Pandemic News/Awareness - Thread 3

Yi Guan on stopping a pandemic before it starts: trust isn't transitive

Can it be done? These epidemologists say not likely.

With permission from Effect Measure:

The Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things.

Trust is not transitive, as someone recently pointed out, when reporting on the airline pilot who carried a gun into the cockpit and then accidentally or negligently discharged it and blew a hole in the plane. We had every reason to trust the pilot to be able to fly a 747, but not necessarily to handle a firearm properly. Trust isn't transitive.

There is no doubt that Yi Guan, a professor at the University of Hong Kong, is an expert on H5N1 virus, its genetic lineages and surveillance for the virus in wild birds. He has reportedly screened, via cloacal swabs and fecal specimens, more than 200,000 wild and free ranging aquatic birds and poultry in China since 2000. So if he has an opinion about whether proper surveillance can stop a pandemic it is reasonable to listen to what he says and consider it seriously. But it is not necessarily reasonable to trust his judgment because he is an expert at the lab bench in using surveillance specimens. Because once Guan talks about a pandemic he is talking about a global scale outbreak of disease in human beings. That involves epidemilogy. So I am slightly skeptical of a pronouncement by someone whose speciality is surveillance of birds, not the epidemiology of influenza in people:

"For disease control, surveillance must be a long term effort. You know where it is and you know it is coming, like a spark of fire you can extinguish it," Guan said.

"If not for all this surveillance and detection ability, the pandemic would probably have already come."

Drawing from what is known of past pandemics, Guan believes that surveillance and strict control measures are the answers.

"Pandemics don't happen suddenly, they have an early phase, mature phase, outbreak phase. The virus changes step by step, it takes a long cooking time," he said.

"If a virus gets into humans in the early phase, the transmission ability is very low. At most, they infect their families, but it can't go further into the community.

"This phase is the golden point to control. Once it matures and becomes (efficient in) human-to-human (transmission), it will be too late." (Tan Ee Lyn, Reuters)

My own view, as an epidemiologist, is that this proposition is highly unlikely. Even in Guan's specialty, we know very little about the movement of the virus. How does it get from one place to another? What is the role of poultry movement versus wild birds? (What are the routes of poultry movement and how do we follow and control them? What are the migratory routes of wild birds? (We only know this in very broad generalities, not at the even fairly coorifice resolution that we need to control the virus if birds are a mode of movement, numerous maps, notwithstanding; you will find these maps are based on scant information and many inferences, insufficient for what would be required to really know and understand bird movements globally). Nor is surveillance for the virus complete, effective or comprehensive. That's just for starters.

There's also the question of human epidemiology. At the molecular level we don't know what makes the virus transmissible (we have clues, only) or virulent (still only clues) or pathogenic (still more clues). In humans we still aren't sure of the relative importance of different modes of transmission (large or small droplets, fomites, possible undiscovered animate vectors). Where does the virus hang out in nature? Are their additional reservoirs besides poultry and wild birds? What accounts for the seasonality? Where does the virus go in the "off season"?

Even taking Guan's conjecture in its strongest possible form, that we know enough about these missing data points to say that stopping a pandemic was possible through surveillance alone, there are the obvious questions about public health in the Real World. Public and veterinary health are grossly under supported and things are getting worse, not better. The international system that supports cooperation between countries cannot even make the half century old influenza virus surveillance system work, much less impose the kind of interference in "national sovereignty" that would be required to snuff out an incipient pandemic even if we knew it was coming. What surveillance can do is warn us to get ready, not be the firewall that prevents the invasion.

Yi Guan is a genuine expert in the virology of H5N1 and an expert in the Art of Surveillance as we now practice it. Surveillance is of supreme importance in global preparation to face a potential pandemic with a very dangerous virus. But just because it is his opinion that the hammer he wields will hit all the nails on the head doesn't mean that a good hammer is even close to being a sufficient tool even under the best of circumstances.

Trust isn't transitive.

From Effect Permission, with permission:

Natural history of influenza infection in human volunteers

If you were infected with seasonal influenza virus, how long before you start having symptoms (the incubation period)? How about how long before you start shedding virus so that you can infect others (the latent period)? When are you most infectious? Expert opinion. based on experience and the scientific literature, says that the incubation period is about 2 days but you might start shedding virus after only a day, i.e., before you get any symptoms. You are most infectious on day 2 of your illness. But will everyone who is infected really "come down with" the flu? We know that a good proportion of people are actually asymptomatic with their flu infections. What proportion? Maybe as much as half. But the basis for these expert opinions is often vague. How about if you could actually experiment on human volunteers, especially those with low levels of flu antibodies? Numerous studies of this type have been done and now a French team has surveyed the English language literature that appeared between 1965 and 2005 and given us a nice summary. One of the surprises is that there are no surprises. There is also some new information.

