MEXICO CITY – A unique strain of swine flu is the suspected killer of dozens of people in Mexico, where authorities closed schools, museums, libraries and theaters in the capital on Friday to try to contain an outbreak that has spurred concerns of a global flu epidemic. The worrisome new virus — which combines genetic material from pigs, birds and humans in a way researchers have not seen before — also sickened at least eight people in Texas and California, though there have been no deaths in the U.S.
A recombination of genetic elements from influenzas that infect different species holds the possibility of a much more deadly virus. Hybrids are bad. Some end up looking unlike any flu our immune systems have resistance to. Plus, they can contain mutations that make them especially lethal. The massive killer 1918 influenza pandemic originated in pigs. (correction: The 1918 virus probably originated in birds) That 1918 outbreak also was of type H1N1 and it killed from 2.5-5% of the world human population.
Richard Besser, MD, the CDC's acting director, told reporters today during a press teleconference that the development is worrisome. "Our concern has grown since yesterday, based on what we've learned," he said. "We do not know if this will lead to the next pandemic, but our scientists are monitoring it and take the threat very seriously."
The swine flu A/H1N1 strain has been confirmed in one more US citizen, a child from San Diego who has recovered, raising the total number of US cases to eight, Besser said. The virus contains gene segments from four different influenza types: North American swine, North American avian, human, and Eurasian swine.
The US Centers for Disease Control and Prevention (CDC) is on the case. The CDC says this influenza does not usually infect humans.
Swine Influenza (swine flu) is a respiratory disease of pigs caused by type A influenza that regularly cause outbreaks of influenza among pigs. Swine flu viruses do not normally infect humans, however, human infections with swine flu do occur, and cases of human-to-human spread of swine flu viruses has been documented. See General Information about Swine Flu.
From December 2005 through February 2009, a total of 12 human infections with swine influenza were reported from 10 states in the United States. Since March 2009, a number of confirmed human cases of a new strain of swine influenza A (H1N1) virus infection in California, Texas, and Mexico have been identified. An investigation into these cases is ongoing. For more information see Human Swine Flu Investigation.
General Information about Swine Flu
Questions and answers and guidance for treatment and infection control
Human Swine Flu Investigation
Information about the investigation of human swine flu in California
"There are things that we see that suggest that containment is not very likely," he said.
Mentally walk yourself thru how you are willing to change your lifestyle to reduce exposure to other people.
The Mexican government was taking the threat seriously, shuttering schools and museums in Mexico City and canceling all government-sponsored gatherings for the weekend. More than six million children were kept out of school. Officials urged residents to avoid crowded public places like the subway and movie theaters.
If this takes off don't expect vaccines for months. If it turns out to be highly lethal consider my "workplace cocooning" proposal. If that isn't feasible for you then at least greatly reduce your physical exposure to other people and to surfaces that others touch.
Also see my previous post Influenza Like 1918 Strain Would Kill 62 Million. Let us hope this strain is not as dangerous as that.
Update: The 1918 pandemic is the standard to compare with. The H1N1 strain from 1918 killed between 50 and 100 million out of a total world population of 1.8 billion at the time. That's a range between 2.7% and 5.5%.
An estimated one third of the world's population (or ≈500 million persons) were infected and had clinically apparent illnesses (1,2) during the 1918–1919 influenza pandemic. The disease was exceptionally severe. Case-fatality rates were >2.5%, compared to <0.1% in other influenza pandemics (3,4). Total deaths were estimated at ≈50 million (5–7) and were arguably as high as 100 million (7).
The impact of this pandemic was not limited to 1918-1919. All influenza A pandemics since that time, and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.
The 1918 fatality rate varied greatly in different parts of the world. How well you are fed, existing infections and diseases, access to health care, and ability to isolate oneself will all influence risk of contracting or dying once infected.
GlaxoSmithKline Plc’s flu treatment Relenza and Roche Holding AG’s Tamiflu appear effective against the strains of the virus the CDC has tested, the companies said.
But if you didn't stockpile in advance your odds of getting either drug now are falling rapidly every day.
