What do you do when the chickens come home to roost and they look healthy (but might not be)? Ask the folks in Hong Kong. Except they don't know either.
Update, 6/15/06: The Chinese Ministry of Health is confirming the diagnosis of H5N1 in the 31 year old truck driver from Shenzhen. He is now officially the 19th human case in China.
China (Mainland) decided to control avian influenza by a massive poultry vaccination program. That's a lot of vaccinations, since they produce 4 or 5 billion new birds a year. Billion, as in one thousand million, or more than 100 vaccinations per second every second for a full year. And a lot of vaccine. And a lot vaccinators. So it's not surprising there is worry that not all the vaccine may be up to standard and not all the vaccinators skilled or conscientious (do they get paid by the piece?). Even if the vaccine is full strength there has always been suspicion it may allow birds to get infected but not show signs of illness. They still shed virus, but at a lower rate. This is fine for the birds, but not so fine if you're trying to keep the virus out of your territory.
The part of China adjacent to Hong Kong, Guangdong province, is known as an incubator for influenza. Shenzhen City, just over the border from Hong Kong, is one of the new economic regions in The Pearl River Delta that has exploded in population to meet the economic demands of China's industrial growth. The description of it in Karl Taro Greenfeld's book on SARS, The China Syndrome, is harrowing. The first recorded SARS case appeared there (although others preceded it). The first human H5N1 cases also came to Hong Kong from Guangdong province in 1997. Now there is another H5N1 case there, this time in Shenzhen.
Hong Kong medical and veterinary experts will go to Shenzhen City in south China's Guangdong Province to gather more information on the human case of avian influenza there, a Hong Kong official said Wednesday.Hong Kong Secretary for Health, Welfare and Food York Chow said the case is worrying and could see the suspension of live Mainland chicken imports for three weeks if confirmed.
He added that what concerns health authorities most is that the patient has no specific history of close contact with poultry, similar to two previous cases in Shanghai and Guangdong. Repeated cases on the Mainland may mean there might be some "silent infections" among poultry, which might carry the virus while not showing symptoms. (Xinhua)
The new case is a 31 year old truck driver whose only exposure is a reported visit to a "wet market" (where live animals are sold) and a family meal of freshly slaughtered chicken sometime prior to onset of illness. The rest of his family is reported to be well (via Channel News Asia). He is in critical condition in a Shenzhen hospital after complaining of fever, coughing and back pain on June 3.
This is not the first Chinese case with only a tenuous history of contact with poultry. The same has been true for several of the 19 officially confirmed Chinese cases (12 deaths). The Hong Kong medical authorities are clearly worried, having already had 18 cases in 1997 (6 deaths) and a terrifying experience with SARS in 2003. Officials are screening for fever the thousands of daily border crossers into Hong Kong from Guangdong, but this is unlikely to stop an outbreak if the virus becomes easily transmissible, as influenza is infectious 12 to 24 hours prior to symptoms.
The odds say this is another sporadic case of H5N1 infection in humans. Why a few people come down with the disease while most others similarly exposed don't, remains a mystery. So far we have no reason to think the low transmissibility has changed with this case. But it's surely past time to put some real blood and muscle on the gaunt skeleton of our public health and social service infrastructures. Few, if any, countries are doing this, spending instead for a vaccine that doesn't exist and antivirals that are in short supply and uncertain or marginal efficacy.
Still fiddling while the tinder smolders in Rome.
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It will be interesting to watch this unfold. If it was the chicken he ate, he probably didn't prepare it. Why then wouldn't the wife or relative who did prepare it be ill as well? Reports say the patient is a truck driver. Does he drive locally or long-distance? I'm wondering if he may have picked this up somewhere else that hasn't reported cases in birds or humans yet.
I visited Shenzhen about 10 years ago, and it was a cowboy town then! The wet markets were the most amazing (disgusting, too) I'd ever seen. A haven for zoonotics. I doubt that much has changed even with the Chinese claiming they're more sanitary.
