Alive and Well: The MMR-Autism Connection

By Red Flags Columnist, F. Edward Yazbak, MD, FAAP
(tlautstudy@aol.com)

Original Article: http://www.redflagsdaily.com/yazbak/2005_oct28.html

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 to15 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:

1. There is no credible link between the MMR vaccine and any long-term disability, including Crohn’s disease and autism.
2. 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.
3. The lack of confidence in MMR has caused great damage to public health.
4. 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 Andrew Wakefield, MD, 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:

1. Influenza vaccination of infants: A useless risk
   http://www.redflagsdaily.com/yazbak/2005_sep30.php
2. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5243a4.htm
3. Review Paper: Demicheli et al: Vaccines for measles, mumps and rubella in children. The Cochrane Database of Systematic Reviews 2005, Issue 4.
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
5. MMR Vaccination rates were down before Wakefield
   http://www.redflagsweekly.com/conferences/autism/2003_dec22.html
6. http://jech.bmjjournals.com/cgi/content/full/54/6/402
7. http://adc.bmjjournals.com/cgi/content/extract/87/1/9
8. http://www.brightoncollaboration.org/internet/en/index/about.html
9. http://weldon.house.gov/UploadedFiles/RepWeldonMDonIOM.pdf

Posted by Becca

« Home | Children's study will be far-reaching » //-->