Worst Flu Season in Years is a Sign of the Coming Apocalypse By Aaron Rowe April 18, 2008 | 5:17:43 PM
Image: Historical reenactment of the black plague. Photo: Hans S / flickr
Yesterday, the Centers for Disease Control confirmed that this year's flu season was the worst in recent history. Even worse, they admitted that the vaccine did not work well.
Back in February, we knew something was up. So did Michael Moyer at Popular Science, who jokingly called it the PopSci plague. He turned to downing packets of Emergen-C to ward off the particularly nasty illness. Sadly enough, it might be our best weapon. The invisible hand has failed us. Pharmaceutical companies, for the most part, are uninterested in developing drugs to protect us from intermittent threats.
In my opinion, the only way out is a massive investment by the government in antiviral drugs -- particularly small molecules like tamiflu and newer technologies like RNA interference. It's their responsibility to defend us from all threats, foreign and domestic, and disease is a really big one -- perhaps more than terrorism or warfare. So far, our leaders have dropped the ball.
If there is an epidemic, do you think that we will be caught with our pants down? What should we do to prepare?
Health inspectors discovered thousands of dead chickens at a Ukrainian poultry farm, with bird flu suspected as the cause, the Interfax news agency reported Thursday. The die-off took place at a poultry-processing plant near the city Shpol, in the northern Cherkassy province.
The above comments describe a suspected H5N1 outbreak in Ukraine. The outbreak was not unexpected. As birds migrate to the north at this time of year, interactions with domestic poultry increase. Surveillance remains poor, so most reports of H5N1 now come from infected farms or processing plants. Sequence data from an earlier outbreak this year indicated the Uvs Lake strain of H5N1 had migrated to the Crimean Peninsula.
a suspected case had been reported at a duck farm in Gongju in South Chungcheong province, 130 km south of Seoul, suggesting the virus is spreading at its fastest rate since the country reported its first case in 2003.
The above comments describe further spread of H5N1 in South Korea. Although the outbreak may be the largest to date, there was no advanced warning. The large number of outbreaks is almost certainly linked to migratory birds returning to northern locations, but neither South Korea nor Japan detected H5N1 when the birds first came into the region, and Japan has not reported cases since the 2004 outbreak.
However, this is the third report in South Korea and all are likely due to wild birds. In 2003/2004 outbreaks were reported in South Korea and Japan. Sequences were closely related and were precursors to the clade 2.2 (Qinghai strain) identified in May, 2005 at Qinghai Lake. Similarly, the outbreak in late 2006 in South Korea were the Uvs Lake strain which is a clade 2.2.3 subclade that developed in the summer of 2006 in Mongolia.
The affected regions in South Korea lie along a migration route between Mongolia and South Korea and samples collected from areas frequented by migratory birds were positive for the Uvs Lake strain. The wild bird link is also supported by the H5N1 detected in Primorie in southeastern Russia, just north of Korea and just west of Japan.
Although Japan has not reported H5N1 since 2004, they have announce plans to use a pre-pandemic vaccine on first responders. Moreover, the possibility of vaccinating 20 million residents is under discussion.
Thus, the threat of H5N1 continues to grow, although surveillance programs continue to fail to detect H5N1 prior to outbreaks in domestic farms.
Japan has already stockpiled 20 million doses of so-called "pre-pandemic" bird flu vaccine for use after a major outbreak.
The plan is to initially use 6,400 doses of vaccine to inoculate doctors, quarantine inspectors and other health and immigration officials.
If successful, the government aims to expand the programme to others.
"If we obtain good results over its effectiveness and safety, we want to consider vaccinating (an additional) 10 million people who are in medical occupations" or other key jobs such as at utilities, Mr Masuzoe told reporters.
The above comments describe Japan’s plans to implement a pre-pandemic vaccination strategy. Although many countries have pandemic vaccines in clinical trials, most have announced plans to stockpile such vaccines, instead of using the vaccine in a strategy targeted at preventing a pandemic or immunizing first responders.
