28 Oct 2005 - Alive and Well: The MMR-Autism Connection
http://www.redflagsdaily.com/yazbak/2005_oct28.html
Zero x 31 is still zero
and if it is not the MMR,
then what was it that damaged our children?
By Red Flags Columnist, F. Edward Yazbak, MD, FAAP
(tlautstudy@aol.com)
Many parents believe that one or more of their children regressed after
receiving the measles, mumps and rubella (MMR) vaccine. No one knows
exactly the number of these children, but they probably constitute 10 to
15 percent of children with regressive autism. The majority of children
appear not to react unfavorably to the triple vaccine. Obviously, for a
couple whose only son is fascinated with garage doors, or makes strange
whirling noises all day, or hits his head against the wall to keep
entertained or answers by pointing to pictures in a book, the percentage
jumps to 100 percent.
The poor parents of affected children, particularly those living in
England, woke up on Oct. 18 to the news that yet another "definitive"
epidemiological study - the most thorough survey of MMR vaccination data -
had concluded that there is no credible evidence behind claims of harm
from the MMR vaccine. The news had been carefully leaked with an
impressive notice that it should be "strictly" embargoed until 00:01 hours
(BST), Oct. 19, 2005. This was the most effective way to guarantee that it
would spread like a California wild fire on Tuesday the 18th. After all,
with everything happening around the world, from earthquakes to
hurricanes, wars, elections and bird flu, it was not safe to take a chance
that some new calamity would distract people on Wednesday from
appreciating the important findings of the study.
It was Tuesday when I received the embargoed press release. It started,
"There was no credible evidence behind claims of harm from the MMR
vaccination. This is the conclusion drawn by the Cochrane Review Authors,
an international team of researchers, after carefully drawing together all
of the evidence found in 31 high quality studies from around the world."
The lead author of the study, Vittorio Demicheli, MD, of the Servizo
Sovrazonale di Epidemiologia, Alessandria, Italy, promptly tempered the
initial sweeping statement by adding, "In particular we conclude that all
the major unintended events, such as triggering Crohn's disease or autism,
were suspected on the basis of unreliable evidence."
He then was quoted as saying, "Public health decisions need to be based on
sound evidence. If this principle had been applied in the case of the MMR
dispute, then we would have avoided all the fuss."
The fuss!
Is that what it was all about?
Is that what regressive autism is? A fuss!
Now Demicheli had my attention.
What was not mentioned in the widely circulated embargoed press release
was the actual first conclusion listed by the authors in their abstract:
"The design and reporting of safety outcomes in MMR vaccine studies, both
pre- and post-marketing, are largely inadequate."
I have to say in fairness that I have always admired the work done by the
Cochrane group. In fact, I quoted their excellent pediatric influenza
vaccination review in "Influenza vaccination of infants: A useless risk"
on Red Flags less than a month ago. (1) The lead author for that review
was Tom Jefferson, MD, who is a Cochrane researcher based in England;
Demicheli was one of the co-authors. Of the most recent 15 reviews listed
in MEDLINE, which they have co-authored with others, Jefferson was the
lead author in eight and Demicheli, the lead author in four. Most studies
were related to influenza vaccination.
It is well known that the Italians have never had much amore for the MMR
vaccination. In 2002, a measles epidemic was attributed to "inadequate"
vaccination coverage (Morbidity and Mortality Weekly Report, Oct. 31,
2003). Actually "inadequate" was a charitable way to describe a
seven-percent vaccination rate in the area with the most cases that year -
3,750 cases per 100,000 children under the age of 15. (2)
To see Demicheli listed as the lead author of this recent MMR review (3)
was, therefore, intriguing to say the least. The MMR-autism issue had
created much "fuss" - indeed, more of an obsession - in the United Kingdom
for years and Jefferson has been connected with it since 1999. So, why was
the apparent expert on the subject not the lead author, while his Italian
colleague was? We'll get to that later.
Details of the Release
"Aware of the controversy surrounding the use of MMR, members of The
Cochrane Collaboration set out to review the evidence for effectiveness of
the vaccine and also to review evidence of adverse events. In a process of
'systematic reviewing' researchers searched international databases and
found 139 articles about MMR use. Because many of them referred to studies
that had been conducted in a way that could not rule out bias or error,
the researchers discarded all but 31 of them. Using rigorously established
methods, the researchers then synthesized the findings from these pieces
of higher-quality research to create the most authoritative assessment yet
available."
The above would suggest that 108 of 139 studies on MMR did not meet the
Cochrane criteria. In fact, the authors reviewed some 5,000 MMR-related
articles and found only 31 that could "possibly" fulfill their inclusion
criteria.
According to the embargoed information, the authors concluded that:
There is no credible link between the MMR vaccine and any long-term
disability, including Crohn's disease and autism.
MMR is an important vaccine, which has prevented diseases that still carry
a heavy burden of death and complications where the vaccine is not used
consistently.
The lack of confidence in MMR has caused great damage to public health.
People arguing for or against the use of any therapy need to make sure
that they base their conclusions on carefully collected evidence, not just
on biased opinion, speculation or suspicion.
>From here on, my comments will be limited to regressive autism.
Conclusion 1
The fact that a review of the 31 studies suggested that no link exists
between the MMR vaccine and autism does not mean that, indeed, no link
exists. We have seen each one of those epidemiological studies make a
splash, get some applause and then fade away while the so-called study of
12 by Wakefield, has endured. Indeed, if one of the adversarial studies
had been strong enough to stand on its merits, we would not have needed
another and another and another to follow. We would not have needed 5,000
of them and we would not have needed the Cochrane review.
In 2002, K. M. Madsen, MD, stated that preceding studies lacked sufficient
statistical power to detect an association and did not have a
population-based cohort design. In time, his own study was proved
deficient by G. S. Goldman, PhD, and myself. (4) The 2004 Smeeth study
only survived a few weeks and now the Cochrane reviewers suggest that it,
too, is lacking something.
