An upsurge in H5N1 bird flu outbreaks in poultry across Asia is driving home the message that even countries that have eliminated the virus once shouldn't become complacent. The continuing high death toll in humans, including two recently detected cases of infection with a Tamiflu-resistant strain in Egypt, is also a grim reminder of how devastating the virus might be if it acquires the ability to spread easily among humans.
...Over the past 3 weeks, Thailand and Vietnam reported their first H5N1 outbreaks among poultry in 6 months. Japan, which seemed to have dodged the bullet since its cluster of outbreaks in 2004, confirmed that the virus hit one farm on 11 January and probably a second farm on the 23rd. South Korea, which last November suffered its first outbreak since containing the virus in 2004, reported that the virus had turned up on a fifth poultry farm. Several wild birds found dead in Hong Kong tested positive for H5N1. And Indonesia on 20 January reported its fifth human death from the virus in just 10 days, bringing its death toll to 62, by far the most of any country.
The increase in outbreaks in the Northern Hemisphere follows what has become an established pattern. The reason for the seasonality is still not well understood, says Les Sims, a veterinarian based in Manunda, Australia, who advises the U.N.'s Food and Agriculture Organization (FAO). It is likely to be some complex interaction among several factors, including cooler temperatures enabling the virus to survive longer in the environment, greater poultry trade in preparation for winter festivals, and movements of wild birds.
The recurrence of the virus in South Korea and Japan is particularly notable. In both the winter of 2003-'04 and this year, outbreaks in South Korea were followed 4 to 6 weeks later by outbreaks in Japan. "The outbreaks in Japan and South Korea suggest to me free-flying birds as the most likely origin," says Sims. Both countries are trying to determine how the virus was reintroduced.
So it seems unlikely we will be rid of the virus through culling programs, the primary mechanism thus far employed for biosecurity. That the virus seems to be spread by wild birds in these cases is interesting, but this isn't the only pathway for reintroduction into poultry or people.
Last week's issue of New Scientist revisits the notion that "Deadly H5N1 may be brewing in cats". (Most of the relevant text is available here at ProMed.) Felines may be serving as a mammalian host that might enable the virus to adapt to mammalian biology and thereby become more dangerous to humans. This is something I started wondering about after cats started dying in Europe so soon after the virus arrived there last year. The New Scientist provides corroborating evidence that cats are important in the dynamics of the virus in Indonesia. The story reports some surprise on the part of scientists doing the field work with regard to the prevalence of the virus in cats in Indonesia:
In the first survey of its kind, an Indonesian scientist has found that in areas where there have been outbreaks of H5N1 in poultry and humans, 1 in 5 cats have been infected with the virus, and survived. This suggests that as outbreaks continue to flare across Asia and Africa, H5N1 will have vastly more opportunities to adapt to mammals than had been supposed.
Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia, told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java, including the capital, Jakarta, and one area in Sumatra, all of which have recently had outbreaks of H5N1 in poultry and people.
Of these cats, 20 per cent carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20 per cent of the original cat populations may have acquired H5N1.
This is a much higher rate of infection than has been found in surveys of apparently healthy birds in Asia. "I am quite taken aback by the results," says Nidom, who also found the virus in Indonesian pigs in 2005. He plans further tests of the samples at the University of Tokyo in February.
The data explicitly contradicts prior statements from the WHO downplaying the role of cats in harboring or spreading the virus, which I wrote about here. I continue to be fascinated by the extent to which the behavior of the virus in the wild contradicts the expectations and public statements of "officials" in various organizations around the world. H5N1 is clearly evolving in ways that are both surprising and worrying.
The New Scientist and Science stories both note that two people in Egypt who recently died from H5N1 infections were carrying strains of the virus evidently resistant to Tamiflu. It is unclear whether the virus carried the relevant mutations before it infected these patients, or whether it evolved during their illness because they were treated with Tamiflu in the hospital. Either way, it seems that many people infected with H5N1 are diagnosed after the window in which antivirals are most effective, in part because diagnosis is both difficult and slow. This phenomenon is described in two articles and a commentary in the 26 November, 2006, issue of The New England Journal of Medicine that report disturbing analyses of human H5N1 outbreaks in Indonesia and Turkey last year.
In a New York Times article about the NEJM papers, Donald Mcneil, reports the following:
Rapid tests on nose and throat swabs failed every time, and in Turkey, so did all follow-up tests known as Elisas. The only tests that consistently worked were polymerase chain reaction tests, or PCRs, which can be done only in advanced laboratories and take several hours.
''It'll be a disaster if we have to use PCRs for everybody,'' said Dr. Anne Moscona, a professor of pediatrics and immunology at Weill Cornell Medical College. ''It just isn't available at a whole lot of places.''
If the A(H5N1) flu mutates into a pandemic strain, rapid tests ''will be really key,'' she said.
What the NYT didn't report is that the patients were infected on average 5 days prior to the appearance of symptoms, outside the window recognized for effective use of antiviral drugs. Robert Webster and Elena Govorkova have an excellent Perspective piece accompanying the NEJM articles, and they note that in the Indonesian cases, "...Treatment [with oseltamivir] began 5 to 7 days after initial infection. Such delayed administration of the drug limits its value in decreasing the viral load and might lead to the selection of resistant strains." It isn't clear from the paper describing the Turkey outbreak when oseltamivir was administered, but those patients did not experience symptoms for an average of 5 days after exposure to the virus, and then received antibiotics for the first 3-7 days of hospitalization before transfer to a unit that treated them for influenza. In summary, it appears the virus is often being exposed to oseltamivir after the period when the drug is expected to be effective, enhancing the probability of selecting for resistant mutants.
Finally, in a slight change of direction, in the 21 December issue of Nature, John Oxford has a review of a new book on influenza, "Bird Flu: A Virus of Our Own Hatching", by Michael Greger. You may recall that Oxford is primarily responsible for the hypothesis that the 1918 flu emerged at a British army camp near Etaples, a tale I wrote about a couple of years ago (The Spanish Flu Story). Oxford notes that:
I am often kicked around by American authors in books about influenza. How dare a Limey suggest that the Spanish influenza A H1N1 virus arose in a gas-infected, pig-ridden and bird-infected army camp of 100,000 people in France in 1916, when the whole world knows it started in Dorothy's home state, Kansas? But I felt less bruised than usual. Perhaps I am getting used to it.
I still find Oxford's version of the origin of the Spanish Flu to be the most compelling, in part because it describes a situation of close contact between animals and people, where those animals were killed and prepared as food by soldiers on a daily basis in conditions not so dissimilar to those in many developing countries where H5N1 is present today.