One Flu Into the Cuckoo’s Nest*

“I don’t seem able to get it straight in my mind….”
― Ken Kesey, One Flew Over the Cuckoo’s Nest

Influenza is going gangbusters at the moment. I like going to Google Flu trends as well as the CDC flu site to see what flu is doing. Using Google searches as a surrogate for infections is an interesting technique that public health officials have tried with less success in other illnesses but is not without utility. Behaviors of populations can presage a problem, my favorite example is the first hint of the 1993 massive Cryptosporidia diarrhea outbreak in Milwaukee was a sudden shortage of Kaopectate and Peptobismol. It appears there are more patients with flu like symptoms this year than  at the height of the H1N1 epidemic of 2009. We have lots of flu like illness, and per the CDC there are buckets of confirmed influenzaflu, but so far the season, while probably having more cases than 2009, the outbreak is clinically not the same.

Compare and contrast, the two words that defined undergraduate liberal arts essay assignments. Get out your blue books and compare and contrast influenza outbreaks from 2009 and 2013. You have one hour.

The H1N1 epidemic was due to, well, influenza A H1N1. Only about 1% of the isolates are currently H1N1, so presumptively almost everyone is immune from prior infection or vaccination. That is what probably ends most epidemics: the herd has immunity and the virus can not longer spread in a population and the virus has to go into hiding in swine populations, biding its time until the population, and genetic shift, render the population susceptible again.

This season it is influenza A H3N2 and influenza B that are causing most of the disease. A lot of disease. Emergency rooms are seeing an increase influenza like illness and it is often caused by influenza. In my hospitals specimens positive for influenza jumped from 2% of submitted specimens to 26% positive and we are almost out of influenza PCR assay kits.

Despite the increase in cases, it is remarkable for what we are not seeing. While people are being admitted to the hospital with flu, and deaths are now increasing,  unlike the H1N1 epidemic, the ICU is not filled with influenza patients on a ventilator.

The most remarkable aspect of the 2009 outbreak was how lucky we were. It still amazes me. We were maxed out in every ICU in my system. All ICU beds and ventilators were in use. If a patient came through the door needing a ventilator, we did not have one to offer. Someone was going to die we might have otherwise saved. And right as we reached our surge capacity, the epidemic peaked. No patients came in needing a ventilator for flu.  Dodged that bullet.

This year we have had only a smattering of patients on a ventilator from influenza, no young people dying (20-30 year olds, there have been at least 20 pediatric deaths so far), no flu encephalitis (we had two deaths from CNS involvement in young people), no one on ECMO  from influenza induced lung failure, no pregnant females with advanced influenza. Lots of morbidity, but different than 2009, milder than 2009.  But it is still early in the season.

It is curious how the strains differ in their effects on populations. Maybe the H1N1 has modified the disease for H3N2, since infection and vaccination to H1N1 in some people can result in a more ‘universal’ antibody against flu. Immunity to influenza flu is not as simple as one antibody against one strain, since for the hemagglutinin and neuraminidase proteins there are multiple areas that can generate an antibody response. Some of these sites are variable and differ every year but some are conserved. If you are lucky enough to develop antibody against conserved regions you could potentially be immune to all influenza A. Or probably there are other factors with the H3N2 virus that result in different clinical manifestations. We will likely know is a year or two after the researchers have their opportunity to investigate the current flu season.

I would expect increased mortality this year from flu and I hope to be wrong:

The magnitude of the seasonal component was highly correlated with traditional measures of excess mortality and was significantly larger in seasons dominated by influenza A(H2N2) and A(H3N2) viruses than in seasons dominated by A(H1N1) or B viruses.

But not only from infection but from an increase in cardiac events:

These data suggest that influenza infections, particularly by A/H3N2 viruses, are directly associated with acute IHD-related events in older individuals.

At the moment it looks like we are having widespread flu and flu like illness but with less severe morbidity and less mortality. Of course, I speak from the perspective of a hospital based doctor in Portland Oregon, and as such have a narrow and probably not representative experience.  Everything is always better in Portland.  It will be interesting for someone with access to all the data to compare and contrast the two flu seasons in the years to come.

The one consistent question I get about the flu vaccine is “Does it work?”

Do not ask me that question if you don’t have at least 10 minutes to kill, because the answer is not yes or no. For some vaccines it is a binary answer and people like binary answers. Yes or no. Good or bad. I get the suspicion that those in the SCAM reality greatly prefer simple binary answers and do not deal will with uncertainty, spectrum and gradients of answers. Perhaps that is their defining characteristic. SCAM proponents seem to like black and white in a world of grey. Does the tetanus vaccine work? Yep. Everyone who gets the vaccine is protected from tetanus. Doe the influenza vaccine work? It depends on who is vaccinated, which vaccine, what the circulating strains are and how well the vaccine matches and what your end point for defining ‘works’ is.

Influenza is complex.