In addition, the impartiality of some authors and the significance of
their findings came into question. The research group led by Heikki
Peltola, MD, received financial support from Merck. The U.K. Medicines
Control Agency (MCA) and Public Health Laboratory Service (PHLS)
commissioned the studies by Brent Taylor, PhD, and friends. Madsen's study
was funded by the Centers for Disease Control and Prevention, MCA and
PHLS. And those are only three of many.
Conclusion 2
The authors are expressing a personal MMR-favorable opinion although they
know or should know, as everyone else does, that measles mortality had
decreased drastically in the Western world before the advent of
vaccination because of improved hygiene and nutrition. In Third World
countries today, improved nutrition and hygiene are the top priorities.
Conclusion 3
The lack of confidence in the MMR vaccine was the result of the inability
of its promoters to instill confidence and maintain it. The so-called, and
so-far theoretical, "damage to public health" would have been nil if the
U.K. Department of Health had not outlawed the monovalent measles, mumps
and rubella vaccines in 1999 - just to force people to their knees. This
should be remembered as the worst public health decision ever:
vaccination's Day of Infamy.
Conclusion 4
No one ever said that MMR vaccination should be withdrawn. In fact,
Wakefield's biggest troubles started when he warned the U.K. health
department to get ready and have some single vaccines available in case
there was a further drop in MMR vaccination rates - following the
publication of his article - as the rates had been falling since 1996. (5)
***
MMR and Autism
The evidence supporting an MMR-autism link was carefully collected and
duplicated and is rock solid. It is certainly not "biased opinion,
speculation or suspicion."
In hundreds of children with post-MMR regressive autism, a specific type
of enterocolitis has been identified by many investigators in several
countries. Some of the affected children have evidence of measles virus
genomic RNA in the cerebrospinal fluid, some in the gut wall and some in
both sites. In many, the sequences obtained were consistent with being
vaccine strains and, in these children, there was no history of exposure
to wild measles.
Many affected children have specific patterns of urinary polypeptides,
high serum measles and MMR antibody titers and elevated myelin basic
protein auto-antibody levels.
In fact, it will be safe to say that it is impossible to find one normal
child who has evidence of both MMR antibody and myelin basic protein
auto-antibodies in his serum or his cerebrospinal fluid or one child, who
regressed after MMR vaccination, who does not have at least one of the
following: the typical enterocolitis of autism, a suggestive pattern of
urinary polypeptides, evidence of measles virus genomic RNA, elevated
serum measles virus antibody, MMR antibody or myelin basic protein
auto-antibodies..
These are not suspicions. These are facts - rock-solid facts.
In many children, two regressions have been clearly documented by
health-care providers, photographs and videos. The first regression
occurred shortly after the first MMR vaccination and the second, much more
severe, after the MMR booster at age 4 or 5, following a period of
relative improvement. This biphasic course, or
challenge-dechallenge-rechallenge, has been accepted as evidence of
causation by the courts and by a special committee of the Institute of
Medicine.
In a May 2005 presentation to the American Gastroenterological Association
of a study titled "Autistic enterocolitis: confirmation of a new
inflammatory bowel disease in an Italian cohort of patients," Frederico
Balzola, MD, of Turin, Italy, and associates described in detail the many
gastrointestinal (GI) findings in nine consecutive patients with autism
who had long-standing and serious GI symptomatology including abdominal
pain, bloating, constipation and/or diarrhea.
The authors concluded, "These preliminary data are strongly consistent
with previous descriptions of autistic enterocolitis and supported a
not-coincidental occurrence. Moreover, they showed for the first time a
small intestinal involvement, suggesting a panenteric localization of this
new IBD. The treatment to gain clinical remission has still to be tried
and it will be extremely important to ameliorate the quality of life of
such patients who are likely to be overlooked because of their long-life
problems in the communication of symptoms."
Now this is the kind of study that Demicheli and his colleagues should
have looked at, instead of reviewing epidemiological studies of dubious
quality financed by the vaccine manufacturer or vaccine agencies.
Conflict or Bias
A conflict of interest is a situation in which someone in a position of
trust has competing personal, professional and/or financial interests.
Bias is an inclination that inhibits impartial judgment.
Jefferson, the real MMR expert of the Cochrane team, did disclose that he
had a "potential" conflict of interest: In 1999, he acted as an ad hoc
consultant for a legal team advising MMR manufacturers.
The Cochrane publication also carried the following acknowledgements: "Drs
Harald Heijbel, Carlo DiPietrantonj, Paddy Farrington, Ms Sally Hopewell,
Melanie Rudin, Anne Lusher, Letizia Sampaolo and Valeria Wenzel. The
authors wish to thank the following for commenting on this review draft:
Bruce Arroll, Lize van der Merwe, Janet Wale and Leonard Leibovici."
***
If the lawyers for the MMR manufacturer(s) in the U.K. hired Tom Jefferson
as a consultant in 1999, while they were preparing for the looming MMR
autism case, they must have been certain that he would be ready to testify
under oath that MMR did not and could not cause autism - in anyone.
In June 2000, Jefferson wrote an editorial in the Journal of Epidemiology
and Community Health Online, titled"Real or perceived adverse effects of
vaccines and the media - a tale of our times." In it, he stated, "Since
the publication of the Wakefield study on 28 February 1998, public concern
fueled by extensive media coverage caused a steady decline in MMR coverage
in parts of the United Kingdom, with a subsequent risk of a decline in
herd immunity and resurgence in morbidity.
"A swift reaction by the U.K. government and the subsequent publication of
studies by the Committee on Safety of Medicines and by Taylor et al,
showing no evidence of a causal link, partly redressed the balance. As
usual with vaccine "scare stories," there was a delay between publication
of the initial case series and that of population-based causal assessment
study. During this time, declining coverage took place." (6)
Jefferson acknowledged that he received help in the preparation of the
editorial from Robert Chen, Ulrich Heininger, Elisabeth Loupi and Harald
Heijbel.
