July 5th, 2009 by Medgadget in Better Health Network
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A team of Canadian researchers analyzed the air traffic patterns during March and April of this year, looking for correlation between departure/arrival cities of passengers and the spread of H1N1 swine-origin influenza. Turns out that the two are closely correlated and confirm that airports are gateways of pathogens as well as vacationing tourists.
Our analysis showed that in March and April 2008, a total of 2.35 million passengers flew from Mexico to 1018 cities in 164 countries. A total of 80.7% of passengers had flight destinations in the United States or Canada; 8.8% in Central America, South America, or the Caribbean Islands; 8.7% in Western Europe; 1.0% in East Asia; and 0.8% elsewhere. These flight patterns were very similar to those during the same months in 2007 (see Fig. 1 in the Supplementary Appendix). We then compared the international destinations of travelers departing from Mexico with confirmed H1N1 importations associated with travel to Mexico, and we found a remarkably strong degree of correlation. Of the 20 countries worldwide with the highest volumes of international passengers arriving from Mexico, 16 had confirmed importations associated with travel to Mexico as of May 25, 2009. A receiver-operating-characteristic (ROC) curve plotting the relationship between international air-traffic flows and H1N1 importation revealed that countries receiving more than 1400 passengers from Mexico were at a significantly elevated risk for importation. With the use of this passenger threshold, international air-traffic volume alone was more than 92% sensitive and more than 92% specific in predicting importation, with an area under the ROC curve of 0.97.
Letter to NEJM: Spread of a Novel Influenza A (H1N1) Virus via Global Airline Transportation
*This blog post was originally published at Medgadget*
June 5th, 2009 by Steve Novella, M.D. in Better Health Network
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The Centers for Disease Control (CDC) currently recommends that children 6 month to 18 years old receive an annual flu vaccine. There are two types of flu vaccines used in the US: a live attenuated virus (LAIV) and a trivalent inactivated virus (TIV) vaccine. Both are safe and effective – while efficacy varies from year to year, they are 70-90% effective in healthy adults. Efficacy is young children appears to be slightly less, about 66%.
There remains, however, many sub-questions about the flu vaccines and by the time researchers have thoroughly explored them vaccine technology is likely to have progressed, and therefore any new vaccines will have to be tested all over again.
One of those sub-questions about vaccine safety and efficacy is the net effect of the flu vaccine in children with asthma. Some have raised concerns that the vaccine may exacerbate asthma, a 1-2% increased wheezing and 3% increased hospitalizations have been reported, although so far the bulk of the data suggests that both types of flu vaccines are safe in children with asthma. There is evidence to suggest that the LAIV may be superior to the TIV in children, particularly with asthma.
A new study, presented but not published, further explores the safety and efficacy of the TIV in children. Study author, Avni Joshi, M.D., of the Mayo Clinic, reports:
“The concerns that vaccination maybe associated with asthma exacerbations have been disproved with multiple studies in the past, but the vaccine’s effectiveness has not been well-established. This study was aimed at evaluating the effectiveness of the TIV in children overall, as well as the children with asthma, to prevent influenza-related hospitalization.”
The study is a retrospective study of 263 children who presented to the Mayo clinic with laboratory confirmed influenza. They found that children who had recieved the TIV vaccine had a 3 times greater risk of hospitalization than those who were not vaccinated. These results raise concerns about the safety and effectiveness of the TIV in children with asthma.
Dr. Joshi concludes:
“While these findings do raise questions about the efficacy of the vaccine, they do not in fact implicate it as a cause of hospitalizations. More studies are needed to assess not only the immunogenicity, but also the efficacy of different influenza vaccines in asthmatic subjects.”
That may seem like a curious conclusion given the results of this study, but it is accurate. The key to understanding the implications of this study is that it is retrospective. That means it looks at children who have the flu and then looks back to see who was vaccinated and who wasn’t. This in turn means that children were not randomized to either be vaccinated or not, and this opens the door to any number of variables that cannot be controlled for in the study.
The authors did look as obvious factors, such as severity of asthma and insurance status, and found that they did not correlate with risk of being hospitalized. But what other factors might there be? The flu vaccine is optional, which means that parents decide whether or not to vaccinate their children, perhaps with advice from their pediatrician. It is likely that sicker or more frail children are more likely to get vaccinated. It is also likely that children who had a bad reaction to the flu in the past are more likely to get vaccinated. The flu vaccine is recommended especially for those who are at high risk for complications if they get the flu.