Unfold? They better hope to God it doesnt unfold as even slightly human infectious. There are 23 million people crammed into a 150 square mile area. Shenzen alone has 4.5. I think HK has another 3 or so. Using the "3%" number that would mean 69,000 cases dead in under six weeks. They wouldnt have any place to bury that many. Thats the slight to moderate projections. If it was 80% there wouldnt be enough people around to even try to bury them.
In HK last time they culled chickens. This time if its not in the poultry they will be culling people. They have the SARS quarantine facilities that are still up and functional and they were designed to house thousands. I wonder if the Chines government think that vaccinating poultry with crappy response vacine the last two years was worth it. Likely it turned them as Revere said into happy, healthy shedders. You pick it up and woof a little feces or feather materials into the air and it kills the world.
The vaccination issue is one of the many uncertainties about H5N1 control. the Vietnamese are allegedly having success with it, although there has been evidence that vaccinated birds can still be infected. Even in this case, however, there is some benefit because the amount of viral shedding is much reduced. On the other hand, it makes it impossible to detect infection in poultry. They aren't sick and they all have antibodies. Trade-off, as usual. Where the balance is we don't know yet. We ar trying to get experience at the same time the game is afoot.
Publication of a recent paper by Zhou et al (ProMed byline and abstract attached below) seems to confirm the hypercytokinemia hypothesis as one of the major virulence mechanisms of H5N1. One of the mantras that has been propagated is that those individuals who are the most immunocompetent, are most at risk from this virulence mechanism, and these results to some extent confirm this concept. However, several months ago, when I analyzed the age distribution of H5N1 fatalities, the number of children who died was fairly high (about 25-30%; children defined as < 15 years of age). At the time, I hypothesized that this, in part, was due to children playing more with sick chickens. But this is a specious argument; it might explain why more children are infected but does not explain the high mortality rate for children. Zhou et al compared neonate and adult macrophage reaction in cell culture to 3 influenza virus types, including both avian and human strains, and while they found a significant different between neonates and adults, we still do not know where children would be in this type of experiment. We say (and I am guilty of this writing in papers, too) that children are to some extent immunocompromised until they become adults. But I wonder, at least as far as H5N1 is concerned. Either their immune systems are developed enough that hypercytokinemia will kill them, or other mechanisms are also at work. Peiris comments that route of infection and viral dose is important. I agree with both. Kids may certainly have higher viral loads in their bodies, but without virulence mechanisms, that doesnt mean much. What higher viral loads might mean is that hypercytokinemia becomes more serious in kids, or that other mechanisms come into play.
[Promed]
[Byline: Helen Branswell]
Some avian influenza viruses, and particularly the dangerous H5N1 subtype, appear to prompt the human immune system to over-produce important pathogen-fighting chemicals called chemokines, triggering an exaggerated response that creates more damage than it fixes, a new study suggests. The study shows that at least with older versions of the H5N1 virus, this response -- referred to as a cytokine storm -- was significantly more acute
in adults than children. The findings could help to explain why the 1997 outbreak of H5N1 was far more deadly for adults than children and why the infamous 1918 Spanish flu -- caused by the H1N1 subtype -- wreaked its greatest havoc on young adults.
They could also offer clues to help in the design of therapies to treat infections caused by these viruses, by pinpointing the response that needs to be moderated to avoid this immune response tidal wave and the damage it
inflicts.
"I think this is starting to provide us with a framework to better understand why H5N1 does what it does," said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. "And I think also it's a reason to be more
concerned about similarities between 1918 H1N1 and 2006 H5N1."
The work, by scientists at the University of Hong Kong, is reported in the July issue of the Journal of Infectious Diseases and was financed by Hong Kong's Research Grants Council. The research is part of a series of studies
done by this group of scientists that is looking at the way human cells respond to H5N1 and related avian influenza viruses. Group leader Dr. Malik Peiris, a leading influenza expert, said the study was inspired by the mortality pattern observed during the first recorded outbreak of human disease with the H5N1 virus in Hong Kong in 1997. Of the 18 recorded cases, 5 of 9 who were over 12 years of age died. Only one patient under that age
succumbed to the virus. "It made us wonder if there was some host factor associated with age," Peiris said in an interview from Hong Kong.