There is an interesting issue in medicine that is usually not explicitly discussed but comes up obliquely in the concept of number needed to treat. Sometimes, like pneumonia, we are treating an individual. Or the tetanus vaccine, where we are preventing an illness in an individual. Much of the time with prevention we are not only treating the individual but also populations. It is an interesting issue: applying population data to individuals. A given individual may gain no benefit from statins or the flu vaccine, whereas populations of often do.

That is one of the strengths and a public relations weakness of modern medicine. Ignoring the individual and treating populations in some circumstances can lead to marked improvement in every ones health, the ‘old rising tide lifts all boats’ approach to public health medicine. And people loathe not being considered a unique and special entity. Influenza vaccination is both a intervention for individual AND populations, since as the Googleflu trends graphs nicely demonstrate, influenza like illnesses affect populations and do so with remarkable rapidly. Look at the slope of those curves. They are almost vertical. I mean, whoa. That’s communicable.

Unlike other respiratory viruses, influenza can kill, directly and indirectly.  So while there are 200 causes of flu like illnesses, influenza is unique in its ability to routinely cause severe morbidity and mortality.  My ICUs do not fill up with rhinovirus and metapneumovirus infections and their complications.

So with influenza vaccination efficacy you can have a narrow perspective: does it prevent influenza in an individual (sometimes) or does it have more widespread population effects.  The problem with the other benefits to vaccination it is like the dog that doesn’t bark.

Gregory (Scotland Yard detective): “Is there any other point to which you would wish to draw my attention?”
Holmes: “To the curious incident of the dog in the night-time.”
Gregory: “The dog did nothing in the night-time.”
Holmes: “That was the curious incident.”

In part I do infection control for a living and we are successful when nothing happens, but people do not notice when nothing occurs, and I have to point out the benefits of events not happening. Potential benefits of flu vaccination include:

  • I don’t influenza.
  • I don’t get influenza and therefore don’t give it my Grandmother.
  • I don’t get the flu and do not pass it on to my hospitalized patient, who tend to die from nosocomial influenza.
  • I get influenza, but it is milder and I miss less work.
  • I get influenza and because it is milder and less infectious I don’t give it to my Grandmother.
  • Because my Grandmother doesn’t get influenza she does not have an exacerbation of her heart failure, diabetes, COPD etc.
  • My grandmother doesn’t get the flu and as a result doesn’t have a secondary  myocardial infarction or bacterial pneumonia and is not hospitalized and doesn’t die as a result.
  • My pregnant wife doesn’t get the flu (from me or due to vaccination) and as such does not have miscarriage or is not admitted to the hospital with ARDS from influenza.
  • My obese Uncle doesn’t get the flu (from me or due to vaccination) and is not admitted with ARDS from influenza.

I have discussed flu vaccination multiple times in the blog. The question is not IF influenza vaccination works. It does. It is the  magnitude of the effect and in what populations it is effective that is the question.   The preponderance of information suggests the for most of the endpoints above, the influenza vaccine has beneficial effects. It’s not a great vaccine but better than nothing.

Then there is the political issue as to whether the bang is worth the buck, whether the benefits of pushing flu vaccines are worth the time and resources. That is a calculus that I am not capable of independently deriving, my sense is the answer is yes, and those with more expertise in these areas than I say influenza vaccination is cost effective.

One aspect of the flu season does not change from year to year is the anti-vaccine crowd, who continue to repeat the same half truths and misrepresentations.  As I keep mentioning, they live in an alternative universe having quantum jumped  into a part of the multiverse where my standards of reality need not apply.

Perhaps the highest profile critic of the influenza vaccine is Dr. Thomas Jefferson of the Cochrane Group. He generally takes the narrow perspective on the efficacy of the flu vaccine, that of preventing a case of influenza in an exposed individual and argues that the clinical trials that demonstrate efficacy are too flawed to make recommendations. I have begged to differ.

Dr. Jefferson was interviewed for Gary Null’s radio show, and I have taken the time to make a transcript of the interview. It makes for an interesting read, and I used the opportunity to add some annotations.

A couple of caveats. First, spoken language is most certainly not written language and I have omitted some the false starts and stumbles. The typo master (me) can hardly complain about others errors. The few times I have been interviewed I have greatly appreciated the editing that made me appear more fluent than I actually am. Speaking coherently about complex topics extemporaneously is difficult and an ability that neither Dr. Jefferson nor Mr. Null have apparently mastered.

I would wonder why Dr. Jefferson would choose appear to be on this podcast, since Mr. Null has been so against flu vaccination in the past he has sued to prevent the distribution of H1N1 vaccine.  Mr. Null is a proponet of alternative medicines for cancer and HIV denialism.  I suppose an Englishman living in Rome cannot be expected to know who Mr. Null is and what is approach to medical care might be, although a little Google searching quickly finds that Mr Null is the antithesis of everything science based medicine supports. And my Dad taught me early that you can judge a man by the company he keeps. Still, guilt by association is not the most reliable way to analyze an intellectual position. It is better to evaluate what they say in their own words (Or really close. I am no transcriptionist, but I think I got it right. Double question marks (??) were words I could not understand).  [My annotations are in square brackets]:

Null: Lets Begin by saying hello to Dr. Thomas Jefferson. Nice to have to with us here today Dr. Jefferson.