Therefore while this study raises important questions, it is not designed to answer them definitively. A prospective trial is required for that, and that is what Joshi means by “more studies are needed.” In general, retrospective studies are useful to find correlations and generate hypothesis, but are not capable of determining causation – there are simply too many variables that are not controlled for.
As expected, the anti-vaccinationists have already jumped on this study and misinterpreted its significance. They did not recognize its retrospective nature nor put it into the context of existing research on the safety and efficacy of the flu vaccines.
Clinical trials are complex, and there are many types that each have their own strengths and weaknesses. Often, many independent lines of basic science and clinical evidence need to be brought together to form a reliable conclusion about a specific intervention. That is the essence of science-based medicine. Individual studies typically only provide a tiny slice of information, but are often presented to the public as if they are definitive. This creates a constant background noise of misinformation about medical questions.
It also provides a rich source of data from which to cherry pick, allowing proponents to support almost any notion by shopping from the vast store of often conflicting medical research. This reinforces the need to look thoroughly at the totality of scientific evidence on any claim or question.
When that is done on the question of the flu vaccines, it is clear that both types of vaccines are safe and effective. However, there is also much room for improvement in the vaccine technology itself, as well as evidence-based recommendations for who, exactly, should get which type of vaccine.
This current study adds incrementally to our knowledge on this question, and suggests questions for future research. It is not the kind of evidence, however, that should lead to changes in the current recommendations.
*This blog post was originally published at Science-Based Medicine*
May 17th, 2009 by DrRob in Better Health Network
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Before you get too “conspiracy theory” on me, let me assure you that I am not going to talk about how the influenza virus pandemic is the work of terrorists (unless the Napoleon and Snowball are trying to take over our farm). I am also not suggesting that children are terrorists (although some do raise my suspicion).
The virus that brought such worry and even panic seems now to be “fizzling out” and people are now questioning if the authorities and the press overreacted to the threat. Will this be a replay of the “boy who cried wolf” and have us complacent when a real threat comes? One writer questioned if the flu “overreaction” was “more costly than the virus itself.“ Another article cites an Australian professor (of what, the article did not say) who stated that “the country would be better off declaring a pandemic of some of the real health problems it has, like diabetes and obesity.”
The real din, however is in the countless letters to the editor and calls to radio talk-show hosts mocking the “alarmism” put forth by the WHO and others about this flu. This does appear to be in the minority, as one poll said that 83% of Americans were satisfied with the management of the outbreak by public authorities. Still, I suspect the volume of the dissent and sniping at the non-serious nature of the pandemic so far will only increase over time. The number of people who know better than public health officials will multiply.
This pandemic is a catch-22 for public health officials, as an excellent article on the subject states:
The irony is that the overreaction backlash will be more severe the more successful the public health measures are. If, for example, the virus peters out this spring because transmission was interrupted long enough for environmental conditions (whatever they are) to tip the balance against viral spread, CDC and local health officials will be accused of over reacting.
Which brings me to the connection to terrorism. If public authorities somehow thought there was a 10% chance that New York City would be hit with another major terrorist attack, how big should their reaction be? If they suspected that there was a reasonable probability, say 5%, that the subways would be flooded with sarin gas, should they shut them down? I would certainly hope they wouldn’t leave that many people open to the chance of death.
And what is the best outcome? The best outcome is that this is an overreaction. The best outcome is that the terrorists, in fact, have reformed and are instead joining the Professional Bowling tour. I would welcome this outcome (not to mention the exciting infusion of young talent to the tour). The problem is, the officials have no idea how it will play itself out. Truth be told, since 9/11, there have not been any major terrorist attacks in the US. Does this mean that the money spent on the department of homeland security has been wasted?
As a pediatrician, I am very accustomed to overreaction. If you bring in your 20 day-old child to my office with a fever of 102, I will do the following:
- Admit them immediately to the hospital
- Draw blood tests looking for serious infection
- Check a urinalysis to make sure there isn’t an infection (using a catheter to get the sample)
- Start IV antibiotics as soon as possible
- Perform a spinal tap to rule out meningitis.
This seems a little over-the-top, doesn’t it? The child just has a fever! The problem is that children this age with a fever caused by a virus look identical to those who have meningitis. By the time their appearance differentiates, it is too late. This forces me to do the full work-up on every infant with fever and treat each one as if they have meningitis or some other serious infection. I do this despite the fact that the cases of meningitis are far outnumbered by that of less serious problems.