Japan’s decision is not a surprise. Although they have only confirmed one H5N1 outbreak, neighboring South Korea has now reported H5N1 outbreaks in 3 of the last 5 seasons. These outbreaks have been linked to wild birds and there is little doubt that the H5N1 in South Korea is also in Japan.
Recent vaccine results for poultry has had mixed results. One of the more alarming developments has been in Egypt, where H5N1 has been isolated from vaccinated stocks. The sequence of the HA from these isolates had a large number of non-synonymous changes, which were likely involved in the immunological escape. The recent H5N1 from Israel had the same series of changes, raising concerns about rapid H5N1 evolution, which may be linked to mismatched vaccines. However, the mis-matches are more of a concern for poultry vaccination programs, because H5N1 can be efficiently transmitted from bird to bird, especially in domestic poultry. In addition, the Israeli isolate, like the recent isolate from Saudi Arabia, was amantadine resistant. Moreover, wild bird isolates from Astrakhan were oseltamivir (Tamiflu) resistant, suggesting that anti-viral may have limited utility in controlling a rapidly expanding pandemic.
Similarly, creating a useful vaccine after the pandemic has gained momentum is also unlikely to be effective. H5N1 diversity has grown markedly in the past few years. There are now four distinct sub-clades linked to human cases, and there is further diversity within the sub-clade. Thus, H5N1 could evolve rapidly during vaccine generation, reducing vaccine effectiveness. This effectiveness would be further compromised because the target population is immunologically naive and would likely require booster shots.
Thus, plans to create a vaccine after a pandemic has begun are unlikely to be successful.
In contrast, a pre-pandemic vaccine would primer the target population and may protect from an H5N1 that is not efficiently transmitted. Thus, the vaccine could delay the start of a pandemic. Moreover, vaccine costs are minimal, as seen in the trivalent vaccine to treat seasonal flu. That vaccine contains three different viruses and is available at nominal cost. Due to the rapid evolution of H5N1, a trivalent H5N1 vaccine may be an approach that would produce cross reactive immunity.
The likelihood of a H5N1 pandemic remains high. The current versions of H5N1 emerged out of China in late 2003/2004. The movement of H5N1 into long range migratory birds has produced an major geographical expansion, and the clade 2.2 strain has been reported in over 50 countries in he past few days. Moreover, receptor binding domain changes have been associated with clusters in multiple countries in the Middle East, and these clusters have maintained a high case fatality rate. Recent data on receptor binding domain changes suggest one or two changes could produce an efficiently transmitted H5N1, which when linked to the current high case fatality, would have catastrophic consequences.
Germany and Switzerland are also considering implementation of a pre-pandemic vaccine, as are Vietnam and Indonesia. It is likely that such a concept will spread in the upcoming months, as the persistence of H5N1 increases, along with its genetic diversity.
Tamiflu Resistance in England Exactly Matches United States
Recombinomics Commentary 14:55 April 19, 2008
Two H1N1 NA sequences from England were just released at Genbank. One isolate, A/England/557/2007(H1N1), had the oseltamivir (Tamiflu) resistance marker, H274Y. The sequence exactly matched three sequences from the United States, A/Wisconsin/01/2008, A/New Jersey/20/2007, A/New Jersey/05/2008. The sample from England was collected November 15, 2007 which was two weeks prior to the 2007 match in New Jersey. The 2008 isolates in the US were collected near the end of January, 2008.
The identity between these four isolates, as well as the close relationship to other isolates in the US with H274Y signals evolutionary fitness for this isolate, and further decreases the likelihood that the acquisition of H274Y in these isolates is due to independent events.
The sudden increase in H274Y in H1N1 seasonal flu has startled influenza experts. In the UK and US, the resistance is in approximately 10% of the H1N1 samples, but is above 40% in samples from Norway, France, and Russia. The genetic change that generates H274Y in H1N1 seasonal flu matches the change in H5N1 pandemic flu, and follows the implementation of Tamiflu blankets to control H5N1 in southeast Asia and the Middle East.
The death of 2 thousand 118 birds recorded in the city of Cherkassy Shpola area within Ltd. "Agro-Ros" in the period from 13 to 17 April, reported Interfax-Ukraine with reference to the press service of Ukraine's Ministry of Emergency Situations.