Jefferson: Hello Gary.

Null: Hi. Dr. Jefferson is a former primary care physician from the UK who is now a leading investigator for the Infectious Disease research at the Cochrane Database Collaboration in Rome and he is the editor of their acute respiratory infection group and been the coordinator of the vaccine field which reviews existing peer reviews vaccine research which determines the accuracy and validity of scientific methodology used and the claims being made. And he was also an editorial board member of the Journal Vaccine and uh…Dr. Jefferson, our biggest concern today is that we have been led to believe that everyone beyond the age of 6 months should have a flu vaccination. We have been told that these vaccines are safe and effective for everyone. The we have an honest look at the literature. Here’s my question.

Can we say with certainly, based on good science, independent science, and a gold standard that it would include safety and efficacy for pregnant women, for women who might be taking chemotherapy,

[Patient with cancer and/or on chemotherapy can get a reasonable serologic response to the vaccine, although there are no studies of clinical efficacy.  We do extrapolate from healthy populations to less healthy populations with vaccines.  A reasonable approach, but not always reliable.  Most of the time if you develop an immune response to a pathogen there will be some degree of resistance to that infection, but not always.  As in all the clinical subsets mentioned by Mr. Null, the best approach is for their family caretakers to be immune and not pass on the virus to those at risk.]

or maybe on heart medication or statins,

[Probably a key population to get vaccinated, since influenza, especially the H3 strains, increase the risk for heart attack and vaccination can likely prevent influenza related myocardial infarctions.]

or impaired immune systems, or people on antipsychotic or antidepression medications, or the old, or people who are senior citizens in nursing homes, in hospices in hospitals, people who are suffering from diabetes and are on medications, can we say that all those people will be safe and actually find efficacy and prevent the flu vaccine.

[The biggest issue with those mentioned is the ongoing problem  that those who need protection from influenza vaccination are those who will respond least to the vaccine. From a public health perspective, the best approach to preventing influenza would be to vaccinate the healthy population that serves as the vector for infection. As an example, use of the pneumococcal vaccine in children led to a marked decrease in invasive disease in adults and some modeling suggests that schools are the epicenter for spread of influenza epidemics. So an important question when discussing flu vaccination efficacy is individual goals or population goals. To paint with a broad brush, those in the anti-vaccine camp have little interest in the concept of helping others through the safe and modestly effective intervention of influenza vaccination.]

That’s what we’ve been told. And I want to know because you have taken the time to look for the truth.

Jefferson: Thank you very much for hosting me on your show Gary. You’ve asked me about 15 questions in one, so let me just start from the first one on pregnant women. When you are talking about pregnant women you are of course not just talking about pregnant women but you are talking about a pregnant woman and the fetus, the unborn baby. Now a pregnancy woman is a healthy adult despite desperate attempts at transforming pregnancy into a deadly disease.

[Pregnancy is a weird state. It is normal but it has the potential for complications and is somewhat immunosuppressive. While no one thinks pregnancy is a deadly disease, maternal death is common in the developing world.  It is estimated to have killed 1 in 100 before the 20th century and  worldwide currently kills about 24/100,000.  Pregnancy is usually safe in the West, but not always. What you can say about influenza and pregnancy is that pregnant women are more likely to die if they get influenza and they are more likely to miscarry if they get the influenza. It it estimated that 1:10 first trimester pregnancies were lost during the 1919 pandemic. Babies born during flu epidemics are more like to be smaller  and have lower lifetime earning potential. Smaller babies from influenza are perhaps stupider babies. Vaccination not only prevents influenza (and by extension death) in the mother but also prevents miscarriage. Vaccinated mothers are less likely to give influenza to their newborns. As to safety,  no problems for mother or fetus have yet been discovered. The miniscule amount of antigen in the vaccine appear to have no adverse effects on either the mother or the baby and would be dwarfed by the massive amount of viral antigen exposure as well as exposure to the adverse effects of the inflammatory response from wild influenza. None of these studies probably meet the standards demanded by Dr. Jefferson, but it is difficult to ignore such a preponderance of data.]

Pregnancy is part of… is a physiological state. It is the reason why our race is still on the planet. So there is nothing wrong with pregnancy. That is, it is normal.

[And potentially filled with influenza related complications.]

Pregnancy women therefore are healthy adults and we do know what the performance of the inactivated influenza vaccine is in healthy adults because there are quite a number of trials, clinical trials, that’s experiments, we summarize them, and to give you some idea, we need to vaccinate about 33 to 99 people to avoid one set of influenza symptoms.