Update II: Check out a Google Maps views of H1N1 swine flu spreading in humans. Note that the first map isn't actually a case map. Check out links on left.
Update III: Here is a Google map of real and suspected human H1N1 swine flu cases. This tracking by individual cases will become unwieldy in a few days. But for now it gives a good sense of how this flu is spreading.
H5N1 avian influenza hasn't spread into humans on a pandemic scale yet because it is not well adapted to spread between humans. In birds it reproduces in a warmer environment and so has genetic variations that make it thrive better at warmer temperatures. However, scientists have now discovered a single mutation that better adapts bird flu to the lower temperatures of the human upper respiratory tract.
MADISON - Since it first appeared in Hong Kong in 1997, the H5N1 avian flu virus has been slowly evolving into a pathogen better equipped to infect humans. The final form of the virus, biomedical researchers fear, will be a highly pathogenic strain of influenza that spreads easily among humans.
Now, in a new study a team of researchers from the University of Wisconsin-Madison report the identification of a key step the virus must take to facilitate the easy transmission of the virus from person to person.
Writing today (Oct. 4, 2007) in the journal Public Library of Science Pathogens, a team of researchers led by virologist Yoshihiro Kawaoka of the UW-Madison School of Veterinary Medicine has identified a single change in a viral protein that facilitates the virus' ability to infect the cells of the upper respiratory system in mammals. By adapting to the upper respiratory system, the virus is capable of infecting a wider range of cell types and is more easily spread, potentially setting the stage for a flu pandemic.
A worldwide flu pandemic of highly lethal virus would certainly up-end our lives in a big way. Your odds of survival would go up substantially if you could find a way to stay home for several months and rarely go to stores and other places with people.
A single H5N1 virus mutation found in one patient gave the virus the ability to survive in the cooler temperatures of the upper respiratoy system.
The new study involved two different viruses isolated from a single patient -- one from the lungs, the other from the upper respiratory system. The virus from the upper respiratory system exhibited a single amino acid change in one of the key proteins for amplification of influenza virus genes.
The single change identified by the Wisconsin study, says Kawaoka, promotes better virus replication at lower temperatures, such as those found in the upper respiratory system, and in a wider range of cell types.
Kawaoka expects H5N1 to eventually get the other mutations needed to spread in humans. By that time will we have good technologies for rapidly scaling up vaccine production? If not then the best response I can think of that would minimize economic disruption and loss of life is what I call workplace cocooning. Work and live in the same place, whether that be at home or in a building converted into a live-in workpace.
You can read the full research paper at Plos Pathogens: Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice.
In fact, Marc Choisy and Pejman Rohani at the University of Georgia at Athens in the US have shown that killing wild animals with a disease like flu could actually lead to more infected animals, not fewer.
This is due to a classic principle of ecology, called compensation. Many wild species produce more offspring than can survive. Hunting removes animals which would otherwise have competed with these excess young, especially as hunters often target bigger, older beasts. So in a hunted population, more young usually survive which compensates – or sometimes even over-compensates – for the loss due to hunting.
But when a disease causes lifelong immunity in its host, most of the older animals in a population have survived it and are therefore immune, leaving only the young susceptible.
A raised death rate of older birds due to hunting would increase food available to younger birds. Therefore more younger birds would survive early youth. These younger birds would be immunologically more immature and at greater risk of getting infected by H5N1 influenza.
The net effect if hunting would depend on the percentage of birds killed and whether the killing of birds was sustained. In the extreme the extinction of a bird species would eliminate it as a bird flu carrier.
In any case, if bird flu becomes pandemic in humans you'll at orders of magnitude greater risk from getting it from humans than from birds.
JAKARTA, Indonesia, May 24 -- The World Health Organization might soon convene an expert panel to decide whether an unprecedented human outbreak of bird flu in Indonesia should trigger a higher global alert for a possible pandemic, health officials said Wednesday.