According to the press service, in highly selected patmateriale bird flu (to the DNA-A influenza virus serotype N5) has been detected, according to the records of the results of research Express Cherkassy Regional State Laboratory of Veterinary Medicine.
The above translation indicates that H5 has been detected at the poultry processing plant in Shopla, Ukraine. Detection of H5 among the 2000 dead birds signals H5N1. This result is not unexpected. Ukraine reported H5N1 earlier this year, and the released partial sequence was closely related to Uvs Lake isolates, which have been reported throughout Europe since the summer of 2007.
Moreover, as birds migrate to the north, more interactions with domestic poultry are expected. Detection at poultry farms or processing plants also signals a surveillance failure. H5N1 is clearly widespread in wild bird populations in Europe, but are not being reported by surveillance programs. Recent H5N1 outbreaks in Turkey were linked to feeding of wild bird intestines to domestic poultry. Similar results were found in southeastern Russia in Primosky recently, as wild birds begin migration throughout Europe and Asia.
Tamiflu Resistance in Turkey Exactly Matches US and UK
Recombinomics Commentary 16:23 April 19, 2008
A full NA H1N1 sequence from England was just released at Genbank which had the Tamiflu resistance marker, H274Y. That sequence was an exact match of three sequences from the United States, indicating the sequence was evolutionarily fit and widespread.
A few days earlier, a partial (495 BP) NA H1N1 sequence was released from Turkey. That sequence also had the H274Y. The partial sequence represent more than 1/3 of the NA gene and it was an exact match of the sequences from the United States and England described above. It was also an exact match of additional sequences from the United States from Arizona and New Jersey. Thus, the total number of public sequences that exactly match the partial sequence from Turkey is eight (one from England and seven from the US – see list here).
Thus, it is clear that the above Brisbane sequences are widespread. However, earlier isolates from the US, which were New Caledonian-like and isolated last season also had the H274Y. Thus, the acquisitions began in the 2006/2007 season and were on a New Caledonia genetic background, but the frequency increased dramatically in the 2007/2008 season, where most of the acquisitions are on a Brisbane genetic background.
Thus, H274Y has been reported recently on four distinct genetic backgrounds. Initial reports were in early 2005 on human clade 1 H5N1 in Vietnam. This was followed by clade 2.2 in wild birds in Astrakhan in late 2005, which was then followed by human New Caledonian-like H1N1 in the United States in 2006/2007, followed by Brisbane-like H1N1 worldwide (but highest in Norway, Russia, and France) in 2007/2008.
This movement is easily explained by acquisitions via recombination.
South Korea Bangladesh and India H5N1 Levels Raise Concerns
Recombinomics Commentary 18:04 April 20, 2008
The latest H5N1 reports out of South Korea indicate H5 has been confirmed at 25 locations (which are almost certainly H5N1), and 21 additional sites are under investigation. Almost 5 million birds have been culled, suggesting that the H5N1 outbreak this month will be at record levels.
Recently, similar reports came out of Bangladesh and India. Although H5N1 in Bangladesh has been reported for over a year, the number of infected farms and level of culling increased dramatically in the spring. The same has been true for India (West Bengal and Tripura). All of these areas are close to major wetlands, including the Ganges Delta in Bangladesh and West Bengal. In South Korea the same regions in southwestern Korea are affected year after year, which lie under a migratory bird flyway between South Korea and Mongolia.
These reports of record levels of H5N1 in these areas raises concerns that as wild birds fly to common nature reserves at the intersections of major flyways, the H5N1 from each region will recombine and generate more genetic diversity, which will the spread south in the fall.
Included in these new combinations are receptor binding domain changes, which have been widely reported in clade 2.2, especially in human cases in the Middle East. Moreover, vaccine resistant strains in Egypt have acquired a large number of non-synonymous changes, which will also be migrating north in the upcoming weeks.
The repeated and record outbreaks in South Korea may have led to the decision in Japan to implement a pre-pandemic vaccine strategy involving first responders, as well as 10-20 million citizens, which may also lead to an increase in vaccine doses.