[Again, the narrow perspective: maternal death, spontaneous abortion, smaller birth babies, post partum influenza in the newborn are additional worries and the data strongly points to benefit from vaccination. If you fail to consider the preponderance of information and the multitudinous effects of both influenza and vaccination, you do the whole topic a major, and distorted, disservice.  But that is Dr. Jeffersons modus operandi: frame the discussion narrowly, minimize the problems and ignore the numerous co-morbidities of influenza:

“Another consequence is the idea that influenza-line illness (“flu”) and its ravages can be prevented or minimised with influenza vaccines. Cochrane reviews show that vaccines could only affect at the most (i. e. if they had 100% efficacy) some 7-15% of the annual flu burden, since this is the proportion of people with the flu who truly have influenza. This “specificity” of approach (go for influenza, disregard all other causes of the flu) is probably based on what I call availability creep (let’s concentrate on influenza because that’s the one we have specifics for). But, if you think about it, it is a wonderful utopian policy against a syndrome as unspecific as this (just think of the role that other viruses play). In my opinion, the lack of logic in this thinking is stunning (7).”

So disingenuous.  We use flu like illness as a surrogate since it is not practical to test everyone for influenza.  Given that “worldwide, these annual epidemics result in about three to five million cases of severe illness, and about 250 000 to 500 000 deaths.” Whittling 10% off that number, in addition to the effects on pregnancy,  cardiovascular disease and productivity lost, seems a reasonable goal.  We go after influenza because of all the complications associated with the illness in addition to the almost unique morbidity and mortality the primary infection can cause.   We fret as historically influenza epidemics have killed millions and we do not want a repeat of 1919. Influenza often is so much more than a flu like illness.]

The harm side, the safety side, is understudied.

[Although numerous studies in a huge number of patients with a wide variety of underlying medical issues fail to reveal any consistant important or unusual complications of the vaccine and the disease is always worse than the vaccine.]

It’s very difficult to actually give you an accurate breakdown of the potential risk of the vaccine.

[Because it you stick to the plausible risks of vaccination based on plausible physiology there are not many. If you include being hit by asteroids as a potential risk, then it is hard to give an accurate breakdown.  After decades of giving the vaccine there are not any major risks, especially compared to the real and well documented risks of influenza. It is always about relative risks and benefits.  The vaccine is safer by many orders of magnitude than the disease.]

There is the potential risk to the mother, there is the potential risk to the unborn baby, there is the potential risk… the certain risk to the taxpayer. And that is something else that should not be forgotten.

[One gets the feeling from his tone that this really fries his bacon, spending HIS money on other peoples health care.]

There are very very few studies on pregnancy women and none of them are high quality.

[But all show benefit and no risk.]

So I was taught at medical school the less you do to pregnant women the better it is.

[That is such a disingenuous use of the naturalistic fallacy it makes my teeth hurt. The reason we do not have maternal death rates of sub Saharan Africa (as high as 1100/100,000 live birth), where they really do the less is better approach, is the multiple interventions to and for the mother and baby.]

This of course goes contrary to modern medicine.

[Yeah, lets go deliver out children in the third world.]

if you like which is more and more interventional, and more and more preventive between inverted commas (ed: I believe he was making air quotes).

As far as effects on the fetus are concerned of the vaccine, the second person, which is involved in this equation, I would be very very cautious, about vaccinating unborn babies even with dead vaccines like these ones.

[Despite all the data to show benefit? Sure, the data isn’t perfect, but hard to kill a few babies  and mothers for the sake of a perfect study.]

Of course live vaccines are out of the question for an unborn baby.

[That is the closest he gets to a declarative sentence.  As I read the interview over and over, I realized he insinuates a lot, but maintains deniability.  He never actually says don’t get the flu vaccine.  I wonder in passing if he ever gets the vaccine. Although what little data there is suggests the live vaccine is safe for the fetus. <sarc>And wild influenza virus is so much better for mother and child</sarc>.]

Does that answer your question?

Null: Yes. Is it also the case when they are testing a vaccine should they also not have pregnant women and all the women with different diseases that would be required to take the vaccine included in the vaccine studies since when I read the literature I saw they were excluding the very people who would later be included in using it, to me that is a contradiction.

Jefferson: It’s not, it doesn’t necessarily have to be a contradiction because experiments, trials are quite artificial, in the way they are carried out, seldom are carried out in a perfect experiment, and there lies, in there lies some of the weakness of, of the design, of that particular design of a study, in as much as the more you select of the population, the less the results are application to the real population, so called reference population.

[That is always the difficulty in medicine: how does the results of a clinical trial apply to the patient you are treating. When I was a resident it seemed that all the studies for cardiovascular disease were done on old white smoking veterans. There are innumerable variables in influenza vaccination: the variability of the virus, the variability in the vaccine, the patient co-morbidities and (probably) the genetic ability of the patient to respond to both the vaccine and wild type infection. Seems daunting and will allow you to continuously quibble about the applicability of the results of a given  vaccine trial. On the other hand, generally speaking, exposure to antigen often leads to protective immunity most of the time in most people for most infections. It is more a matter of trying to maximize those effects in a heterogeneous population and why flu vaccination is better approached as a population effect than an individual effect.]