If this is your child, don’t you want me to do that?
Knowing what we know about pandemics, the same caution was, in my opinion, absolutely the right thing to do. If the virus turns out to be nothing serious, hallelujah. I don’t want my patients (or family members) dying at the rate that some of the previous H1N1 viruses caused. I want this to be a lot of worry for “nothing.” Please let it be so.
But I still don’t think it is time to relax. As one commenter on an earlier post I wrote about this pandemic stated:
It’s still a bit early to relax. The 1918 flu went around first in the spring and was very mild – kinda like this. Then it came back in the fall after incubating and mutating and was a killer.
I think the CDC and WHO probably will be concerned about this until next year, at least. Just to be on the safe side.
Remember that that flu, which was mild in the spring, went on to kill 20-100 million people.
For this reason, I hope the voices of reason win out over the armchair quarterbacks that don’t have to make these decisions that could mean the life or death of millions. Will you tell me that evacuating the NY subways wouldn’t be a good thing on the threat of Sarin gas? Would you criticize me for “overreacting” if your infant with a fever turned out to just have an upper respiratory infection? I hope not.
If you would, then that gives us ample reason to ignore your opinions on how this flu was handled.
*This blog post was originally published at Musings of a Distractible Mind*
May 6th, 2009 by SteveSimmonsMD in Primary Care Wednesdays
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Swine Flu has brought an awareness of the catastrophic potential inherent in pandemic influenza to the public consciousness and led many to panic. Industry has long played a major role in protecting us against epidemic influenza, providing doctors and patients with vaccinations and medications to help protect and treat the weakest individuals in our society: the young and old. However, pandemic flu frequently kills the healthiest in society; a hallmark of the 1918 Swine Flu Pandemic that left 500,000 dead in the U.S., far more that the average of 36,000 dead in a typical year.
This week, I had a discussion with Bill Enright, President and CEO of Vaxin Inc., about their efforts to create a vaccine for pandemic Flu. Our daughters are kindergarten classmates and over the last two years I have enjoyed the opportunity our friendship has afforded me to learn about the vaccine industry. As “Swine Flu” began to dominate the headlines I asked him to participate in a dialogue with me believing that a discussion between a clinical physician and a vaccine scientist would be interesting and informative for a reader without giving in to hysteria. He was kind enough to give of his own time and a part of the discussion follows:
STEVE: What is Vaxin, Inc.?
BILL:. Vaxin is a vaccine development company focused on needle-free vaccines to protect against influenza (both seasonal and avian influenza) and anthrax. Using technology developed at the University of Alabama at Birmingham, by our scientific founder Dr. De-chu Tang, we have been able to show proof of principle with our platform, intranasal seasonal influenza vaccine, and have just completed enrollment in a Phase I clinical study with an intranasal pre-pandemic influenza vaccine. We are also investigating patch-based vaccines.
STEVE: What is the difference between the vaccine you are developing for Pandemic Influenza and the vaccine given yearly for Epidemic Influenza?
BILL: Epidemic, or seasonal, vaccines are trivalent vaccines composed of three influenza strains (two A and one B) anticipated to be circulating. The CDC and the WHO spend considerable effort in monitoring the circulating strains around the world before making a decision on which strains should be included in that year’s vaccine. However, several changes could occur which result in the vaccine not being a good match for a particular year: mutations could change a strain, new strains could evolve or different strains than anticipated could predominate.
Pandemic vaccines will be made to the circulating influenza virus causing the pandemic. Vaccines made in advance of a pandemic are really “pre-pandemic” vaccines as they are attempting to estimate which influenza strain may make the jump to a pandemic and enable stockpiling and/or vaccination of at-risk individuals with the belief that the vaccine will mitigate symptoms and decrease mortality through cross-strain protection while a true pandemic vaccine is being developed/manufactured.
STEVE: How long does it take to produce an epidemic trivalent vaccine and is it feasible to have the current H1N1 strain or “swine flu,” included in the standard flu shot this fall?
BILL: That is a complex question. Do you include it as a 4th component? Replace one of the other A strains? Provide it as a separate vaccine? Manufacturers are currently trying to assess how much and of which type of vaccine they would be able to provide given a limited egg supply (since vaccine components require incubation in chicken eggs). Chicken populations take a significant amount of time to increase to add egg capacity. Seasonal vaccine antigen doses are typically 15µg and it takes approximately 1 egg for one, 15µg dose. To date it has taken 90µg of antigen to show similar levelsof efficacy for pandemic vaccines. Therefore, whether or not there is a sufficient egg supply and how that may impact the traditional epidemic vaccine is being discussed and calculated as we speak.