Why this concern? Suspected Human-To-Human (H2H) transmission of bird flu in 8 members of an Indonesia family got bird flu. Only 1 survived! A strain this lethal would exact a terrible toll if it mutates into a pandemic strain.
Indonesian health authorities this week confirmed that the virus had killed at least six members from one extended family on Sumatra island, including a 32-year-old man Monday. A seventh family member also died from what investigators suspect was bird flu, but she was buried before samples could be taken. Another relative is hospitalized with a confirmed case and is recovering.
May 24, 2006 (CIDRAP News) – For the first time, evidence suggests that the H5N1 avian influenza virus may have passed from one person to another and on to a third, according to a World Health Organization (WHO) official.
Referring to the extended-family case cluster in Indonesia, the WHO's Maria Cheng told the Canadian Press (CP) yesterday, "This is the first time we have seen cases that have gone beyond one generation of human-to-human spread."
The big fear about bird influenza is that it could mutate so that such human-to-human transmission becomes easy.
One of the major puzzles about the cluster, in which human-to-human-to-human transmission is suspected, is the lack of an identifiable animal source of infection for the first case. Steven Bjorge, a WHO epidemiologist in Jakarta, told the AP that the 37-year-old deceased woman who is regarded as the first case-patient might have picked up the virus in her home or workplace. She died April 29 and was buried before samples could be collected for testing, but the WHO believes her illness was avian flu.
"We believe she may have had some contact either with dead or dying chickens in her household or through her activities as a vegetable grower and a seller in a market," Bjorge said of the woman.
On April 29, three people who later fell ill shared a small room with the mother of the family, who was gravely ill and coughing, and has since died. Others who have been stricken cared for family members who were dying. There are no cases reported in the village outside of the family.
The fact that other members of their village have not yet become ill is good news. Hopefully this cluster won't get any larger.
Recombinomics influenza commentator Henry Niman argues that the incubation time of H5N1 bird flu is overestimates by some public health officials and therefore they are underestimating the extent of human-to-human transmission.
WHO assumes that the incubation time for bird flu in humans is 7 to 10 days, longer than that of regular flu, she said.
Henry Niman, who runs recombinomics.com, a Web site tracking the genetics of flu cases, argues that the incubation period is closer to the two to four days of regular flu, so the boy may have been infected by another family member, meaning that the virus may have made three consecutive human-to- human jumps.
But Cheng said the health agency's "working hypothesis" was still that it had jumped only twice.
Niman thinks the number of human-to-human (H2H) clusters has been underestimated due to the overestimate of the H5N1 incubation time. Niman therefore believes that we are already at phase 4 of the development of a pandemic virus strain. Phase 5 would include a much higher level of H2H transmission. Phase 6 would be "it is time to move to that cabin in the country with lots of survivalist supplies".
I do not know if or when H5N1 will mutate into a pandemic strain. I hope it does not. But if it does then you should prepare yourself to rapidly and radically restructure your life to decrease your odds of getting exposed to carriers.
Scientists might have identified one of the reasons why the bird flu virus H5N1 is so deadly to humans. A study published today in the open access journal Respiratory Research reveals that, in human cells, the virus can trigger levels of inflammatory proteins more than 10 times higher than the common human flu virus H1N1. This might contribute to the unusual severity of the disease caused by H5N1 in humans, which can escalate into life-threatening pneumonia and acute respiratory distress.
Michael Chan and colleagues from the University of Hong Kong and collaborators in Vietnam, studied the levels of a subset of the pro-inflammatory proteins called 'cytokines' and 'chemokines', induced by the virus H5N1 in human lung cells, in vitro. The authors compared protein levels induced by strains of the H5N1 virus that had appeared in Hong Kong in 1997 (H5N1/97) and Vietnam in 2004 (H5N1/04), with levels induced by the human flu virus H1N1.
Their results show that H5N1 is a much more potent inducer of pro-inflammatory proteins than H1N1. Twenty-four hours after infection with H5N1/04, the levels of the chemokine IP-10 in bronchial epithelial cells reach 2200 pg/ml, whereas in cells infected with H1N1 they only reach 200pg/ml. In H5N1/97-infected cells, IP-10 levels reach 1750 pg/ml. Similar results were found for other chemokines and cytokines.