A broad literature search by the French researchers turned up 71 usable studies in which people were challenged with wild type influenza virus (various subtypes) and some outcome measured. Bird flu (subytype H5N1) has never been given to volunteers. Current case fatality rates (over 60%) make this unethical. But all other subtypes that infect humans on a seasonal basis have been studied in experimental settings with volunteers. The 71 papers described only 56 different studies, comprising 79 subgroups and 1280 subjects in all. Because of the nature of volunteer studies almost all participants were young adults, between the ages of 18 and 40 to 50 years old (a single study had subjects up to the age of 65). The virus was given either as nose drops (most studies), throat spray (3 studies) or aerosol (1 study). The doses ranged over three orders of magnitude, so some examination of dose was possible. Most subjects had low antibody titers against the flu hemagglutinin protein. Where subgroups were reported to have had some immunity, the data were not used in summarizing the viral shedding results. The subjects were almost always kept isolated for a week and studied during that interval for symptoms, signs and viral shedding. Follow-ups ranged from a short 3 ays to 14 days.

The results of this systematic summary of the literature on infected volunteers confirmed current expert opinion. Most volunteers got infected (almost 90%), at least as revealed by a rise in antibody. Viral shedding was also very high: over 90% with A/H1N1 and AH3N2. If these volunteers were exposed they got infected and they shed virus. But not all of them got sick. Only two of three infected got sick and this didn't differ by subtype. Getting infected and shedding virus does not mean you are clinically ill, something we've known for a long time (but often forget). In fact the rate of asymptomatic infection is quite high, over 30%. On the other hand, if you were asymptomatic you shed much less virus, in quantity, than those who were sick.

If you do get sick, what is the most common symptom? Again, no surprises. Upper respiratory symptoms like a stuffy and runny nose, sore throat, sneezing, hoorificeness, ear pressure/ear ache were at the top of the list (60%). Only about 20% had lower respiratory symptoms like cough, chest discomfort or trouble breathing. Subtype didn't seem to matter. Fever was more common than lower respiratory illness, with a third reporting a body temperature above 37.8 degrees. C. (100 degrees F.). A curious and unexplained finding was that the proportion with fever was higher in the studies that used lower doses.

As for duration of illness, this peaked on days 2 or 3 and were mainly back to baseline by day 8. Average length of illness was 4- 5 days. Fever and muscle and body aches subsided before the respiratory symptoms. These are the acute symptoms, however. There is no report on the oft reported enervation after flu infection.

What did these studies who about viral shedding? On average, detectable virus shedding appeared about a day after inoculation (83% of subjects), the rest (only one in six) on days two or rarely three. That means that after someone sneezes in your face during flu season you can do the same to others a day, probably at most two days, later and get the same result. There is a sharp increase in shed virus the first day following inoculation, reaching a peak on day two. You keep shedding virus for about 5 days. Most people were done throwing off virus after a week, but occasional people kept shedding for a few days more. These studies indicate a mean generation time (infection to infection) of only 2.5 days, shorter than usually estimated.

This is a valuable review of an important literature. There still remain some questions as to how generalizable these volunteer studies are, however. First, there were no studies of two vulnerable subpopulations, children and the elderly, for obvious ethical reasons. Second, inoculation was mainly by intranasal drops. Does this make a difference, say in the proportion of lower respiratory symptoms? We don't know. Were the viral strains used in these studies more or less (or differently) virulent than the circulating viruses? We don't know, although other information suggests they weren't very different.

How do the authors sum this all up?

Optimistically, viral shedding, the surrogate marker for infectiousness, was of moderate duration, and its dynamics largely overlapped those of systemic symptoms, thus (in theory) permitting efficient isolation of infectious individuals. Pessimistically, viral shedding peaked rapidly, infections were rarely "typical," and symptoms or signs widely used for influenza case definitions (e.g., fever or cough) would be unreliable for identifying infectious individuals. (Carrat F. et al. Am J Epidemiology 176:775-785, 2008).

This is a very interesting paper on one of the major uncertainties in the influenza world: what is the "natural history" of the disease.

The Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things.

South Korea

http://in.reuters.com/article/worldNews/idINIndia-32801220080402

Given the number of birds that died in such a short time, it seems likely that

this is a highly pathogenic bird flu (HPAI), and probably H5N1 given the history

of this virus in that country.

The farm, which raises 150,000 birds, has reported the death of nearly 2,400 poultry since Saturday, the ministry said.