The length of time it takes to manufacture the epidemic trivalent vaccine depends a lot on the specific strains and how different the vaccine is from the previous year. For instance, the 09/10 vaccine will contain 2 of the same strains as the 08/09 version, only the B strain is different. The CDC put forward this years policy document on February 25th, identifying which exact strains were to be included in this year’s vaccine. Many manufacturers had already started the production efforts on the seed strains guessing that these would be the strains based on available surveillance of circulating strains. Typically the total process begins in December or January for most manufacturers. Usually the first vaccines are ready to ship to distributors in August or September. In certain years the process can take longer than usual because not all strains of influenza grow well in chicken eggs, including the recent H1N1 virus. New “reverse genetic” techniques are helping to alleviate this problem but the rate of growth and yield of virus continues to be a concern to manufacturers.
STEVE: Do you have any ongoing clinical trials for the H5 pre-pandemic flu?
BILL: Vaxin is currently completing a Phase I clinical trial for an intranasally delivered vaccine against the H5N1 influenza virus. This is the first step in getting a vaccine approved for use by the FDA. Typically Phase I trials involve a small number of otherwise healthy volunteers that agree to be vaccinated to allow us to test and ensure that our vaccine does not cause any serious unwanted safety concerns. Vaxin’s study involved 48 people that were divided into 3 groups of 16. Each group of 16 received a different dose of the vaccine on the first day and then received a second administration of a second dose 28 days later. Within each group of 16, only 12 people actually receive the vaccine and 4 people receive a placebo. Until the end of the study, no one knows who received the vaccine and who received the placebo.
STEVE: The mortality rates for H5 influenza have been between 30% and 70%. Did this lead you to choose H5 as a focus for your pre-pandemic vaccine?
BILL: The focus on H5 as a target for pre-pandemic vaccines is a result of the high degree of mortality seen in those that have been infected with the virus. While the 1918 flu had a catastrophic impact on the world and a large loss of life, it is estimated that the mortality rate was about 2%. However, it was able to spread very rapidly. Similarly, other pandemics from H2 and H3 outbreaks had relatively low mortality rates (estimated to be between 0.1%-0.5% for both the 1957 and 1968 pandemics).
STEVE: Can you speak about the delivery system you are using to deliver this vaccine?
BILL: Vaxin’s technology includes the use of another virus called adenovirus. This is a virus commonly found in nature which typically causes mild respiratory illnesses or cold like symptoms. It has a natural ability to infect humans at a very high rate. We have modified this virus so that it can no longer reproduce and we have incorporated a very small piece of the flu virus into the adenovirus. The adenovirus then infects people like normal but instead of making more adenovirus, it makes a piece of the flu virus. The body sees this in the same way it sees the flu…as a bad foreign protein and jump starts the immune system to get rid of it. In addition, our vaccine is given intranasally, the same way that the body normally sees both adenovirus and the flu. We believe the body responds in a very similar fashion in identifying and clearing the potential threat.
STEVE: Too many suffered complications to the H1N1 Swine Flu vaccine rushed through production in 1976; this leads me to ask if any corners would need to be cut, in terms of patient safety, to get a swine flu vaccine ready in time this year?
BILL: I am not familiar enough with the issues associated with moving the 1976 swine flu vaccine through the process to know about shortcuts taken, but the issues identified may still be issues. The result however was a significantly higher incidence of Guillain-Barre Syndrome (GBS) in those vaccinated vs those unvaccinated; 13.3 vs 2.6 per millions of people contracting Guillain-Barre, respectively. Note, significantly larger safety studies than are typically done for influenza vaccines would have been required to detect this event.
The current H1N1 swine flu vaccine would be against a very similar antigen and made with similar technologies for the most part and therefore the risk of GBS may still be prevalent. This will be weighed as a risk/benefit calculation when deciding how to proceed. It will depend in large part on the true mortality rate of the H1N1 swine flu vaccine. This was originally estimated at about 10%, but as identified cases of H1N1 and associated deaths are “confirmed” as opposed to being “probable” cases and the reporting becomes more accurate, it is now about 1% and falling. At 10% it is likely worth the calculated risk of GBS but at what point does the risk of death have a higher impact than the potential risk of GBS
STEVE: What percentage of health care workers, in our country, typically receive a flu shot?”