Stockpiling vaccines makes little sense because H5N1 is constantly evolving away from the early vaccine targets, and this evolution is along multiple parallel pathways.
These changes highlight the need for more active surveillance. However, the detection of H5N1 in farms prior to the detection in wild birds points toward failed surveillance systems, which limits the predictability of the changes because of gaping holes in the sequence database.
The increasing pace of H5N1 evolution highlights the need for a more robust surveillance system. as well as the likelihood of a major pandemic sooner rather than later.
SKorea culls 5 million poultry over bird flu 04.20.08, 6:20 AM ET
SEOUL (Thomson Financial) - Almost 5 million poultry have been slaughtered in South Korea to contain the spread of bird flu since it hit the country earlier this month, the agriculture ministry said Sunday.
The avian influenza has hit 25 farms with 4.85 million chickens and ducks culled since the first outbreak on April 1, the ministry said in a statement.
The ministry statement on Sunday did not specify how many of the 25 outbreaks, though all involving the H5 virus, were of the 'deadly' H5N1 strain that sometimes claims human lives.
'We have not made a full count of H5N1 outbreaks yet, which should be released after putting this epidemic under control first,' Kim Chang-Sup, a director handling bird flu at the ministry, told Agence France-Presse Sunday.
'Simple test kits we use now in the field can verify if it is of avian influenza or not, but not of a subtype. If we confirm outbreaks, our priority goes to culling, not testing.'
But Kim denied some news reports that 25 outbreaks were all of the H5N1 strain. Officials have privately confirmed at least seven H5N1 outbreaks.
South Korea reported seven cases of H5N1 infection between November 2006 and March last year, resulting in the temporary suspension of poultry exports to Japan, Hong Kong, Taiwan and elsewhere.
But last June the World Organisation for Animal Health classified the country as free from the disease.
The H5N1 strain has killed more than 240 people worldwide since late 2003. No South Koreans are known to have contracted the disease.
China Crewmen Die Of 'Virus' - Peru Keeps Ship At Sea From Patricia Doyle, PhD 4-20-8
PERU -- 2 people died on board a vessel with suspected flu virus. Ship stranded on the high seas near the port of Callao, Peru.
Peruvian health authorities declared an epidemic alert and quarantined at sea the crew of a fishing vessel in which 2 Chinese people died, apparently due to a type of influenza virus, the newspaper "La Republica" reported this Saturday [19 Apr 2008].
The alert forced the Peruvian Navy to isolate the 22 crew members of the ship on the high seas and 30 Peruvians, among sailors and health staff, who entered the ship when the death of the cook and a fisherman was reported, 9 Apr 2008.
According to "La Republica", "a strange mutant virus was the cause of the agonizing death of 2 Chinese crew of the fishing vessel 'Chan An 168', who died on 9 Apr 2008, off the coast of the port of Callao."
The vessel was isolated 12 km off the main Peruvian port and is guarded by the Navy, while Peruvian sailors and medical personnel are being observed to see if they have been infected.
firstname.lastname@example.org There is no mention of any lab tests confirming the diagnosis of any type of influenza virus etiology, let alone "a strange mutant virus". I suspect the fact that these were apparently sudden deaths of Chinese led to a perhaps understandable over-reaction by Peruvian health authorities, fearing bird flu. It must have taken the fishing vessel a number of days to reach the Peruvian coast from China, and the incubation period of human influenza is 2-5 days. Assuming the same holds for bird flu, the fatal illness was probably not contracted in China. Perhaps the cook prepared a meal from stored chicken that had been infected with bird flu before freezing, although I'd always thought that fishermen lived on fish. A violent attack of food poisoning could have been the cause. We would like to hear about the lab results. - Mod.JW
An army corporal, identified by his surname Cho, has been suffering from a high fever since Sunday after participating in the culling of AI infected chickens and ducks in Sunchang, North Jeolla province.
Cho showed symptoms of AI infection in the primary and secondary tests but a definite conclusion will be made after the results of a serum and virus cultivation test are made known three weeks later, according to military authorities.