Dr. Niman over at Recombinomics seems to think so:

http://www.recombinomics.com/News/04020802/H5N1_Korea_Likely.html

UPDATE

Positive for highly pathogenic (HPAI) H5N1, the bird flu.

http://www.flutrackers.com/forum/showpost.php?p=145950&postcount=18

Very bad news because within 10 square miles of the index farm is this:

http://www.flutrackers.com/forum/showpost.php?p=145843&postcount=16

From Effect Measure with permission, please note that H1N1 and H3N2

are our current seasonal flu strains, the kind humans are vaccinated for

every year. One of them has been found to infect dogs also. H5N1 is

the bird flu.

Flu in dogs again, but not H5N1

The index case was a 5 year old Miniature Schnauzer with 5 days of nasal discharge and sneezing. The dog recovered but the next case, a 3 year old Cocker Spaniel wasn't so lucky, nor were the 2 Korean hunting dogs (Jindos) or a 3 year old Yorkshire terrier. Then 13 dogs in a shelter started to show signs of nasal discharge, cough and high fever. Antibody studies showed that they had all been suffering from influenza infection, subtype H3N2. These cases happened in the spring and summer of 2007 (NB: this is not flu season). H3N2 is the most common subtype involved in human seasonal influenza. Is that where the virus came from? A team of Korean researchers got specimens from the schnauzer, the cocker spaniel and the Yorkshire terrier and have just reported their findings in the CDC journal, Emerging Infectious Diseases (Song et al., Transmission of Avian Influenza Virus (H3N2) to Dogs).

The specimens were used to inoculate eggs and replicated influenza virus was isolated and subjected to genetic analysis and used to experimentally infect 9 beagle pups intranasally. The researchers were looking for signs of infection, including severe illness, development of antibodies ("seroconversion") and viral shedding. They got all three. The pathologic findings were confined to the respiratory tract but they were relatively severe. The virus was shed in nasal discharge but not feces. And all inoculated dogs seroconverted.

This virus efficiently infected the dogs, as might be expected from the size of the kennel outbreak. The sequence analysis suggested the virus was of bird origin, not human origin. Certainly this is not the first time a bird flu virus has jumped from birds to mammals and become transmissible there. The 1918 Spanish flu is suspected to be of that kind and an H7N7 bird virus caused a fairly large outbreak of conjunctivitis (and one death) in The Netherlands in 2003. Cats, ferrets and marine mammals have also been infected with avian viruses. The current "bird flu" (H5N1) is also an avian virus. H3N8 has caused outbreaks of influenza in dogs, but this outbreak is H3N2, so it is different. The H3N2 designate only two of the proteins comprising the influenza A proteome and two viruses with serotype H3N2 can have very different "internal" genes. These genes in the Korean isolates bear similarities to internal genes of ducks in Hong Kong, Japan and southeast China.

So why did the dogs get infected with bird H3N2 viruses and not the ubiquitous H3N2 from humans? The authors suggest it is because the dog respiratory tract is mainly equipped with avian type receptors (alphas (2, 3) rather than alpha (2, 6); see our posts here on this topic). This is a reasonable explanation but more work needs to be done. http://scienceblogs.com/effectmeasure/2007/10/flu_biology_receptors_i.php

So how did the dogs get infected? It is common practice to feed them scraps from birds, including untreated duck and chicken muscle, internal organs, and heads. Dogs are not only pets but livestock in Korea, eaten as a delicacy. Fattening them up and selling and keeping them in live animal markets is a common practice:

Live-bird markets are thought to constitute "a missing link in the epidemiology of avian influenza viruses" because they bring together numerous hosts, such as chickens, ducks, turkeys, geese, and doves, in a high-density setting, which represents an ideal environment for virus interspecies transmission. (Song et al. Emerging Infectious Diseases)

So what is the lesson here? One is the usual humbling one: there is still a lot to learn about the influenza virus. Another is that there are a lot of potentially susceptible species that we have not looked for or at in a systematic fashion. In much of southeast asia and asia birds are ubiquitous companions of humans. They live together and sometimes sleep together. In the industrialized west dogs are common companion animals that live in close proximity to humans. If it turns out that they are a common reservoir for bird viruses, then much more of the world's population could be liable to a virulent influenza virus that got into dogs just as H5N1 got into poultry. The H3N2 case is probably not a likely pandemic source (despite what the Korean scientists say in their Discussion) because there is widespread immunity to H3N2 in the global population, even though changes in the strain mean the protection varies as the virus mutates. On the other hand, H3N2 keeps infecting humans because it changes enough from year to year to make that immunity less effective and H3N2 is sufficiently virulent on its own that it and H1N1 kill an estimated 30,000 to 40,000 Americans yearly. If a variant that was much more virulent came around it could get nasty.