So some public health bodies have turned to commissioning what they call real life studies or studies on real life data. These are almost certainly observational studies, the vast majority observational studies. The difference between a trial and an observational study is that in a trial the researcher decides who gets the vaccine and who doesn’t or who gets the vaccine and who gets the control. In an observational study that decision has already been made. There observation study therefor is probably closer to reality. The only problem with that is the design itself is the carrier of problems. It is very very difficult to have good well designed prospective observational studies, and we do know that studies carried out in the United States in the 90’s, huge database studies, which showed the influenza vaccines effect were so biased as to give the wrong answer, to give an answer which was completely implausible

[I am not certain what he is referring to here. The protection of the vaccine from mortality when there is no flu circulating? I am suspicious that may be due to the reduction in deaths that follow any infection. Patients who are hospitalized for infections have a higher post discharge mortality rate than those who are admitted without infections and all infections seem to lead to an increase in MI, PE or stroke that risk  can persist for months after the infection. I wonder if that implausible effects of the flu vaccine are due to the lack of subsequent vascular events associated many infections.

Or he could be referring to the decrease in death from all causes  but in that article, which he alludes to in other interviews, the definition of all cause mortality is not stated. Since the cause of death is not certain it is difficult to say of it was implausible or not. Interesting is a better term and given the widespread morbidities from influenza worthy of investigation.]

So we have to be very careful.

In general the answer is that we have to design better trials prospectively and enrolling significant populations, but these trials cost money and of course you have the problem that as the decisions have already been made, on evidence which is of very low quality, what bodies like CDC say is unethical to carry out trials now

[While placebo trials are not ethical in the US, it doesn’t prevent interesting comparisons of vaccinated and unvaccinated  populations, while not randomized or placebo controlled, efficacy with  huge populations vaccinated and unvaccinated have been compared with good results:

“From 245 schools, 25,037 students participated in the mass vaccination and 244,091 did not. During the period from October 9 through November 15, 2009, the incidence of confirmed cases of 2009 H1N1 virus infection per 100,000 students was 35.9 (9 of 25,037) among vaccinated students and 281.4 (687 of 244,091) among unvaccinated students. Thus, the estimated vaccine effectiveness was 87.3% (95% confidence interval, 75.4 to 93.4).”

By no means a perfect study, but it demonstrates good vaccine efficacy in a healthy population with a good vaccine-disease match. I might add with no GBS in the vaccine group and who were unlikely too pass the flu along to their 50,000 parents and 100,000 grandparents.]

Null: How do we actually know, unless we have two groups of people, lets say 5000 people who have not had the vaccine and 5000 cross matched who do have the vaccine and then do regular work up on them to see whether there is really efficacy because rarely to they use a non vaccinated group against a vaccinated group. More often than not they use one vaccine against another and they often say it’s a placebo and then we find out that the placebo was not a sugar pill, there was actually active ingredients in the placebo and yet you wouldn’t have known that from your physician or nurse or hospital or pharmacist or the CDC or the FDA. Its only when you take away all of the promotion and you look at the actual hard beginning data that there are these flaws and most people are not aware that these flaws exist, your thoughts?

Jefferson: Well, I entirely agree.

[Agree with what? I have reread the question multiple times: “More often than not they use one vaccine against another and they often say it’s a placebo and then we find out that the placebo was not a sugar pill, there was actually active ingredients in the placebo and yet you wouldn’t have known that from your physician or nurse or hospital or pharmacist or the CDC or the FDA.”  What is he talking about? And how would one entirely agree?]

We published in 2009 we published a review of 270 of these studies and we found that only 5% of these studies were reliable, had reliable design and were reliably carried out.

[But that doesn’t mean they are all worthless. Dr. Jefferson and Mr. Null talk as if clinical studies are either perfect and valid or imperfect and worthless.  All or nothing. The medical literature has a spectrum of quality and just because the study is note perfect does not mean it is worthless. Every study needs to be evaluated on its strengths and weaknesses and in the context of the entire literature.

And the unstated assumption, with which at one time I would have agreed, is that bias due to poor methodology in studies will overestimate efficacy of interventions.  Maybe not.  One interesting model of flu vaccine suggests bias results in an underestimation of flu vaccine efficacy:

“We found an average difference between observed and true vaccine effectiveness of 211.9%. Observed vaccine effectiveness underestimated the true effectiveness in 88% of model iterations. Diagnostic test specificity exhibited the strongest association with observed vaccine effectiveness, followed by the likelihood of receiving a diagnostic test based on vaccination status and the likelihood that a child hospitalized with acute respiratory infection had influenza. Our findings suggest that the potential biases in case-control studies that we examined tend to result in underestimates of true influenza vaccine effects.”

It is a complicated literature.]

We also found that studies which had been funded by industry were more likely to be published on prestigious journals. That, for you listeners, means, cited more, and more in the public eye, compared to other studies which had not been funded by pharmaceutical industry. But these studies funded by the pharmaceutical industry of influenza vaccines were not better quality nor were they larger. So there must have been another reason why medical journals found them irresistible which had nothing to do with the design, or the results, or the size of the study.