Since 1998, and until a short while ago, Chen, an epidemiologist with the
National Immunization Program (NIP), had been the CDC's point man for all
MMR matters arising from the Wakefield publication. He wrote frequent
anti-Wakefield articles and gave many interviews. He was also always in
close contact with Elizabeth Miller of the U.K. Department of Health, who
co-authored the Taylor studies and who led the charge against Wakefield in
England.
Ulrich Heininger was the European editor of the Archives of Disease in
Childhood. In 2002, he wrote, "However, safety questions raised about
certain vaccines - whether true (intussusception associated with rotavirus
vaccine) or false (autism due to MMR) - have challenged pediatricians."
(7)
Elizabeth Loupi was senior director of Pharmacovigilance, Sanofi Pasteur
SA, Lyon, France. Sanofi Pasteur MSD is the only European company
dedicated exclusively to vaccines and was founded in 1994, as a joint
venture between Sanofi Pasteur and Merck & Co., Inc.
Lastly, Harald Heijbel was the coordinator, Immunization Registry Project,
Swedish Institute of Infectious Disease Control, Stockholm, Sweden
Jefferson was obviously a big booster of MMR vaccination and a firm
believer in its safety - no matter what. He also had to be anti-Wakefield.
Even if he only had a "potential" financial conflict of interest, he
certainly had a major personal conflict and bias and he should have
declared them. A father who regularly contributes comments on the autism
situation to the electronic British Medical Journal has always added
"father of an autistic child." And I certainly have always declared that I
had a grandson who regressed after MMR vaccination. I thought it was only
fair that readers know.
As stated earlier, the Cochrane researchers who designed the present
study, evaluated the 31 "chosen epidemiological works" and wrote the
present report received assistance and scientific support from Harald
Heijbel, Carlo DiPietrantonj, Paddy Farrington, Sally Hopewell, Melanie
Rudin, Anne Lusher, Letizia Sampaolo and Valeria Wenzel.
Information about Harald Heijbel was reported earlier.
Paddy Farrington co-authored Brent Taylor's and Elizabeth Miller's first
article "Autism and measles, mumps, and rubella vaccine: no
epidemiological evidence for a causal association" (The Lancet, June 12,
1999). Having him help review that study and others like it is strange -
to say the least.
Farrington's statistical contribution to the first Taylor study was
criticized by James H. Roger, PhD, at a meeting of the Royal Statistical
Society in London. In a letter to the editor of The Lancet (July 8, 2000),
Roger wrote, "Sir - Rather than clarify the measles, MMR, and autism
confusion with your editorial, you perpetuated the myth that good
scientific evidence rejects a link between MMR vaccination and autism.
You quote Taylor and colleagues as publishing "epidemiological evidence
contradicting this alleged association." On March 28, 2000, I presented a
talk to the Royal Statistical Society, in which I showed how the currently
published data, including that from this study, are consistent with an
appreciable number of autism cases being triggered by MMR vaccination. In
short, Taylor and colleagues used the wrong study design to detect an
association between immunization and a disease with chronic onset, such as
autism."
Sally Hopewell, Melanie Rudin and Ann Lusher are employed at the U.K.
Cochrane Centre.
Scientists Valeria Wenzel and Letizia Sampaolo work at the Istituto
superiore di sanità in Rome, the main Italian Institute of
technical-scientific research, control and advice in public health.
Because the listing of personal bias is not required, Jefferson's past
association with the Brighton Collaboration was also not disclosed.
No wonder Vittorio Demicheli of the Servizo Sovrazonale di Epidemiologia,
Alessandria, Italy, became the lead author of the Cochrane MMR review.
The Brighton Collaboration
On its Web site (8), The Brighton Collaboration reports:
"[It] was founded by Robert Chen, Harald Heijbel, Tom Jefferson, Ulrich
Heininger, and Elisabeth Loupi in 1999 at a meeting in Brighton, England.
It was officially launched in autumn 2000. The Collaboration consists of
volunteers from patient care, public health, scientific, pharmaceutical,
regulatory and professional organizations coming from developed and
developing countries. They are experienced and knowledgeable in the field
of immunization safety and corresponding medical specialties."
It says its objectives are:
"A. Global Collaboration
To establish a global collaboration of professionals and organizations
concerned with immunization safety.
B. Development
To develop a single standardized case definition per AEFI and guidelines
for data collection, analysis, and presentation for global use.
C. Evaluation
To develop and implement study protocols for evaluation of case
definitions and guidelines in clinical trials and surveillance systems.
D. Implementation
To raise global awareness of the availability, educate about the benefit
of use, facilitate access to and monitor worldwide use of standardized
case definitions and guidelines for data collection, analysis, and
presentation."
It reports the following about its sources of support:
"The work of the Brighton Collaboration is based on a large number of
volunteers worldwide. It obtained its first funding in 1999. The Brighton
Collaboration is presently supported by the Centers for Disease Control
and Prevention (CDC) and the World Health Organization (WHO). From 2000
until 2003, the Collaboration also received funding through the European
Research Program for Improved Vaccine Safety Surveillance (EUSAFEVAC).
"In December 2003, the Brighton Collaboration Foundation was established
by the University Children's Hospital Basel, Switzerland. The purpose of
the Foundation is to protect and preserve public health by promoting
immunization safety. The Foundation promotes the development and
availability of globally accepted, high quality scientific standards for
research on and communication of immunization safety. The Foundation may
also conduct immunization safety research itself or support such research
projects."
It is well known that U.S. Congressman Dave Weldon, MD, of Florida has
been watching health matters carefully as a member of the committee on
government reform of the House of Representatives.