High levels of cytokines cause excessive levels of inflammation and that can help to kill you.
Chemokines and cytokines are the "messengers of the immune system" and are critical in coordinating and regulating the immune response. Altering this balance is likely to lead to an uncontrolled inflammatory response in the lung and probably explains, at least in part, the severe lung inflammation associated with avian flu virus H5N1.
Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, says cytokine storm caused excessive immune response in 1918 pandemic victims and this caused organ damage and high fatality rates.
Today we are very concerned that the H5N1 virus circulating in wild and domesticated birds in Asia is moving genetically towards a human-to-human transmitted agent and could result in a 1918-like pandemic. If this happens, we expect that the illnesses that we see among those infected with H5N1 virus will be similar to those individuals who were infected in 1918 and the limited number of humans who have been infected with H5N1 to date. Many of the deaths that occurred in these populations resulted from the explosive growth of the virus in humans and a subsequent cytokine storm. A cytokine storm is the release of a chemical in the body that stimulates the human immune system to respond to the virus infection. In these serious illnesses and deaths, it's actually been an over vigorous immune response elicited by this infection that result in the organ damage and ultimately the death of the individual. Ironically this means that those with the strongest immune systems may be at highest risk for a serious outcome if infected with the H5N1 virus.
Also see the Flu Wikie Cytokine Storm entry for more discussion on how a cytokine storm can kill you. Adults between the ages 18 and 40 suffered most of the deaths from the 1918 strain probably because their immune systems were stronger than those of older people. Hence their immune systems were better able to overreact to the cytokines which the 1918 flu caused to be made.
As Mr. Mackey might say, "Cytokine storms are bad, mmmmkay?" and so we need ways to stop cytokine storms, mmmmkay? Well, back in 2003 an Imperial College London team showed that a molecule named OX40:Ig that blocks the effect of OX40
Until now, treatments to eliminate the cytokine storm have focused on inhibiting all T cells. But this leaves the patient unable to clear the virus and susceptible to other infections. Dr Hussell's team have developed a way of down regulating a molecule known as OX40 that only targets T cells that have recently been alerted to the presence of the flu virus.
"OX40 sends out a 'survival signal' instructing activated T cells to remain in the lungs for longer to help fight the infection. However, because new cells are arriving all the time this prolonged presence is not needed," explains lead researcher Ian Humphreys of Imperial's Centre for Molecular Microbiology and Infection.
"Inhibiting this signal therefore allows T cells to vacate the lungs earlier whilst leaving behind a sufficient immune presence."
Using a fusion protein OX40:Ig supplied by the pharmaceutical company Xenova Research, the scientists were able to demonstrate that OX40:Ig blocks active T cells.
Results show six days after infection with flu, mice treated with OX40:Ig were indistinguishable from uninfected control mice. But infected mice that had not been treated lost 25 per cent of their body weight, appeared hunched, withdrawn and lost their appetite - all characteristic symptoms of flu.
When treatment with OX40:Ig was delayed for several days after infection, until the mice had lost 20 per cent of their body weight and OX40:Ig was administered, symptoms were reversed.
Re-infection also indicated that the ability of mice to respond to a second infection was not affected by the reduced T cell immunity during the initial infection.
Parenthetically, OX40 is also known as CD134.
Sounds hopeful, right? That was 2003. Xenova was supposed to begin human testing in 2004.
Hussell believes the drug could potentially treat any illness with an excessive inflammatory response, including asthma and possibly SARS. The researchers are testing the fusion protein as an asthma treatment in mice. They hope to test OX40:Ig in adult humans in a phase one trial in 2004.
Near as I can tell no such human trial took place in 2004. Poking around Xenova's web site I found indications that Xenova probably has not moved on to human trials.