[I find this intimation of a sinister reason for the difference disingenuous. I presume he is referring to his study where “Two reviewers, independently unblinded to the authors and institutions of the article, extracted data from the studies in three phases.”

Seriously.  Readers working for someone with a long standing and well known antipathy towards influenza vaccination are expected to read papers and come up with unbiased summaries for their boss? Snort.  The reviewers had plenty of opportunity to be biased in their interpretation of the studies.

Dr. Jefferson makes it sound like there are a selection of studies from which the editors choose, like a fish at Pike Street Market.  Oh, I’ll take that study, that you very much.  The important question is whether the articles were submitted and rejected based on funding or were the government sponsored trials only submitted to lower impact journals and the editors of the high impact journals never even had the opportunity to be bribed, er, I mean, reject them.  We don’t know and for a someone whose complains about the conclusions of influenza  vaccine literature because of sloppy methodology and overstated conclusions making an insinuation based on a sloppy study with poor methodology and overstated conclusions does not add to his credibility. Relation of study quality, concordance, take home message, funding, and impact in studies of influenza vaccines: systematic review  nicely demonstrates that when there is an ax to grind how easy it is to give it a sharp edge with a touch of spin.

Dr. Jefferson does like to position himself as the rare pure soul in a sea of venality and corruption:

“Much has been said about the role of experts in advising policy makers on both seasonal and pandemic influenza. We know that some of them have been parsimonious with declaring their interests and their role as members of lobbying organizations which are financed by industry and some did not think it important to disclose pretty hefty industry funding of their institutions. We know that transparency is proably not taken very seriously by WHO. However, few people realize that even experts with no ties to industry or government civil servants have career motivations, especially if they make policy and evaluate its effects.

I’ll leave the description of how this works to Professor Philip Alcabes in his modern classic Dread: “We are supposed to be prepared for a pandemic of some kind of influenza because the flu watchers, the people who make a living out of studying the virus and who need to attract continued grant funding to keep studying it, must persuade the funding agencies of the urgency of fighting a coming plague”(15).

Before you start wondering how I can myself escape this kind of criticisms I would like to inform readers that 2 months before the hearing I circulated a note of activities and interests in which I disclose all that I can think are relevant to this debate. The note was sent to the Secreteriat and can be viewed by any member of the Commission. In addition I would like to remind you of what I have written and stated to the media countless times since 2004: beware of catastrophic predictions, stick to the scientific evidence: all the evidence, not just what supports your theories (16).”

Dr. Jefferson tends to torpedo the conclusions of his own work, taking modest efficacy of the flu vaccine and treatment in the Cochrane and other meta-analysis and making sure we know the glass is half empty, not half full.  Much of what he has published demonstrates modest flu vaccine efficacy, although he does his very best to muddy the water:

Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age…The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies.

[Attention.  Attention. This is the Pot speaking. The Kettle is black.  Not me. Just the Kettle. That is all.] 

The content and conclusions of this review should be interpreted in the light of this finding.

We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly.

Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission. WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.

Influenza vaccines (especially two-dose live attenuated vaccines) are efficacious in children older than 2 years. Efficacy and effectiveness of the vaccines differed strikingly. Only two small studies assessed the effects of influenza vaccines on hospital admissions and no studies assessed reductions in mortality, serious complications, and community transmission of influenza. If influenza immunization in children is to be recommended as public-health policy, large-scale studies assessing such important outcomes and undertaking direct comparisons of vaccines are urgently needed.

Amantadine prevented 23% of clinical influenza cases (95% confidence interval 11% to 34%), and 63% of serologically confirmed clinical influenza A cases (95% confidence interval 42% to 76%). Amantadine reduced duration of fever by one day (95% confidence interval 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine.
Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine.

No effect was shown for specific outcomes: laboratory-proven influenza, pneumonia and death from pneumonia. An effect was shown for the non-specific outcomes of ILI, GP consultations for ILI and all-cause mortality in individuals >/= 60. These non-specific outcomes are difficult to interpret because ILI includes many pathogens, and winter influenza contributes < 10% to all-cause mortality in individuals >/= 60. The key interest is preventing laboratory-proven influenza in individuals >/= 60, pneumonia and deaths from pneumonia, and we cannot draw such conclusions. The identified studies are at high risk of bias. Some HCWs remain unvaccinated because they do not perceive risk, doubt vaccine efficacy and are concerned about side effects. This review did not find information on co-interventions with HCW vaccination: hand washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, anti-virals, and asking HCWs with ILI not to work. We conclude there is no evidence that vaccinating HCWs prevents influenza in elderly residents in LTCFs. High quality RCTs are required to avoid risks of bias in methodology and conduct, and to test these interventions in combination.

But remember, I have given up on the Cochrane Group, which recently gave us:

Cochrane Database Syst Rev. 2012 Sep 12;9 Acupuncture for mumps in children. He J, Zheng M, Zhang M, Jiang H.