But the current wave of human infections with H5N1, which began in late 2003, includes many cases under 12, many of whom have died. Peiris acknowledged that host response -- in other words, the immune system reaction -- obviously isn't the only factor involved in determining the
severity of disease caused by H5N1 viruses. He suggested the route of infection, or the dose of virus to which an individual is exposed, may also play a role. Peiris's team tested their age hypothesis using blood from healthy adult blood donors and donated umbilical cord blood from healthy, full-term babies.
The scientists tested the response to 3 influenza viruses: a human H1N1 virus from 1998, an H5N1 virus from 1997, and a 1997 H9N2 virus. The last is considered an ancestor of the H5N1 virus, because while the 2 wear different hemagglutinins (the H in a flu virus's name) and neuraminidases (the N) on their outer shell, their 6 internal genes are very closely related. The blood samples were used to isolate macrophages -- immune system warriors which are drawn to the site of infection by signalling
chemicals such as chemokines. Once at the site of infection, macrophages engulf and destroy invading pathogens. In this experiment, the flu viruses
were added to cultures of macrophages to see what responses were provoked. Interestingly, the flu viruses all replicated at about the same rate, in both the adult and infant cells. "So these differences weren't due to
differences in the extent of virus growth that they could discern, but rather something intrinsic to the viruses themselves which were causing the different (chemokine) expression levels that they reported," said Dr.
Frederick Hayden, a scientist with the World Health Organization's global influenza program.
But while the viruses generated the same amount of infection, the immune response to the infection varied greatly, both between the human and avian viruses and between the adult and infant cells. In particular the avian viruses triggered the production of significantly higher levels of a chemokine called CCL3 in the adult cells. The authors noted elevated levels of CCL3 have also been found in the blood of patients who have died from
H5N1 infection as compared to those who were infected but survived. "The higher CCL3 response in adult (macrophages) may be one of the important factors responsible for the age-related severity of avian influenza virus infection in 1997," they wrote.
Peiris also noted that in fatal human cases of H5N1 infection it has been observed that macrophages have virtually swarmed the lungs. Chemokines like CCL3 draw macrophages, he noted, saying the pattern of actual disease and the experiments done by his team "do fit." Chemicals like these play a crucial role in the body's response to invading pathogens. But overproduction can create a cascading hyper-response that actually
exacerbates the damage already done by the virus.
The authors noted that mice infected with the newly reconstituted 1918 H1N1 Spanish flu virus produced high levels of the same immune system signalling chemicals as were seen to be over-produced by the H5N1 and H9N2 viruses. Since these more contemporary avian flu viruses carry a number of the same mutations on their internal genes as the 1918 virus did, they argued, further analysis of the role of these mutations is needed to determine what
role they play in the disease process.
For Osterholm, the work provides further supporting evidence that the cytokine-storm phenomenon was at work during the deadly 2nd wave of the Spanish flu. It also supports the concern he and others share about the
similarities between the type of human disease H5N1 causes and reports of what patients suffered during the 1918 pandemic, which claimed an estimated 50 million lives worldwide. "We'll never be able to go back to 1918 and
demonstrate that the cytokine storm was the key feature of those early and dramatic deaths in patients," Osterholm said. "But clinically those patients were so similar and [from a] patho-physiologic standpoint it makes so much sense that that's what was happening that I've got to believe that there are important parallels here."
[The paper referred to above is published in The Journal of Infectious Diseases, Volume 194, Number 1, 1 Jul 2006, and entitled: Differential Expression of Chemokines and Their Receptors in Adult and Neonatal Macrophages Infected with Human or Avian Influenza Viruses. The authors are: Jianfang Zhou,1,3 Helen K. W. Law,1,3 Chung YanCheung,2,3 Iris H. Y. Ng,2,3 J. S. Malik Peiris,2,3 and Yu Lung Lau1,3, at the Departments of 1Paediatrics and Adolescent Medicine and 2Microbiology, Hong Kong Jockey
Club Clinical Research Centre, Faculty of Medicine, and 3Research Centre of Infection and Immunology, University of Hong Kong, Pokfulam, Hong Kong SAR, China.