OX40 is a platform technology capable of producing multiple drug candidates targeting cancer, autoimmune and other diseases where the immune system is involved. Xenova is developing the OX40 technology for the up-regulation of the immune system, for the development of novel treatments for cancer and infectious diseases. Xenova's rights to down-regulate the immune system have been the subject of development and licence agreements entered into with Celltech and Genentech (April 2002).
Xenova’s rights to the OX40 technology include rights relating to the up-regulation of the immune system which may be used for the development of novel treatments for cancer and infectious disease. Xenova’s rights to down-regulate the immune system have been the subject of development and licence agreements entered into with Celltech and Genentech.
Here's an August 2004 press release which states more clearly that Xenova has sold the rights for OX40 development to down-regulate against, for example, a cytokine storm caused by an influenza infection.
Xenova retains all rights for the use of OX40 in up-regulation whilst Genentech Inc and Celltech Group plc have the rights for down-regulation.
While neuraminidase inhibitors like Tamiflu can be used against all manner of flu types and hence have a market even when there is no pandemic the OX40 blockers probably do not have much utility against influenza under normal conditions. So OX40 blocker development probably isn't going to get much funding against flu unless governments step in (and my guess is governments are probably not smart enough and prudent enough to do that).
I haven't been able to find indications that Celltech and Genentech are pursuing OX40 development for flu treatment. Rapid development and production of OX40:Ig during an H5N1 pandemic might save millions of lives. Would any governments show sufficient regulatory flexibility to allow rapid introduction of a prototype drug during a pandemic?
So what to do about the cytokine storm threat come a pandemic? Statin drugs such as Lipitor and Crestor (widely used to lower cholesterol) probably will lower the risk of death of those infected by an influenza strain that causes a cytokine storm. If you have high cholesterol and haven't done anything about it go get a statin drug prescription and it might just save your life two different ways: Avoid a heart attack and avoid death in an influenza pandemic.
Scientists have re-created the “Spanish flu” virus that killed up to 50 million people in 1918-19 and shown that it shared traits with the H5N1 strain of avian flu.
An analysis of the re-created pathogen has shown that, like its modern cousin, it began as a bird virus and jumped species into humans with mutations that made it peculiarly virulent and lethal.
Dr. Jeffrey Taubenberger of the US Armed Forces Institute of Pathology and other scientists have just published papers in Science and Nature demonstrating that the 1918 virus was an avian virus in origins.
"We now think that the best interpretation of the data available to us is that the 1918 virus was an entirely avian-like virus that adapted to humans," Taubenberger told reporters in a telephone briefing.
"It suggests that pandemics can form in more than one way."
The more deadly 1918 pandemic virus is unlike the 1957 and 1968 flus in that the 1918 flu did not recombine with human influenza strains. That the 1918 strain did not recombine with human influenza strains and at the same time that it was orders of magnitude more lethal is probably not a coincidence.
"We now think that the 1918 virus was an entirely avian-like virus that adapted to humans," said Mr. Taubenberger. This is a different situation than the last two pandemics we had, the Asian flu in 1957 and the Hong Kong flu in 1968, which are mixtures in which a human-adapted influenza virus acquired two or three new genes from an avian influenza source. So it suggests that pandemics can form in more than one way, and this is a very important point."
He says it also suggests that the current Asian bird flu, known by its scientific designation H5N1, could evolve into a human killer with just a few more mutations that allow it to jump more efficiently among people.
"It suggests to us the possibility that these H5 viruses are actually being exposed to some human adaptive pressures and that they might be acquiring some of these same changes," he added. "In a sense, they might be going down a similar path that ultimately led to 1918."
This is the most important fact here: The 1918 H1N1 influenza virus did not need to co-infect a human and swap genes with a human influenza strain in order to gain the mutations needed to cause a highly lethal human influenza pandemic. That ups the probability that H5N1 could start a human pandemic.
"We felt that we had to re-create the virus and run these experiments to understand the biological properties that made the 1918 virus so exceptionally deadly," said Terrance Tumpey, a flu researcher at the Centers for Disease Control and Prevention and lead author of the Science study. "We wanted to identify the specific genes responsible for virulence, which we feel will advance our ability to prepare vaccines and make antiviral medicines that are effective against future pandemic strains."