In one particular address to the House of Representatives in 2004, Weldon
discussed autism, MMR research and the Brighton Collaboration among other
things. The address (9) is now part of the Congressional Record, June 18,
2004, beginning on page H4564 and can be seen in its entirety at
http://weldon.house.gov/UploadedFiles/RepWeldonMDonIOM.pdf
The following segment is relevant to this discussion:
"Mr. Speaker, I want to touch on one more additional issue, and that is
something called the Brighton Collaboration. I am very concerned about
the development of the Brighton Collaboration, which began in the year
2000. This is an international group comprised of public health officials
from the CDC, Europe, and world health agencies like WHO and vaccine
manufacturers.
The first task of the Brighton Collaboration, created several years ago,
was to define what constitutes an adverse reaction to a vaccine. They have
established committees to work on various adverse reactions to vaccines.
Particularly troubling to me is the fact that serving on these panels
defining what constitutes an adverse reaction to a vaccine are the vaccine
manufacturers. What is even worse is the fact that some of these
committees are chaired by vaccine manufacturers.
It is inappropriate for a manufacturer of vaccines to be put in the
position of determining what is and what is not, an adverse reaction to
its product. Do we allow GM, Ford and Chrysler to define the safety of
their automobiles? Do we let airlines set the safety standards for their
airlines and determine the cause of an airline accident? Do we allow food
processors to determine whether or not their food is contaminated or
causing harm? Then, I ask, why we are allowing vaccine manufacturers to
define what constitutes an adverse reaction to a vaccine?
This collaboration is fraught with pitfalls, and merges regulators and the
regulated into an indistinguishable group. It is critical that the
American public look at what is going on here and how this entity may
further erode the ability for us to fully understand the true relationship
between various vaccines and some adverse reactions in some subsets of our
population. I plan to devote additional attention to this effort in the
future.
Mr. Speaker, I look forward to working with you and others in this body to
address the problem that we face today.
As I stated at the outset of my comments this afternoon, autism was once
in America a rare and infrequently seen condition. I went through four
years of medical school, internship, residency, and years of private
practice and practice within the military and had not seen one single
case. I have seen case after case in my Congressional District over the
last seven years, a disease that I had never seen before.
The disease incidence was previously thought to be one in 10,000. It is
now thought to be as high as possibly one in 167, an almost 100-fold
increase in the incidence.
We need to get answers to these questions. We need to restore public
confidence and safety in our vaccine program. Our vaccine program saves
millions of lives, it saves millions of kids from a life of disability,
and the best way for us to ensure public confidence and make sure that all
the kids get vaccinated properly is to get answers to these questions.
The way the CDC and the Institute of Medicine and the industry is going
about trying to answer these questions is highly flawed.
Mr. Speaker, I encourage my colleagues to begin to look at this issue. I
know that many of them are coming to me saying they have parents coming in
their offices now with autistic kids, saying something needs to be done.
Something needs to be done."
Discussion:
Epidemiological and statistical studies - even the best - cannot prove
that the MMR vaccination does not cause regressive autism in a small
percentage of genetically predisposed children.
So far, we have not seen one unbiased, well-done and convincing
epidemiological study.
Hundreds of weak studies have come and gone after they made a little noise.
The Wakefield study of 12 certainly seems to have endured.
Reliable histories with documentation have clearly shown regression occurs
following vaccination and specifically MMR vaccination.
Accurate clinical studies have revealed the presence of typical and
similar intestinal findings in children with post MMR regressive autism.
Reproducible laboratory investigations have confirmed the relationship of
the findings with the measles component of the MMR.
Challenge-dechallenge-rechallenge has been documented repeatedly.
Diet and therapeutic management of the gastrointestinal component of the
disease has improved behavior and speech.
Though technically impressive, the recent MMR review by the Cochrane group
will please those who are already "on board" and convince only those who
know little about the subject.
For everyone else, the huge effort did fall short.
The hierarchy of the Cochrane Institution should examine the impartiality
of all involved.
For an institution of that caliber, even the appearance of bias is
unacceptable.
The authors of the Cochrane review revealed their partiality when they
endorsed the MMR vaccine without reservation and declared that it could
not cause harm. Multiple reports to VAERS and a review of the vaccine
compensation programs in the U.S., the U.K., Japan and other countries
show otherwise.
Something Is Not Right When:
Epidemiological studies about MMR and autism are financed by the CDC, the
U.K. Department of Health, the vaccine manufacturers or someone supporting
them.
Those studies - even the worst of them - are easily published in the best
medical journals, while their criticism is not.
The same studies are applauded after publication by the CDC, the U.K. DOH
and friends who made them happen.
The studies are then reviewed by friends.
And they are re-reviewed by sympathizers who minimize their problems and
attest that "there is no credible link," while not looking at all the
evidence contradicting them.
Something Is Certainly Not Right When:
All this is happening and the only one accused of conflict of interest is
Andy Wakefield because his hospital received a grant of £55,000 to support
GI research.
Conclusion:
The recent Cochrane Review of the MMR vaccine epidemiological research is
not convincing.
References:
Influenza vaccination of infants: A useless risk
http://www.redflagsdaily.com/yazbak/2005_sep30.php
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5243a4.htm
Review Paper: Demicheli et al: Vaccines for measles, mumps and rubella in
children. The Cochrane Database of Systematic Reviews 2005, Issue 4.
Goldman GS, Yazbak FE: An Investigation of the Association between MMR
Vaccination and Autism in Denmark. JAmPhysSurg 2004; 9(3):70-75
http://www.jpands.org/vol9no3/goldman.pdf
MMR Vaccination rates were down before Wakefield
http://www.redflagsweekly.com/conferences/autism/2003_dec22.html
http://jech.bmjjournals.com/cgi/content/full/54/6/402
http://adc.bmjjournals.com/cgi/content/extract/87/1/9
http://www.brightoncollaboration.org/internet/en/index/about.html
http://weldon.house.gov/UploadedFiles/RepWeldonMDonIOM.pdf
Zero x 31 is still zero
and if it is not the MMR,
then what was it that damaged our children?