The abstract reads as follows: "In 1997, avian influenza virus H5N1 was transmitted directly from chicken to human and resulted in a severe disease that had a higher mortality rate in adults than in children. The characteristic mononuclear leukocyte infiltration in the lung and the high inflammatory response in H5N1 infection prompted us to compare the chemokine responses between influenza virus-infected adult and neonatal monocyte-derived macrophages (MDMs). The effects of avian influenza virus A/Hong Kong/483/97 (H5N1) (H5N1/97), its precursor A/Quail/Hong Kong/G1/97 (H9N2) (H9N2/G1), and human influenza virus A/Hong Kong/54/98 (H1N1) (H1N1/98) were compared. Significantly higher expression of CCL2, CCL3,
CCL5, and CXCL10 was induced by avian influenza viruses than by human influenza virus. Moreover, the increase in CCL3 expression in H5N1/97-infected adult MDMs was significantly higher than that in neonatal MDMs. Enhanced expression of CCR1 and CCR5 was found in avian
virus-infected adult MDMs. The strong induction of chemokines and their receptors by avian influenza viruses, particularly in adult MDMs, may account for the severity of H5N1 disease." - Mod.CP]
Part of my previous message was truncated. here it is in full:
Publication of a recent paper by Zhou et al (ProMed byline and abstract attached below) seems to confirm the hypercytokinemia hypothesis as one of the major virulence mechanisms of H5N1. One of the mantras that has been propagated is that those individuals who are the most immunocompetent, are most at risk from this virulence mechanism, and these results to some extent confirm this concept. However, several months ago, when I analyzed the age distribution of H5N1 fatalities, the number of children who died was fairly high (about 25-30%; children defined as < 15 years of age). At the time, I hypothesized that this, in part, was due to children playing more with sick chickens. But this is a specious argument; it might explain why more children are infected but does not explain the high mortality rate for children. Zhou et al compared neonate and adult macrophage reaction in cell culture to 3 influenza virus types, including both avian and human strains, and while they found a significant different between neonates and adults, we still do not know where children would be in this type of experiment. We say (and I am guilty of this writing in papers, too) that children are to some extent immunocompromised until they become adults. But I wonder, at least as far as H5N1 is concerned. Either their immune systems are developed enough that hypercytokinemia will kill them, or other mechanisms are also at work. Peiris comments that route of infection and viral dose is important. I agree with both. Kids may certainly have higher viral loads in their bodies, but without virulence mechanisms, that doesnt mean much. What higher viral loads might mean is that hypercytokinemia becomes more serious in kids, or that other mechanisms come into play.
[Broke it up into paragraphs--seems to be a truncation problem with this blog.]
Publication of a recent paper by Zhou et al (ProMed byline and abstract attached below) seems to confirm the hypercytokinemia hypothesis as one of the major virulence mechanisms of H5N1. One of the mantras that has been propagated is that those individuals who are the most immunocompetent, are most at risk from this virulence mechanism, and these results to some extent confirm this concept.
However, several months ago, when I analyzed the age distribution of H5N1 fatalities, the number of children who died was fairly high (about 25-30%; children defined as < 15 years of age). At the time, I hypothesized that this, in part, was due to children playing more with sick chickens. But this is a specious argument; it might explain why more children are infected but does not explain the high mortality rate for children.
Zhou et al compared neonate and adult macrophage reaction in cell culture to 3 influenza virus types, including both avian and human strains, and while they found a significant different between neonates and adults, we still do not know where children would be in this type of experiment. We say (and I am guilty of this writing in papers, too) that children are to some extent immunocompromised until they become adults.