And there are other bird viruses that might also get into dogs or other companion animals. It's about time a serious, systematic investigation and any indicated surveillance of many more animal species got underway.

The Editors of Effect Measure are senior public health scientists and practitioners. Paul Revere was a member of the first local Board of Health in the United States (Boston, 1799). The Editors sign their posts "Revere" to recognize the public service of a professional forerunner better known for other things.

Bangladesh culls 100,000 fowl in a week

http://crofsblogs.typepad.com/h5n1/2008/04/bangladesh-cull.html

Bangladesh authorities have culled more than 100,000 chickens at farms over the last one week over suspected bird flu outbreaks, officials said on Thursday, although the disease had begun subsiding across the country.

Follow the Money (and the PPEs)

I always enjoy Scott McPherson's entertaining posts. For those who do not know,

Scott is the chief information officer (CIO) for the Florida House of Representatives.

http://www.scottmcpherson.net/journal/2008/4/1/follow-the-money-and-the-ppes.html

I have always said that in the fight to contain pandemic influenza, as in law enforcement, Follow the Money. And Follow the Tamiflu. Nowhere was that more evident than in the efforts of the US, Indonesian authorities and the WHO to contain what appeared to be an outbreak of human H5N1 in Cikelet, West Java, in August, 2006. More than 2,000 villagers from all adjacent hamlets were placed on Tamiflu as a precaution...

Limited H5N1 H2H "likely occurred" in Pakistan - WHO

OK, so the CDC and NAMRU 3 (the US Naval lab in Egypt) have agreed that

human to human transmission occurred again Pakistan. No surprise there, but

why take until April for the WHO to admit it what had to have been known months

ago? The outbreaks occurred in October-November of 2007. Building public trust

requires timely information sharing, and readily admitting what has happened even

if it is unpleasant news.

http://www.scottmcpherson.net/journal/2008/4/3/limited-h5n1-h2h-likely-occurred-in-pakistan-who.html

In the April 3, 2008 Update 2, three of the four family members (all male) were confirmed to have contracted H5N1, and the fourth is unconfirmed but "probable". It is unknown if chain H2H2H transmission occurred, but judging by the onset dates, it is quite reasonable to assume this event is also likely.

http://www.flutrackers.com/forum/showpost.php?p=146031&postcount=10

Will a pandemic bring down civilisation?

https://www.singtomeohmuse.com/viewtopic.php?t=2397

Thank you to pixie at PFI for this article and the thread following it.

Before you dismiss any of this as hysteria or go into denial, take a moment

to think about how you would fix any of these problems noted in the link.

Our world is more fragile than we would like to think.

Cities typically have only three days' worth of food, and the old saying about civilisations being just three or four meals away from anarchy is taken seriously by security agencies such as MI5 in the UK. In the US, plans for dealing with a pandemic call for people to keep three weeks' worth of food and water stockpiled. Some planners think everyone should have at least 10 weeks' worth. How long would your stocks last if shops emptied and your water supply dried up? Even if everyone were willing, US officials warn that many people might not be able to afford to stockpile enough food.

Hospitals rely on daily deliveries of drugs, blood and gases. "Hospital pandemic plans fixate on having enough ventilators," says public health specialist Michael Osterholm at the University of Minnesota in Minneapolis, who has been calling for broader preparation for a pandemic. "But they'll run out of oxygen to put through them first. No hospital has more than a two-day supply." Equally critical is chlorine for water purification plants.

South Korea, Again

http://crofsblogs.typepad.com/h5n1/2008/04/south-korea-a-s.html

Another outbreak has occurred, this time on a duck farm.

Of course, they have to test, but, with this many birds dead this quickly, this can not

be a low pathogenic virus.

Of the 10,000 ducks on the farm, half have died since Monday.The farm is located 27 kilometers away from a chicken farm that was hit by avian influenza earlier this week.

The ministry said that further tests will be needed to determine if the virus is a low or high virulent strain of bird flu.

Indonesia

http://www.scottmcpherson.net/journal/2008/4/4/three-more-indonesian-h5n1-human-positives.html

It is bad enough to admit that bird flu is occurring within the borders of a

country, but human cases, especially clusters of cases is very alarming,

and it would seem that many excuses are being used to keep from having

to admit that they ARE occurring.

...two of the most recent H5N1 cases had family members who died suddenly at about the same time. As I have maintained, in public health there are no coincidences. The possibility that family members would die of different diseases in the same timeframe is remote and not nearly as plausible as the suggestion they all died from the same thing. H5N1. And if that were true, the number of family clusters in Indonesia is accelerating even more than we have previously confirmed.