By Red Flags Columnist, F. Edward Yazbak, MD, FAAP
(tlautstudy@aol.com)
Many parents believe that one or more of their children regressed after
receiving the measles, mumps and rubella (MMR) vaccine. No one knows
exactly the number of these children, but they probably constitute 10 to
15 percent of children with regressive autism. The majority of children
appear not to react unfavorably to the triple vaccine. Obviously, for a
couple whose only son is fascinated with garage doors, or makes strange
whirling noises all day, or hits his head against the wall to keep
entertained or answers by pointing to pictures in a book, the percentage
jumps to 100 percent.
The poor parents of affected children, particularly those living in
England, woke up on Oct. 18 to the news that yet another "definitive"
epidemiological study - the most thorough survey of MMR vaccination data -
had concluded that there is no credible evidence behind claims of harm
from the MMR vaccine. The news had been carefully leaked with an
impressive notice that it should be "strictly" embargoed until 00:01 hours
(BST), Oct. 19, 2005. This was the most effective way to guarantee that it
would spread like a California wild fire on Tuesday the 18th. After all,
with everything happening around the world, from earthquakes to
hurricanes, wars, elections and bird flu, it was not safe to take a chance
that some new calamity would distract people on Wednesday from
appreciating the important findings of the study.
It was Tuesday when I received the embargoed press release. It started,
"There was no credible evidence behind claims of harm from the MMR
vaccination. This is the conclusion drawn by the Cochrane Review Authors,
an international team of researchers, after carefully drawing together all
of the evidence found in 31 high quality studies from around the world."
The lead author of the study, Vittorio Demicheli, MD, of the Servizo
Sovrazonale di Epidemiologia, Alessandria, Italy, promptly tempered the
initial sweeping statement by adding, "In particular we conclude that all
the major unintended events, such as triggering Crohn's disease or autism,
were suspected on the basis of unreliable evidence."
He then was quoted as saying, "Public health decisions need to be based on
sound evidence. If this principle had been applied in the case of the MMR
dispute, then we would have avoided all the fuss."
The fuss!
Is that what it was all about?
Is that what regressive autism is? A fuss!
Now Demicheli had my attention.
What was not mentioned in the widely circulated embargoed press release
was the actual first conclusion listed by the authors in their abstract:
"The design and reporting of safety outcomes in MMR vaccine studies, both
pre- and post-marketing, are largely inadequate."
I have to say in fairness that I have always admired the work done by the
Cochrane group. In fact, I quoted their excellent pediatric influenza
vaccination review in "Influenza vaccination of infants: A useless risk"
on Red Flags less than a month ago. (1) The lead author for that review
was Tom Jefferson, MD, who is a Cochrane researcher based in England;
Demicheli was one of the co-authors. Of the most recent 15 reviews listed
in MEDLINE, which they have co-authored with others, Jefferson was the
lead author in eight and Demicheli, the lead author in four. Most studies
were related to influenza vaccination.
It is well known that the Italians have never had much amore for the MMR
vaccination. In 2002, a measles epidemic was attributed to "inadequate"
vaccination coverage (Morbidity and Mortality Weekly Report, Oct. 31,
2003). Actually "inadequate" was a charitable way to describe a
seven-percent vaccination rate in the area with the most cases that year -
3,750 cases per 100,000 children under the age of 15. (2)
To see Demicheli listed as the lead author of this recent MMR review (3)
was, therefore, intriguing to say the least. The MMR-autism issue had
created much "fuss" - indeed, more of an obsession - in the United Kingdom
for years and Jefferson has been connected with it since 1999. So, why was
the apparent expert on the subject not the lead author, while his Italian
colleague was? We'll get to that later.
Details of the Release
"Aware of the controversy surrounding the use of MMR, members of The
Cochrane Collaboration set out to review the evidence for effectiveness of
the vaccine and also to review evidence of adverse events. In a process of
'systematic reviewing' researchers searched international databases and
found 139 articles about MMR use. Because many of them referred to studies
that had been conducted in a way that could not rule out bias or error,
the researchers discarded all but 31 of them. Using rigorously established
methods, the researchers then synthesized the findings from these pieces
of higher-quality research to create the most authoritative assessment yet
available."
The above would suggest that 108 of 139 studies on MMR did not meet the
Cochrane criteria. In fact, the authors reviewed some 5,000 MMR-related
articles and found only 31 that could "possibly" fulfill their inclusion
criteria.
According to the embargoed information, the authors concluded that:
There is no credible link between the MMR vaccine and any long-term
disability, including Crohn's disease and autism.
MMR is an important vaccine, which has prevented diseases that still carry
a heavy burden of death and complications where the vaccine is not used
consistently.
The lack of confidence in MMR has caused great damage to public health.
People arguing for or against the use of any therapy need to make sure
that they base their conclusions on carefully collected evidence, not just
on biased opinion, speculation or suspicion.
>From here on, my comments will be limited to regressive autism.
Conclusion 1
The fact that a review of the 31 studies suggested that no link exists
between the MMR vaccine and autism does not mean that, indeed, no link
exists. We have seen each one of those epidemiological studies make a
splash, get some applause and then fade away while the so-called study of
12 by Wakefield, has endured. Indeed, if one of the adversarial studies
had been strong enough to stand on its merits, we would not have needed
another and another and another to follow. We would not have needed 5,000
of them and we would not have needed the Cochrane review.
In 2002, K. M. Madsen, MD, stated that preceding studies lacked sufficient
statistical power to detect an association and did not have a
population-based cohort design. In time, his own study was proved
deficient by G. S. Goldman, PhD, and myself. (4) The 2004 Smeeth study
only survived a few weeks and now the Cochrane reviewers suggest that it,
too, is lacking something.