But I wonder, at least as far as H5N1 is concerned. Either their immune systems are developed enough that hypercytokinemia will kill them, or other mechanisms are also at work. Peiris comments that route of infection and viral dose is important. I agree with both. Kids may certainly have higher viral loads in their bodies, but without virulence mechanisms, that doesn?t mean much. What higher viral loads might mean is that hypercytokinemia becomes more serious in kids, or that other mechanisms come into play.
Revere, you often refer, like today, to "putting some blood and muscle" on to our public health and social service infrastructure.
Since this could be an enormously broad, expensive, long-term task, I would be very interesting in hearing your thoughts on priorities, strategic approaches and a broader vision. What does this entail, what are the key roles, and how would it unfold differently in the U.S., or in a public healthcare system like Canada's, or in an impoverished Third World country?
Name,
If it just came today at the 722,000 that Leavitt said for the US there would be a need for 700,.000 ventilators in the first six weeks. There are 100,000 at any given time and 3/4's of those are in use. Cost for one is about 20,000. The math on that is about 22 billion dollars, and thats if you had someone to operate them. The Indonesian cost to get to one survivor so far has been about 50,000 USD. So call it 700,000 for grins and mulitiply. Its 35 trillion dollars if all things were equal and they all survived. Long term care for many afterwards that do survive. They damned sure could be stockpiling food and creating the distribution network that will be needed to move it. I havent seen anything like that and the federal government is putting it onto the states.
Priority 1-Stay alive. Priority 2-Keep the infrastructure working Priority 3. Inform and educate Priority 5.-Care as best able those that havent prepared or have become infected. Priority 6. Assess long term effects and mitgate now.
To be honest with you name, I am involved in the incident management for this and there is NO way that the federal government or the states will be able to cope with this other than using the military. I have many times said that I wouldnt want this under military control. If we can keep the governors in line and not call a "state of emergency" or "martial law" then there will be fewer deaths in all reality. If churches and NGO's keep it going then we will lose a bunch and then recover. Else the military deals harshly with every thing. I am ex military and I can tell you that you dont want them in charge of anything other than a complete collapse of a system (Katrina).
Its like going to an MD, he will give you a pill fix. If you go to a surgeon , he will give you a surgeon fix. You go to the states that are skating around on this issue and anything can happen. The national plan says that the USGOVT will assist the states but its their ball game. The will deal with the big stuff but not micromanage.
Helicopters on roofs in Katrina was the federal response because that was in the mission statement of the units involved. Bush by law could NOT violate LA sovereignty except where it was already part of their normal job. The Navy could have been in there in a day but were blocked while Blanco was told that federal law prohibited federal operations to be under a states control. You are going to see a lot of that if it comes.
Canada? Havent a clue.
Name: DemFromCT (our flu wiki colleague) has been nudging us about the same thing. We need to do this. Right now it is a matter of scarce resources: time. But I'll take this as another nudge.
Its all about the resources that will be brought to bear before, during and after. We will see a significant kill rate afterwards of a moderate to severe pandemic. They all complain about the response of the federal government. They'll say its a money response...Partially true. I agree with the Reveres that they better dust their collective asses off and get cranking because if they dont we are going to be in deep trouble.
I was on one of my little cyber-jaunts reading articles that caught my interest and following links, searching on terms I was unfamiliar with etc.
I started with the article Marissa posted on immune over reaction and then found myself reading about Infection-associated hemophagocytic syndrome (IAHS) http://www.mednet.gr/eae/haema/h14-5.htm
and some promising results with IVIG which lead me to this site
http://www.fffbiosupplytrends.com/fff_news/may22006/
Which is pretty scary. Fff are pharm distributors and the trends page has a flashing banner headline Customer Alert - Take Action to Resolve the IVIG Shortage and some graphs showing days supply of various products. Reading a little further down we get this quote Patients and healthcare providers across the country are reporting difficulties acquiring IVIG, and at least five patients have died as a direct result of lack of access to the product. They also run a VIP program (Virtual Inventory Program) which promotes the virtues of virtual stock with just in time delivery for expensive drugs.