Mumps is an acute, viral illness transmitted by respiratory droplets and saliva. A number of studies published in China have suggested that acupuncture is beneficial for children with mumps but the literature reporting the benefits or harms of acupuncture for mumps has not been systematically reviewed.
To determine the efficacy and safety of acupuncture for children with mumps.
We searched CENTRAL (2012, Issue 4), MEDLINE (1950 to April week 4, 2012), EMBASE (1974 to May 2012), CINAHL (1981 to May 2012), AMED (1985 to May 2012), the Chinese BioMedicine Database (CBM) (1979 to May 2012), China National Knowledge Infrastructure (CNKI) (1979 to May 2012), Chinese Technology Periodical Database (CTPD) (1989 to May 2012) and WANFANG database (1982 to May 2012). We also handsearched a number of journals (from first issue to current issue).
We included randomised controlled trials comparing acupuncture with placebo acupuncture, no management, Chinese medication, Western medication or other treatments for mumps. Acupuncture included either traditional acupuncture or contemporary acupuncture, regardless of the source of stimulation (body, electro, scalp, fire, hand, fine needle, moxibustion).
Two review authors independently extracted data and assessed the quality of included studies. We calculated risk ratios (RR) with their 95% confidence intervals (CI) for the effective percentage and standardised mean differences (SMD) with 95% CIs for the time to cure.
Only one study with 239 participants met our inclusion criteria. There were a total of 120 participants in the acupuncture group, of which 106 recovered, with their temperature returning back to normal and no swelling or pain of the parotid gland; the condition of 14 participants improved, with a drop in temperature and alleviation of swelling or pain of the parotid gland. There were 119 participants in the Western medicine group, of which 56 recovered and the condition of 63 improved. The acupuncture group had a higher recovery rate than the control group. The relative RR of recovery was 1.88 (95% CI 1.53 to 2.30). However, the acupuncture group had a longer time to cure than the control group. The mean was 4.20 days and the standard deviation (SD) was 0.46 in the acupuncture group, while in the control group the mean was 3.78 days and the SD was 0.46.There was a potential risk of bias in the study because of low methodological quality.
We could not reach any confident conclusions about the efficacy and safety of acupuncture based on one study. More high-quality research is needed.”

A meta-analysis on one study on an intervention of magic. Pu-lease.  I think they are running out of topics to meta-analyze. Next they will do a  meta-analysis and systematic review of the written content on cereal boxes. And this is from Dr. Jefferson’s Group,  the Cochrane Acute Respiratory Infections Group. I know, guilt by association again.]

Null: Also, if there are almost 200 different infectious organism that can cause flu like symptoms, and there is no standardized testing and proper diagnosis for people when they go to the doctor or clinic to be treated for a flu like illness, then what are we to make of all the warnings given about the seriousness of a particular flu season and also the world health Organizations record at predicting which strains of flu should be used in a given years flu vaccine is rather dismal and then there are studies such as Danish study that those receiving a seasonal flu vaccine in 2009 were more likely to get infected with swine flu and Canadian studies by ?? and ?? seem to confirm this same finding. So even the predictions of the flu strains are frequently inaccurate and what good is the flu vaccine against other flu strains not in the formulation.

[It depends on what part of the flu antigens you develop a response to; as H1N1 demonstrated, some people may develop universal antibody.  I feel great sympathy for Public Health officials as they cannot win. Influenza is impossible to predict correctly.  If the season is bad and they don’t call it in advance or of the season is bad and they predict a mild season, they are criticized.  At least the CDC is not in Italy.]

Jefferson: The trademark of influenza and all acute respiratory infections, lets call it influenza like illness, is its unpredictably. That’s where the name comes from: it comes from the (??), which is Italian for influence of the planets.

[Ruh-Roh. The use of word origin is always a diagnostic clue. I am surprised he did not call flu a  dis-ease.]

Because in the middle ages they could not understand why these local epidemics came and went. Mainly benign, they are self limiting, they last a few days, and they are unpredictable.

[My understanding is that influenza was particularly bad in the era of poor nutrition and hygiene; its English name was the gasping oppression” with cough, fever, and a sensation of constriction of the heart and lungs began to rage, seemingly everywhere at once” and was not so mild:

To observers later in the 16th century, influenza came to be recognized as a distinct disease with consistent clinical features including acute onset of fever, headache, cough, and myalgia, with uncommon complications that included pneumonia and fatal outcomes in pregnant women and their fetuses, in infants and young children, and in the old and debilitated. Its epidemiologic featureswere understood to include explosive spread with high attack rates and directional movement along travel or trade routes, prevalence in a town or city for no more than 4–6 weeks, appearance at unpredictable intervals and at any time of year (influenza was frequent in the summer months until the 19th century 8]), and low-to-moderate population mortality.]

There is a very very long and complex literature reporting, for instance, what happened in the year of the French Revolution, which I believe was also the year of the inauguration of George Washington, in 1789. There were two outbreaks, one on the East coast and one on the West coast, which happened almost synchronously, like springing out mushrooms, and you can’t blame that on air travel.