In addition, the impartiality of some authors and the significance of
their findings came into question. The research group led by Heikki
Peltola, MD, received financial support from Merck. The U.K. Medicines
Control Agency (MCA) and Public Health Laboratory Service (PHLS)
commissioned the studies by Brent Taylor, PhD, and friends. Madsen's study
was funded by the Centers for Disease Control and Prevention, MCA and
PHLS. And those are only three of many.
Conclusion 2
The authors are expressing a personal MMR-favorable opinion although they
know or should know, as everyone else does, that measles mortality had
decreased drastically in the Western world before the advent of
vaccination because of improved hygiene and nutrition. In Third World
countries today, improved nutrition and hygiene are the top priorities.
Conclusion 3
The lack of confidence in the MMR vaccine was the result of the inability
of its promoters to instill confidence and maintain it. The so-called, and
so-far theoretical, "damage to public health" would have been nil if the
U.K. Department of Health had not outlawed the monovalent measles, mumps
and rubella vaccines in 1999 - just to force people to their knees. This
should be remembered as the worst public health decision ever:
vaccination's Day of Infamy.
Conclusion 4
No one ever said that MMR vaccination should be withdrawn. In fact,
Wakefield's biggest troubles started when he warned the U.K. health
department to get ready and have some single vaccines available in case
there was a further drop in MMR vaccination rates - following the
publication of his article - as the rates had been falling since 1996. (5)
***
MMR and Autism
The evidence supporting an MMR-autism link was carefully collected and
duplicated and is rock solid. It is certainly not "biased opinion,
speculation or suspicion."
In hundreds of children with post-MMR regressive autism, a specific type
of enterocolitis has been identified by many investigators in several
countries. Some of the affected children have evidence of measles virus
genomic RNA in the cerebrospinal fluid, some in the gut wall and some in
both sites. In many, the sequences obtained were consistent with being
vaccine strains and, in these children, there was no history of exposure
to wild measles.
Many affected children have specific patterns of urinary polypeptides,
high serum measles and MMR antibody titers and elevated myelin basic
protein auto-antibody levels.
In fact, it will be safe to say that it is impossible to find one normal
child who has evidence of both MMR antibody and myelin basic protein
auto-antibodies in his serum or his cerebrospinal fluid or one child, who
regressed after MMR vaccination, who does not have at least one of the
following: the typical enterocolitis of autism, a suggestive pattern of
urinary polypeptides, evidence of measles virus genomic RNA, elevated
serum measles virus antibody, MMR antibody or myelin basic protein
auto-antibodies..
These are not suspicions. These are facts - rock-solid facts.
In many children, two regressions have been clearly documented by
health-care providers, photographs and videos. The first regression
occurred shortly after the first MMR vaccination and the second, much more
severe, after the MMR booster at age 4 or 5, following a period of
relative improvement. This biphasic course, or
challenge-dechallenge-rechallenge, has been accepted as evidence of
causation by the courts and by a special committee of the Institute of
Medicine.
In a May 2005 presentation to the American Gastroenterological Association
of a study titled "Autistic enterocolitis: confirmation of a new
inflammatory bowel disease in an Italian cohort of patients," Frederico
Balzola, MD, of Turin, Italy, and associates described in detail the many
gastrointestinal (GI) findings in nine consecutive patients with autism
who had long-standing and serious GI symptomatology including abdominal
pain, bloating, constipation and/or diarrhea.
The authors concluded, "These preliminary data are strongly consistent
with previous descriptions of autistic enterocolitis and supported a
not-coincidental occurrence. Moreover, they showed for the first time a
small intestinal involvement, suggesting a panenteric localization of this
new IBD. The treatment to gain clinical remission has still to be tried
and it will be extremely important to ameliorate the quality of life of
such patients who are likely to be overlooked because of their long-life
problems in the communication of symptoms."
Now this is the kind of study that Demicheli and his colleagues should
have looked at, instead of reviewing epidemiological studies of dubious
quality financed by the vaccine manufacturer or vaccine agencies.
Conflict or Bias
A conflict of interest is a situation in which someone in a position of
trust has competing personal, professional and/or financial interests.
Bias is an inclination that inhibits impartial judgment.
Jefferson, the real MMR expert of the Cochrane team, did disclose that he
had a "potential" conflict of interest: In 1999, he acted as an ad hoc
consultant for a legal team advising MMR manufacturers.
The Cochrane publication also carried the following acknowledgements: "Drs
Harald Heijbel, Carlo DiPietrantonj, Paddy Farrington, Ms Sally Hopewell,
Melanie Rudin, Anne Lusher, Letizia Sampaolo and Valeria Wenzel. The
authors wish to thank the following for commenting on this review draft:
Bruce Arroll, Lize van der Merwe, Janet Wale and Leonard Leibovici."
***
If the lawyers for the MMR manufacturer(s) in the U.K. hired Tom Jefferson
as a consultant in 1999, while they were preparing for the looming MMR
autism case, they must have been certain that he would be ready to testify
under oath that MMR did not and could not cause autism - in anyone.
In June 2000, Jefferson wrote an editorial in the Journal of Epidemiology
and Community Health Online, titled"Real or perceived adverse effects of
vaccines and the media - a tale of our times." In it, he stated, "Since
the publication of the Wakefield study on 28 February 1998, public concern
fueled by extensive media coverage caused a steady decline in MMR coverage
in parts of the United Kingdom, with a subsequent risk of a decline in
herd immunity and resurgence in morbidity.
"A swift reaction by the U.K. government and the subsequent publication of
studies by the Committee on Safety of Medicines and by Taylor et al,
showing no evidence of a causal link, partly redressed the balance. As
usual with vaccine "scare stories," there was a delay between publication
of the initial case series and that of population-based causal assessment
study. During this time, declining coverage took place." (6)
Jefferson acknowledged that he received help in the preparation of the
editorial from Robert Chen, Ulrich Heininger, Elisabeth Loupi and Harald
Heijbel.