Cho's temperature went up to 39.8 degrees Celsius [103.6 F] and he fell unconscious, so we suspected it was an avian influenza infection,¡± Capt. Wi Seong-hyeon of Cho¡¯s unit told the newspaper. ¡°We transported him to the army hospital and reported the case to the Sunchang health authorities.¡±
The ministry later denied that the soldier in question became unconscious.
The above comments indicate the soldier hospitalized in South Korea has tested H5N1 positive in two initial tests. Media reports indicate his condition is improving after taking “antibiotics” which is likely Tamiflu.
If positive in additional tests, this would be the first confirmed human H5N1 case in South Korea. Confirmation would likely accelerate Japan’s plans to implement a pre-pandemic vaccine program. Although Japan has not reported H5N1 in the past two years, the outbreaks in neighboring South Korea strongly suggest that H5N1 has also recently been in Japan. In the 2003/2004, both countries reported genetically similar H5N1 outbreaks.
The two farms, which reported the deaths of 2,500 and 450 chickens, respectively, are located around 25 kilometers from an area where a bird flu outbreak was confirmed last Thursday, the ministry said. Samples tested positive in preliminary tests but the ministry said further investigation is required.
The latest cases in Iksan brought the number of suspected avian influenza outbreaks to 49 as of Tuesday morning. Of them, 26 have been confirmed to be related to a highly pathogenic bird flu virus, according to authorities.
The above comments describe further spread of H5N1 in South Korea. However, the parsing by the ministry raises additional concerns of additional poultry and human cases.
Concern over the wording of statements became clear in the most recent OIE report on April 15. At that time there were 11 confirmed outbreaks, but the report was careful to distinguish between the 6 H5N1 confirmed outbreaks and the 5 outbreaks that were HPAI H5 confirmed.
However HPAI H5 confirmed indicates an HA cleavage site sequence has been generated, which is not only definitive for H5 and HPAI, but also indicates that the infection was due to H5N1 and probably the Uvs Lake strain of H5N1. However, distinguishing between H5N1 and HPAI H5 allows the total number of cases to be split into the two categories. Operationally, there is no difference since all birds are culled regardless of the state of characterization of the H5 infection.
However, the parsing of statements regarding H5N1 in birds also raises issues regarding H5N1 in soldiers culling the birds. There appears to be one hospitalized culler with symptoms and two initial positive tests, which would indicate lab confirmed H5N1. However, the issue of bacterial pneumonia has been raised, but bacterial pneumonia is a secondary infection associated with influenza, so the detection of bacteria or improvement after antibiotic treatment does not eliminate a primary diagnosis (or positive lab tests) of H5N1.
In addition to the cited 22 year old soldier, local media reports suggest as many as 20 additional suspect cases are hospitalized. Concerns are also increased by the decision of the military to withdraw from culling operations.
Military Withdrawal from H5N1 Culling in South Korea
Recombinomics Commentary 15:08 April 22, 2008
The military decided to cut the number of troops deployed to help slaughter avian-influenza infected poultry after news broke that a soldier may have contracted the disease.
``We believe the corporal is unlikely to have contracted avian influenza, but we are taking every precaution with other troops,'' a military official told Yonhap.
The above comments describe the withdrawal of the military from culling operations in South Korea. The withdrawal follows the news on the hospitalized soldier who appears to have initially tested positive for H5N1. Media reports described additional hospitalized patients, but their link to culling operations or the military is unclear.
The poultry outbreak in South Korea is at record levels, and the military was deployed for the first time. There are almost 50 suspect or confirmed locations, and recently plans were announced to increase testing on duck farms. Although there have been reports of H5N1 in dead waterfowl, H5N1 can also cause asymptomatic infections in waterfowl, even though the same virus is lethal in chickens and humans.
However, there have been prior reports of mild H5N1 in Egypt and the H5N1 status of symptomatic patients in India and Bangladesh remains unclear, because most are not tested. The outbreak in South Korea is unusual because the temperature in Korea is milder, but the H5N1 is spreading at record levels and rates in South Korea, raising concerns of genetic change and altered transmissibility.