Given that there have been repeated calls to increase holdings of drugs to mitigate the effects of supply chain disruption, all of the above just reinforces the fear we are nowhere.
Mr. Kruger, what do you mean by signicant kill rate? 2% , 35%?
Some call it case fatality rates, others mortality rate. I am ex-military and we would call this a kill rate in a bio-weapons experiment. Just a terminology.
The 1918 flu was 3% estimated "kill rate". That basically is all that the WHO and CDC want to put out there as possible. None of the virologists are saying anything higher because it will start a panic. A few months ago a modeling was done by computer to show the spread of H5N1 across the United States. By week 3 one hell of a lot of people had it and it was saturated at about the 90 day mark, then it began to wane-Wave 1.
Now Americans being the sheep that they are and the lovely media being less than what we need no one asked about mortality projections so we could see that on a screen. Once the models are made its just adjust the parameters of the input to produce a result. I am looking for those newer modelings that show both kill rate and the effects of a multi-wave scenario. It would be colorized likely with black being mortality at the end of the computer run. It would be bad at 3%, terrible in fact.
But we jump back to the reality that this mother is currently killing at 52% for all that have caught it in the last five years, 56.6% since the beginning of the year overall, and in Indonesia 81.8% without including any of the new cases. Thats a horrendous number. Because of that kill rate I made some suggestions that I wont go into now to slow it. Not necessarily stop that particular version but it would slow it to a snails pace crawl.
The big banana for the US as I stated in the previous posts was for 114 million Americans would die in a 40% mortality rate H5N1. No one has stepped up to correct me either. If Indonesian H5N1 departs in a highly infectious manner and head our way it will mean that if it slipped to 40% we would have the big banana in the US and a disaster on the planet of 2.6 billion people.... FIRST WAVE. This stuff mutates like you change your socks so multiple wave scenario's are out there and likely based upon the original work. I would hate to think of this possibly happening but in a maximum 4 wave scenario that cuts the Indonesian version by 1/2 each time it mutates and then goes back into the population, we could be faced with the possibility of extinction. It would be mighty close at the 4th wave. 6.5 billion would be cut to 3.2 billion and change, then second wave 3.2 billion would cut to 1.7 billion and change, third wave we would be cut to 560 million and change and by fourth wave we would be at 250 million starving people total worldwide give or take a city or two.
could it happen? I wouldnt want to guess either way. Prepare for the absolute worst and if it doesnt happen, then you can donate the food to the local charities.
Scorbee.
I am getting bounceback on your email address. Plz advise.
Randy: There is a difference between case fataliy rate and mortality rate. The former is really a proportion not a rate (remember my post here?) while the latter is a rate. The denominator in a mortality rate is the at risk population. It is a number from zero up and is properly referred to a period of time (and place). The case fatality rate is referred only to those who are sick from the specific disease. It is a risk (of dying). You are apparently talking about a case fatality rate when you are saying "kill rate" but seem to define it like a mortality rate. Transferring terminology from one setting to another can be hazardous.
Okay I'll buy that. But are the numbers any different? 40% of our population ? Whats your gut feel on this as its continuing to roll. I think it would wipe out east China in about 3 weeks and then show up in the gateway cities.
Here are my guesses (and they are only guesses): If there is an H5N1 pandemic it will infect 30% of the population and of those the fatality rate (proportion) will be 6%. That means about 2% of the whole populaiton, which would be a frightful mortality but most people would survive.
This is a pure guess, or hunch. A pandemic may never occur with this subtype. It may be an H9, as some think. It may be nothing or more like seasonal flu. I am just blinldy guessing like everyone else and why anyone should pay attention to my guess or Randy's or Marc Siegel's or Mike Osterholm's I don't know. I think they shouldn't.
But they should plan anyway.
Revere: I posted on the wrong thread before. Any thoughts about York Chow's suspicions that H5N1 may be becoming more virulent and more widespread?