Since 1998, and until a short while ago, Chen, an epidemiologist with the
National Immunization Program (NIP), had been the CDC's point man for all
MMR matters arising from the Wakefield publication. He wrote frequent
anti-Wakefield articles and gave many interviews. He was also always in
close contact with Elizabeth Miller of the U.K. Department of Health, who
co-authored the Taylor studies and who led the charge against Wakefield in
England.
Ulrich Heininger was the European editor of the Archives of Disease in
Childhood. In 2002, he wrote, "However, safety questions raised about
certain vaccines - whether true (intussusception associated with rotavirus
vaccine) or false (autism due to MMR) - have challenged pediatricians."
(7)
Elizabeth Loupi was senior director of Pharmacovigilance, Sanofi Pasteur
SA, Lyon, France. Sanofi Pasteur MSD is the only European company
dedicated exclusively to vaccines and was founded in 1994, as a joint
venture between Sanofi Pasteur and Merck & Co., Inc.
Lastly, Harald Heijbel was the coordinator, Immunization Registry Project,
Swedish Institute of Infectious Disease Control, Stockholm, Sweden
Jefferson was obviously a big booster of MMR vaccination and a firm
believer in its safety - no matter what. He also had to be anti-Wakefield.
Even if he only had a "potential" financial conflict of interest, he
certainly had a major personal conflict and bias and he should have
declared them. A father who regularly contributes comments on the autism
situation to the electronic British Medical Journal has always added
"father of an autistic child." And I certainly have always declared that I
had a grandson who regressed after MMR vaccination. I thought it was only
fair that readers know.
As stated earlier, the Cochrane researchers who designed the present
study, evaluated the 31 "chosen epidemiological works" and wrote the
present report received assistance and scientific support from Harald
Heijbel, Carlo DiPietrantonj, Paddy Farrington, Sally Hopewell, Melanie
Rudin, Anne Lusher, Letizia Sampaolo and Valeria Wenzel.
Information about Harald Heijbel was reported earlier.
Paddy Farrington co-authored Brent Taylor's and Elizabeth Miller's first
article "Autism and measles, mumps, and rubella vaccine: no
epidemiological evidence for a causal association" (The Lancet, June 12,
1999). Having him help review that study and others like it is strange -
to say the least.
Farrington's statistical contribution to the first Taylor study was
criticized by James H. Roger, PhD, at a meeting of the Royal Statistical
Society in London. In a letter to the editor of The Lancet (July 8, 2000),
Roger wrote, "Sir - Rather than clarify the measles, MMR, and autism
confusion with your editorial, you perpetuated the myth that good
scientific evidence rejects a link between MMR vaccination and autism.
You quote Taylor and colleagues as publishing "epidemiological evidence
contradicting this alleged association." On March 28, 2000, I presented a
talk to the Royal Statistical Society, in which I showed how the currently
published data, including that from this study, are consistent with an
appreciable number of autism cases being triggered by MMR vaccination. In
short, Taylor and colleagues used the wrong study design to detect an
association between immunization and a disease with chronic onset, such as
autism."
Sally Hopewell, Melanie Rudin and Ann Lusher are employed at the U.K.
Cochrane Centre.
Scientists Valeria Wenzel and Letizia Sampaolo work at the Istituto
superiore di sanità in Rome, the main Italian Institute of
technical-scientific research, control and advice in public health.
Because the listing of personal bias is not required, Jefferson's past
association with the Brighton Collaboration was also not disclosed.
No wonder Vittorio Demicheli of the Servizo Sovrazonale di Epidemiologia,
Alessandria, Italy, became the lead author of the Cochrane MMR review.
The Brighton Collaboration
On its Web site (8), The Brighton Collaboration reports:
"[It] was founded by Robert Chen, Harald Heijbel, Tom Jefferson, Ulrich
Heininger, and Elisabeth Loupi in 1999 at a meeting in Brighton, England.
It was officially launched in autumn 2000. The Collaboration consists of
volunteers from patient care, public health, scientific, pharmaceutical,
regulatory and professional organizations coming from developed and
developing countries. They are experienced and knowledgeable in the field
of immunization safety and corresponding medical specialties."
It says its objectives are:
"A. Global Collaboration
To establish a global collaboration of professionals and organizations
concerned with immunization safety.
B. Development
To develop a single standardized case definition per AEFI and guidelines
for data collection, analysis, and presentation for global use.
C. Evaluation
To develop and implement study protocols for evaluation of case
definitions and guidelines in clinical trials and surveillance systems.
D. Implementation
To raise global awareness of the availability, educate about the benefit
of use, facilitate access to and monitor worldwide use of standardized
case definitions and guidelines for data collection, analysis, and
presentation."
It reports the following about its sources of support:
"The work of the Brighton Collaboration is based on a large number of
volunteers worldwide. It obtained its first funding in 1999. The Brighton
Collaboration is presently supported by the Centers for Disease Control
and Prevention (CDC) and the World Health Organization (WHO). From 2000
until 2003, the Collaboration also received funding through the European
Research Program for Improved Vaccine Safety Surveillance (EUSAFEVAC).
"In December 2003, the Brighton Collaboration Foundation was established
by the University Children's Hospital Basel, Switzerland. The purpose of
the Foundation is to protect and preserve public health by promoting
immunization safety. The Foundation promotes the development and
availability of globally accepted, high quality scientific standards for
research on and communication of immunization safety. The Foundation may
also conduct immunization safety research itself or support such research
projects."
It is well known that U.S. Congressman Dave Weldon, MD, of Florida has
been watching health matters carefully as a member of the committee on
government reform of the House of Representatives.