BILL: Only 36% of health care workers in the U.S. on average receive an influenza vaccine annually. (Source: CDC. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2003; 52 (RR8): 1-44.) Therefore, with a disease that can be spread two or more days before a person is symptomatic, an individual healthcare worker has a tremendous opportunity to spread the disease, without knowing it, to a population that is likely very susceptible, those that are sick and immune compromised to begin with.
STEVE: Do you have any suggestions for my colleagues and friends who tell me they get the flu from a flu shot?
BILL: It is scientifically not feasible to get the flu from a flu shot unless the vaccine has not been made appropriately and tested adequately. The licensed influenza vaccines on the market today are primarily inactivated whole virus or split subunit vaccines. Essentially the flu virus is grown in chicken eggs, purified and inactivated by heat or chemicals. The virus is unable to replicate and therefore cannot cause the flu. Usual side effects from any vaccination, because of the stimulation of a robust immune response from the body, include symptoms that some people associate with the flu, e.g., fever, body aches, sniffles etc. These symptoms are typical of many vaccinations including flu. Similarly in the new live virus vaccine (FluMist ®), the virus has been adapted to grow only in a cold environment. Once in the body its ability to replicate is severely limited and again not feasible to cause the flu.
All in all vaccines are the most cost effective medical procedure invented. Their use over the past century has saved millions of lives and untold expense with several previously common diseases now relatively under control or near complete eradication. Many people do not realize the annual cost, in lives lost, hospitalizations and subsequent economic costs, that influenza outbreaks inflict. Our ability to track and monitor influenza outbreaks and continual improvements in technologies and manufacturing processes are allowing us to attack influenza with the same vigor. While the world is more prepared than ever before to deal with potential pandemic influenza outbreaks, we still have room for improvement to ensure adequate, rapid access in all parts of the world. Vaxin is hopeful that our technologies and products will continue to advance this effort for rapidly available, safe, effective, easy to administer vaccines.
May 2nd, 2009 by Jon LaPook, M.D. in Better Health Network, Video
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Yesterday I visited the Centers for Disease Control in Atlanta and was taken inside the command center, where almost 100 staffers have been working around the clock to monitor and stem the current outbreak of flu.
I first spoke to Toby Crafton, the manager of the command center, who oversees the day-to-day operations. He and his team have been preparing for a possible pandemic of flu or another infectious illness for years. I also spoke to Michael Shaw, PhD, who heads up the virology labs that are studying the H1N1 virus causing the current outbreak. He’s spent a career learning the laboratory techniques that are so urgently needed right now. The third person I spoke to was Dr. Richard Besser, Acting Director of the CDC, who has been working at the agency for 13 years and is an extensively published expert in infectious diseases.
I mentioned that last week I had received an email notification from the New York City Department of Health (NYCDOH) about how I should be managing my patients with flu-like symptoms. The advice was actually not intuitively obvious to me. For example, the Department of Health said that for patients with mild illness, treatment with anti-viral meds like Tamiflu and Relenza was only recommended for patients who also had underlying conditions that increased their risk for complications due to influenza. Dr. Besser pointed out that it was especially important right now for physicians to stay up to date with the recommendations being made by public health officials. Doctors can contact their local department of health and sign up for the same type of email notification that I received.
This brings us to the main point of today’s blog post. Many of us – patients and physicians alike – have been thinking about the influenza virus for about a week. Public health officials like the teams at the CDC and the NYCDOH have been thinking about it for years. Physicians, me included, are used to practicing medicine based on “clinical judgment.” We understand that medicine is an art and not a science, that there are many different ways to approach a problem, that there’s often no clear “right” or “wrong.” We are also used to doing things “our way”, whatever that way is. But this is not a time for doing things “our way” if it’s at significant odds with strong recommendations being made by public health officials. There are recommendations that may seem logical – like prescribing medication for somebody with mild flu symptoms “just in case” that nevertheless go against the judgment of people who have trained for years to think about how to deal with an epidemic.
What if you’re a physician who strongly disagrees with a suggestion of public officials? Then challenge that recommendation publicly. Bring the discussion to light; maybe you’re right. While this is no time to go rogue, doctors have an obligation to think carefully and independently and to challenge recommendations that seem illogical. But don’t silently do things your own way.
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