[Almost only counts for horse shoes and hand grenades. Although I can find no specific information on the start of the 1789 epidemic in the US, it appears it started in the East Coast and then hit the West by way of the Caribbean and Central America. Flu does travel fast, the 1919 pandemic went around the world three time in one year, long before jet travel.]

It appears that (??) in 1789 there was no air travel.

[And there was air travel: birds. There is always the worry that avian flu will get here in a migratory bird, although an unlikely event.

The genetic elements of influenza A viruses circulate globally in an extensive ecosystem comprised of many avian and mammalian species and a spectrum of environments. Unstable gene constellations found in avian species become stable viruses only upon switching to secondary hosts, but may then adapt and circulate independently. It may be desirable to think of influenza A viruses as existing and evolving in a large ecosystem involving multiple hosts and environments. Implications for understanding human influenza are discussed.” ]

It is an understudied, the real science behind this is understudied. It is covered in dogma, it is covered in public health marketing, and it is covered really in poor science as you pointed out. Very difficult to find good quality research in this area. It is not an easy area to research of course.

[I don’t really know what area he is talking about here. Flu spread? Vaccines? What does dogma have to do with 1789 flu outbreak?  Public health marketing?  It really gripes my cookies how he dismisses an enormous number of hard working professionals whose main goal is to prevent as many people as possible from dying from influenza and other diseases and an equally enormous supporting literature as dogma marketing.  But Dr. Jefferson knows better.]

And the influenza vaccine mutates its coat, changes its coat very frequently, so it’s a, it’s a running target, the (??) influenza virus. It’s a running target, it changes. And you are quite right, clinically it is impossible to tell an influenza like illness, what you call the flu, caused by influenza virus from that caused by any of the other agents.

Bear in mind Gary that some studies show that almost 40% of these episodes have no recognizable cause.

[So? What does that have to do with flu vaccine efficacy.]

So that may mean they are caused by microorganisms which we cannot culture, which we cannot grow, or we cannot recognize, or are unknown, or they may not even be infectious, they may be stress related,

[Stress causing fevers to 104, severe myalgias, headache, intractable cough and shortness of breath?!?!?!?!? Glad he is not my GP.]

so it is a completely understudied area. The good science of it. The bad science part, well there’s tonnes of bad studies out there that show whatever they want to show.

[By that criteria all of medicine is understudied.  Our knowledge of the causes of respiratory infections grows yearly and I suppose if we to devote the entire NIH budget to its investigation all would be clear.  That last part “tonnes of bad studies out there that show whatever they want to show” is again disingenuous and dismissive of a preponderance of data that shows results that Dr. Jefferson doesn’t agree with, including the conclusions of his own work.]

Null: Well, I appreciate your coming on and sharing this insight with us today and we really support all your good efforts because you and your group over in Rome and Italy, you are not motivated by money you get from pharmaceutical industries. You just tell us the truth and what you are telling us gives us a reason for pause and to demand more independent, quality scientific research

[Such as the quality scientific research, free of financial incentive, that  Mr. Null has demonstrated for his products, including the effects of vitamin D toxicity.]

before people in the public health sector tell us to take our flu vaccine, it’s safe and effective and will prevent the flu when they do not have the ?? of scientific integrity on their side to prove their point and so we need good science which is substantially lacking. Thank you Dr. Tom Jefferson for being with us today.

Jefferson: Thanks for having me.

When I read the Atlantic article about Dr. Jefferson, I was struck by the section that mentioned he was ostracized at meetings, eating alone:

Among his fellow flu researchers, Jefferson’s outspokenness has made him something of a pariah. At a 2007 meeting on pandemic preparedness at a hotel in Bethesda, Maryland, Jefferson, who’d been invited to speak at the conference, was not greeted by any of the colleagues milling about the lobby. He ate his meals in the hotel restaurant alone, surrounded by scientists chatting amiably at other tables.

and I thought, what a bunch of bastards. I spend lots of time with people with whom I disagree and we have fun arguing back and forth.  Just because we disagree does not mean we can’t enjoy a good conversation and be civil.

Now I am not so certain. The interview suggests a conspiracy theorist  who has a narrow viewpoint and ignores or misstates his own studies and the studies of others and prefers a simple message to the complexity of influenza and its many complications. What comes across in his interview, and in his written, and presumably carefully considered oeuvre, is buckets of anti-influenza vaccine bias; someone who has an opinion first which he defends with the narrowest of data second.   He was interviewed in the appropriate venue after all.


As I was writing this entry the Secret kicked into high gear in its spooky way yet again. Our editor received the folllowing letter:

I am the Social Media Marketing Manager here at Progressive Radio Network which is the #1 Progressive Internet Radio Station. We currently have a very popular Health and Nutrition Show on the network called “The Gary Null Show”. It is hosted by Gary Null who also owns his own Power Foods site ( He also has numerous award winning documentaries and articles. We would like to get the show featured on your website if possible.

You ask, the Universe provides. Creepy.

*I have been trying to work influenza into the title of the Ken Kesey book for years.


Posted in: Clinical Trials, Epidemiology, Public Health, Science and Medicine, Science and the Media, Vaccines

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