In one particular address to the House of Representatives in 2004, Weldon
discussed autism, MMR research and the Brighton Collaboration among other
things. The address (9) is now part of the Congressional Record, June 18,
2004, beginning on page H4564 and can be seen in its entirety at
http://weldon.house.gov/UploadedFiles/RepWeldonMDonIOM.pdf
The following segment is relevant to this discussion:
"Mr. Speaker, I want to touch on one more additional issue, and that is
something called the Brighton Collaboration. I am very concerned about
the development of the Brighton Collaboration, which began in the year
2000. This is an international group comprised of public health officials
from the CDC, Europe, and world health agencies like WHO and vaccine
manufacturers.
The first task of the Brighton Collaboration, created several years ago,
was to define what constitutes an adverse reaction to a vaccine. They have
established committees to work on various adverse reactions to vaccines.
Particularly troubling to me is the fact that serving on these panels
defining what constitutes an adverse reaction to a vaccine are the vaccine
manufacturers. What is even worse is the fact that some of these
committees are chaired by vaccine manufacturers.
It is inappropriate for a manufacturer of vaccines to be put in the
position of determining what is and what is not, an adverse reaction to
its product. Do we allow GM, Ford and Chrysler to define the safety of
their automobiles? Do we let airlines set the safety standards for their
airlines and determine the cause of an airline accident? Do we allow food
processors to determine whether or not their food is contaminated or
causing harm? Then, I ask, why we are allowing vaccine manufacturers to
define what constitutes an adverse reaction to a vaccine?
This collaboration is fraught with pitfalls, and merges regulators and the
regulated into an indistinguishable group. It is critical that the
American public look at what is going on here and how this entity may
further erode the ability for us to fully understand the true relationship
between various vaccines and some adverse reactions in some subsets of our
population. I plan to devote additional attention to this effort in the
future.
Mr. Speaker, I look forward to working with you and others in this body to
address the problem that we face today.
As I stated at the outset of my comments this afternoon, autism was once
in America a rare and infrequently seen condition. I went through four
years of medical school, internship, residency, and years of private
practice and practice within the military and had not seen one single
case. I have seen case after case in my Congressional District over the
last seven years, a disease that I had never seen before.
The disease incidence was previously thought to be one in 10,000. It is
now thought to be as high as possibly one in 167, an almost 100-fold
increase in the incidence.
We need to get answers to these questions. We need to restore public
confidence and safety in our vaccine program. Our vaccine program saves
millions of lives, it saves millions of kids from a life of disability,
and the best way for us to ensure public confidence and make sure that all
the kids get vaccinated properly is to get answers to these questions.
The way the CDC and the Institute of Medicine and the industry is going
about trying to answer these questions is highly flawed.
Mr. Speaker, I encourage my colleagues to begin to look at this issue. I
know that many of them are coming to me saying they have parents coming in
their offices now with autistic kids, saying something needs to be done.
Something needs to be done."
Discussion:
Epidemiological and statistical studies - even the best - cannot prove
that the MMR vaccination does not cause regressive autism in a small
percentage of genetically predisposed children.
So far, we have not seen one unbiased, well-done and convincing
epidemiological study.
Hundreds of weak studies have come and gone after they made a little noise.
The Wakefield study of 12 certainly seems to have endured.
Reliable histories with documentation have clearly shown regression occurs
following vaccination and specifically MMR vaccination.
Accurate clinical studies have revealed the presence of typical and
similar intestinal findings in children with post MMR regressive autism.
Reproducible laboratory investigations have confirmed the relationship of
the findings with the measles component of the MMR.
Challenge-dechallenge-rechallenge has been documented repeatedly.
Diet and therapeutic management of the gastrointestinal component of the
disease has improved behavior and speech.
Though technically impressive, the recent MMR review by the Cochrane group
will please those who are already "on board" and convince only those who
know little about the subject.
For everyone else, the huge effort did fall short.
The hierarchy of the Cochrane Institution should examine the impartiality
of all involved.
For an institution of that caliber, even the appearance of bias is
unacceptable.
The authors of the Cochrane review revealed their partiality when they
endorsed the MMR vaccine without reservation and declared that it could
not cause harm. Multiple reports to VAERS and a review of the vaccine
compensation programs in the U.S., the U.K., Japan and other countries
show otherwise.
Something Is Not Right When:
Epidemiological studies about MMR and autism are financed by the CDC, the
U.K. Department of Health, the vaccine manufacturers or someone supporting
them.
Those studies - even the worst of them - are easily published in the best
medical journals, while their criticism is not.
The same studies are applauded after publication by the CDC, the U.K. DOH
and friends who made them happen.
The studies are then reviewed by friends.
And they are re-reviewed by sympathizers who minimize their problems and
attest that "there is no credible link," while not looking at all the
evidence contradicting them.
Something Is Certainly Not Right When:
All this is happening and the only one accused of conflict of interest is
Andy Wakefield because his hospital received a grant of £55,000 to support
GI research.
Conclusion:
The recent Cochrane Review of the MMR vaccine epidemiological research is
not convincing.
References:
Influenza vaccination of infants: A useless risk
http://www.redflagsdaily.com/yazbak/2005_sep30.php
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5243a4.htm
Review Paper: Demicheli et al: Vaccines for measles, mumps and rubella in
children. The Cochrane Database of Systematic Reviews 2005, Issue 4.
Goldman GS, Yazbak FE: An Investigation of the Association between MMR
Vaccination and Autism in Denmark. JAmPhysSurg 2004; 9(3):70-75
http://www.jpands.org/vol9no3/goldman.pdf
MMR Vaccination rates were down before Wakefield
http://www.redflagsweekly.com/conferences/autism/2003_dec22.html
http://jech.bmjjournals.com/cgi/content/full/54/6/402
http://adc.bmjjournals.com/cgi/content/extract/87/1/9
http://www.brightoncollaboration.org/internet/en/index/about.html
http://weldon.house.gov/UploadedFiles/RepWeldonMDonIOM.pdf