandemic. We report 20 cases, which ranged from asymptomatic to fatal, in Pakistan in 2007.
These cases indicate human-to-human-to-human transmission of this virus, and the number of cases may be higher than realized.
We identified 20 cases—4 laboratory confirmed, 7 likely, and 9 possible—resulting in a ratio of 4 likely/possible cases for each laboratory-confirmed case
The human-to-human transmission from the index case-patient to at least some household contacts seems clear, and the extended period over which these contacts became ill supports subsequent human-to-human transmission.
Figure 2 supports the conclusion that patient 2 initiated a chain of infection in which further human-to-human transmission to patients 7 and 8 occurred. Possible nosocomial transmission is of concern because full implementation of isolation procedures in resource-poor settings may be problematic.
Of concern is the 4:1 ratio of likely/possible to laboratory-confirmed cases, suggesting that official tallies understate true incidence of infection.
Factors that may contribute to undercounting are the difficulty of obtaining virologic confirmation or of storing and transporting samples in resource-poor settings and reluctance by relatives to consent to autopsy.
Another reason to believe that less fulminant cases may go unreported is the occurrence in Pakistan, and elsewhere, of clinically mild and asymptomatic cases (5,8–14), indicating that influenza (H5N1) virus may cause a spectrum of illness.
This dispatch is one of those good-news – bad-news type deals.
The bad news is that these results from Pakistan suggest that human H5N1 infections and clusters (as many assume) are probably undercounted around the world.
The good news is that despite more human cases than we are aware of, the virus hasn’t managed to spark an ongoing and efficient chain of transmission.
The big open question is how many mild, sub-clinical, or asymptomatic infections occur in an exposed population. The follow up testing of contacts in the Pakistan cluster suggests that number may be higher than suspected.
The authors write:
Of note, patient 6 (a cousin of the index case-patient) had a microneutralization titer of 80 but a negative Western blot result. Although 4 contacts of patient 6 exhibited no signs or symptoms of influenza, they did have positive H5 microneutralization titers ranging from 80 to 160.
It should be noted that previous seroprevalence studies have failed to show much evidence of mild infections, although the data is limited.
In May of 2009 (see Cambodian Study Finds Rare Asymptomatic H5N1 Infections) we saw a seroprevalence study published in the Journal of Infectious Diseases conducted on more than 600 members of a Cambodian village where 2 human H5N1 cases were detected in 2006.
Antibody titers showed that only 1% (7 of 674) of the villagers tested had contracted, and fought off, the H5N1 virus. A figure much lower than many had expected.
Another study – presented at the Options For Influenza Control VI Conference in Toronto in 2007, came up with similar results (see Seroprevalence Study).
Which, if we are to resolve this impasse, leaves us sorely in need of better and more frequent H5N1 seroprevalence studies from around the world.
In conclusion, the authors write:
Several features of the outbreak are unusual or give cause for concern: human-to-human-to-human transmission, possible nosocomial transmission, occurrence of mild and asymptomatic cases, and difficulties of establishing laboratory confirmation of likely and possible cases (which also prevented genotypic matching of specimens from primary and putative secondary cases).
Taken together, these features suggest that current surveillance might undercount the extent of human infection with influenza (H5N1) virus and that human-to-human transmission might possibly be associated with less severe disease.
Which is why – despite H5N1’s failure thus far to spark a pandemic - researchers continue to watch this virus intently, looking for any signs that it is adapting to human physiology.