Milder human cases raise concerns about human to human transmission, because infected hosts are more mobile, leading to more contacts and opportunities for transmission.
Sequence data from the earlier poultry outbreaks would be useful. Last season the H5N1 in South Korea was the Uvs Lake strain, but since that outbreak there has been human to human transmission in Pakistan as well as record levels of H5N1 in India and Bangladesh.
The possibility of mild H5N1 in South Korea raises pandemic concerns and may be linked to the recent decision in Japan to implement a pre-pandemic vaccine program targeting first responders and up to 10-20 million citizens in Japan.
More Hospitaized Suspect H5N1 Patients in South Korea
Recombinomics Commentary 14:11 April 22, 2008
In South Korea three additional patients with the suspicion to the bird influenza are hospitalized. According to the communication of the Ministry of Public Health of this country, during the past two weeks with the suspicion to this severe illness were hospitalized 15 people, reported Ynet.
Furthermore in South Korea 11 cases of bird influenza in different economies of the country are officially confirmed. One such case occurred near the capital of the country of Seoul.
The above translation appears to describe at least 15 hospitalized suspect H5N1 cases, since the following paragraph distinguishes the suspect cases from confirmed poultry outbreaks. The status of the patients remains confused because some reports refer to H5N1 outbreaks in poultry as “cases”.
However, multiple local media reports are clearly describing suspect human cases, which is a concern. At least one soldier appears to have tested positive, but other local media reports are discounting the H5N1 infection indicated by the positive lab tests, and are proposing that the H5N1 infections are harmless, and the clinical symptoms of pneumonia are due to an unrelated bacterial pneumonia. This explanation was used by Indonesia to try to explain away the first confirmed cluster in 2005. In that instance the bacterial pneumonia explanation was discounted because the patients died, and bacterial pneumonia infections are usually treated with antibiotic and not fatal.
The human infections in South Korea may be milder cases, and there are reports of the soldier responding to antibiotic treatment. However, a secondary bacterial infection does not erase the diagnosis of H5N1, especially when lab tests are positive. Mild H5N1 cases are dangerous because infected patients are more likely to remain mobile and spread the H5N1 to contacts. This possibility is supported by the recent announcement that the military is withdrawing from culling operations.
Thus, the current situation in South Korea remains confused.
Soldier With Mild Confirmed H5N1 Raises Pandemic Concerns
Recombinomics Commentary 15:08 April 22, 2008
Tests have shown that the virus detected in the patient's body was an H5 strain, according to the Korea Center for Disease Control and Prevention. It will take up to three weeks for a lab to confirm whether or not the strain is the deadly H5N1 strain, which has caused massive outbreaks in the Jeolla region since April 1.
The young corporal, identified only by his family name Cho, was sent to help kill infected chickens and ducks on Friday and Saturday. He suffered from high fever and was transported to an army hospital Sunday.
Authorities said his sickness was not related to the bird flu and that his condition has improved.
The above comments provide more detail on the H5N1 infected soldier in South Korea. The “H5” designation for the soldier is similar to comments on the H5 infected birds in South Korea. There is no data supporting anything other than H5N1 for the outbreaks in South Korea. In the OIE report, some were H5N1 confirmed while others were HPAI H5 confirmed at the time of filing. No H5 had been confirmed to be low path H5.
The rapid recovery could have been due to both antibiotic and Tamiflu treatment, if the patient had secondary bacterial pneumonia. However, the bacterial infection does not invalidate the H5 detection.
More detail on how the soldier was infected would be useful. Pictures of culling operations showed cullers in PPE’s from head to toe. Moreover, cullers are usually on prophylactic Tamiflu (oseltamivir).
The denial of the associated of bird flu symptoms with H5N1 infections raise concerns of additional H5N1 patients that are not considered H5N1 infections because of arbitrary and capricious definitions. The infected culler also raises concerns about infected farmers who have not used PPE’s or Tamiflu.
The H5 positive result raises concerns of widespread mild H5N1 patients in South Korea as well as Bangladesh and India. The passage of H5N1 through human hosts increases the likelihood of human adaptation and efficient transmission.