Although the genetic data has been made part of a public database, the 10 or so vials of the virus itself - grown in human kidney cells - are contained under tight security guidelines set for potential biological weapons at the CDC's lab in Atlanta.
Fox News has a good article reporting that some of the mutations which H5N1 has already picked up are similar to 1918 H1N1 mutations and probably are moving H5N1 closer to human transmissibility and a human pandemic.
The good news is that the H5N1 flu bug still has a long way to go. The 1918 bug seemed to need several changes in every one of its eight genes. The H5N1 virus is making similar changes but isn't very far along.
"So, for example, in the nuclear protein gene we speculate there are six genes crucial [for human adaptation]," Taubenberger says. "Of those six, three are present in one or another H5N1 strain. But usually there is only one of these changes per virus isolate. That is true of other genes as well. You see four, five, or six changes per gene in the 1918 virus, whereas H5N1 viruses only have one change or so. It shows they are subjected to similar [evolutionary] pressures, but the H5 viruses are early on in this process."
Which H5N1 strains is Taubenberger comparing the 1918 H1N1 strain to? How old are the strains he is comparing to? Has he compared to any H5N1 strains isolated from recent Indonesians who have recently died from bird flu?
H5N1 appears to have picked up important mutations on the road toward human adaptation including one that has made it much more lethal in mice.
There is one ominous sign. It's in a flu gene protein called PB2. A single change in this gene makes H5N1 extremely deadly to mice. The same single change helps bird flu to adapt to mammals.
For example, the change in PB2 was seen in six of the seven H5N1 viruses spreading among captive tigers in Thailand.
Robert Webster of St. Jude Children's Research Hospital showed in a PNAS paper in the summer of 2004 that H5N1 has become much more lethal in mice and this is an indicator that H5N1 is becoming better adapted to mammals. Webster also points to an expanded range for H5N1 including tigers and domestic cats. The expanded range gives the virus more ecological niches in which it can further adapt to mammals and pick up more mutations that would help it become transmissible in humans.
Also check out a CDC report on possible H5N1 transmission between tigers. I realize some of my readers think I'm being excessively alarmist by writing posts about avian flu. But I just do not see humans as so different from all the other mammals as to think that a virus that is hopping between a bunch of species is going to draw the line and avoid humans. These new reports about the 1918 H1N1 strain which hopped from birds to humans and the parallels with H5N1 strike me as a strong reason not dismiss the threat this virus poses.
The New Scientist has a good article on the latest findings. The 1918 H1N1 virus was less dependent on cellular machinery to replicate.
Meanwhile, Terrence Tumpey at the US Centers for Disease Control in Atlanta and colleagues used the sequences to rebuild the virus itself, and infect mice with it. They report this week that unlike other flu viruses, 1918 does not need a protein-splitting enzyme from its surroundings to replicate, instead using some hitherto-unknown mechanism. And as in 1918, it rapidly destroys lungs (Science, vol 310, p 77).
Pathogens that jump species are a lot more lethal that pathogens that have been transmitted primarily between members of a species for a long time. The knowledge that the 1918 influenza was from birds and had no recombination with human influenza strains should give pause to anyone wondering whether H5N1 poses a serious threat.
The bird flu viruses now prevalent share some of the crucial genetic changes that occurred in the 1918 flu, scientists said, but not all. The scientists suspect that with the 1918 flu, changes in just 25 to 30 out of about 4,400 amino acids in the viral proteins turned the virus into a killer. The new work also reveals that 1918 virus acts much differently from ordinary human flu viruses. It infects cells deep in the lungs of mice and infects lung cells, like the cells lining air sacs, that would normally be impervious to flu. And while other human flu viruses do not kill mice, this one, like today's bird flus, does.
As these researchers advance along in their work they are going to come up with much better metrics for measuring how far the H5N1 avian flu is from being capable of creating a pandemic in humans.
Update II: Henry Niman claims the 1918 flu was the product of a human flu and swine flu recombination.