The Age of Autism: Pox -- Part 1

By DAN OLMSTED, UPI Senior Editor  |  April 19, 2006 at 5:46 PM
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Children in families with problematic reactions to chickenpox virus may be at risk for developing autism if they get that live-virus immunization too close to other live-virus vaccines, a three-month United Press International investigation of cases in one northwest U.S. city suggests.

Several such families in the Washington state capital of Olympia watched their children regress into full-syndrome autism -- losing language and social skills and adopting repetitive behaviors -- in the months following the shots. Two children had participated in small clinical trials in Olympia of investigational Merck & Co. chickenpox vaccines in combination with the live-virus mumps-measles-rubella vaccine -- the MMR.

Federal health authorities consistently have rejected concerns about a link between immunizations and autism. But a family background of problems coping with viruses used in live-virus vaccines has not been considered a possible risk factor, experts said.

One of the children in the clinical trials, Jimmy Flinton, now 4, got about 10 times the standard dose of chickenpox vaccine in a shot that also contained the MMR.

Called ProQuad, that combined immunization was approved by the U.S. Food and Drug Administration last September -- the first time four "attenuated" or weakened live viruses have been mixed together in a single shot.

The second child, Timothy Baltzley, now 6, got an investigational "process upgrade" chickenpox shot and a separate MMR shot at the same office visit.

Both children have a parent who had unusual reactions to chickenpox virus.

Timothy's Baltzley's mother, Kimberly, had chickenpox three times, the last at age 16, just three years before he was born. Jimmy Flinton's father, Paul, had shingles as a teenager. Shingles is reactivated chickenpox virus that painfully inflames nerves and mostly affects older people or those with weakened immune systems.

Both children got the vaccines at 12 months, the age at which chickenpox and MMR immunizations are first recommended by the Centers for Disease Control and Prevention. They were among a total of 101 subjects in the two trials in Olympia, according to the Western Institutional Review Board, which approved the trial protocols.

Half-a-dozen other parents of preschool-age autistic children from the same neighborhood in Olympia recognized a common thread: unusual chickenpox histories in their families and simultaneous or closely timed chickenpox and MMR shots in their children.

"It's the proximity of the chickenpox and MMR vaccinations" and the family histories that stand out, said Denise Rohrbeck, mother of 3-year-old Grant.

Rohrbeck has not been able to develop immunity to chickenpox despite being twice vaccinated as an adult, the last time just two years before her son was born. A couple of months before he got the standard chickenpox and MMR shots at the same office visit at age 1, Grant had a stubborn and severe case of roseola, which like chickenpox is a herpesvirus.

Four days after the MMR and chickenpox injections he became ill with a fever and lay limp in his mother's arms for the first time in his life.

"He began having chronic diarrhea, and by his 15-month checkup he had regressed so drastically that his pediatrician suggested he could be autistic," Rohrbeck recalled. The doctor agreed to the parents' request for an immediate neurodevelopmental evaluation, which resulted in a diagnosis of full-syndrome autism.

Rohrbeck said she began looking for a possible connection between vaccines and autism among neighborhood children after the Thurston County Health Department did not follow up on parents' concerns raised at a meeting last October. With the parents' continued involvement, she has now compiled vaccination records of 14 Olympia children diagnosed with autism, as well as 16 who are not.

The admittedly unscientific chickenpox-MMR association continues to be striking, and the two cases following the clinical trials seemed to underscore it, she said.

A Merck spokeswoman said the company reported those two cases to the FDA this March -- the same month UPI asked Merck about them.

"We just received these reports in March 2006, six months after ProQuad was approved in the U.S., and they were sent to the FDA after we received them," Merck's Christine Fanelle said in a statement. She said Merck received "the two reports of autism AEs from Olympia -- one from the parent of a child in the ProQuad trial and one from the parent of a child in (the 'process upgrade' chickenpox) study."

Parents Jennifer Flinton and Kimberly Baltzley say they never called Merck and wouldn't know who to contact there; last summer, Jennifer Flinton reported Jimmy's autism to the federal government's Vaccine Adverse Events Reporting System, attributing it to the cumulative effects of vaccination. The federal health employee she spoke to on the phone said she would follow up by gathering lot numbers and other information on the vaccines.

The parents said their pediatrician, who conducted both of the Merck-funded trials in Olympia, knew about their children's autism diagnoses within months of their participation in January 2001 and October 2002.

The Olympia trials were part of wider Merck studies conducted at several sites in the United States and abroad. Fanelle said Merck would not disclose information about any other reports of autism.

"We have confirmed your original inquiry on whether we received the two reports out of Olympia," she said. "We are not going to comment on reports beyond this.

"There were more than 7,000 children in our ProQuad trials, 5,800 of whom received ProQuad vaccine," she added.

Diana Sparby of the Western Institutional Review Board in Olympia said it had not received reports of autism from the local ProQuad study, but she noted the protocol "was not designed to assess long-term safety, as it called for follow-up for only 42 days following vaccine administration."

The FDA, which approves drugs after determining they are safe and effective and monitors reports of side effects after they come on the market, did not respond to repeated inquiries from UPI about the Olympia cases or parents' concerns about family chickenpox histories.

Other unusual histories in neighborhood families with autistic children 6 and under:

-- Another child had roseola 12 weeks before getting his chickenpox and MMR shots;

-- Another father had shingles as a teenager;

-- Another mother had chickenpox as an adult two years before her pregnancy;

-- A mother had chronic cold sores, also a herpesvirus, as a child that were so severe they had to be treated medically;

In addition, another mother had a case of measles as an adult.

Merck, which manufactures the standard MMR shot and the standalone Varivax chickenpox shot as well as the experimental vaccines used in the clinical trials, said repeated studies show no relation between vaccines and autism.

"We don't see an association," spokeswoman Fanelle said, citing as confirmation a 2004 report by the widely respected Institute of Medicine, part of the National Academies. That report rejected a link between autism and either the MMR vaccine or the mercury-based preservative thimerosal. The report also urged that research dollars be spent on "more promising" autism research.

"There will always be some people who say vaccines cause autism despite the lack of scientific evidence," Fanelle said.

In the United States, controversy over a possible link has centered on thimerosal. Beginning in the late 1980s children were exposed to increasing amounts of thimerosal, which is half ethyl mercury, as more vaccines were mandated.

Thimerosal was phased out of routine childhood immunizations -- but not all flu shots given to children and pregnant women -- beginning in 1999. Although the Olympia children with autism were born after the phase-out was recommended, their vaccine records show more than half of them got at least one shot containing thimerosal during the first year of life. It is possible all of them did, but incomplete information from manufacturers makes that uncertain.

Chickenpox and MMR immunizations don't contain thimerosal because the mercury would inactivate the viruses, but some proponents of a vaccine-autism link suspect thimerosal exposure from other immunizations could have a potentiating effect, damaging a child's defenses and paving the way for live viruses to wreck havoc.

All live-virus vaccines are attenuated -- significantly weakened based on the theory that this creates immunity without causing the actual disease or other adverse health consequences. Other vaccines on the U.S. childhood immunization schedule, including hepatitis B and the polio shot, contain killed or so-called inactivated viruses. Live polio virus was dropped in 2000 after health authorities determined it was actually causing polio in a small number of cases.

Despite the Olympia parents' concern, none points an accusing finger at doctors.

"I worry about pediatricians being vilified," said Rohrbeck. "We vaccinated our son because we shared their faith that vaccines were safe.

"If it turns out that some vaccines are not safe for all children and that these hazards could have been found with more rigorous testing -- or worse, that the dangers were already known -- that's the fault of the CDC, the FDA and the manufacturers," she said.

"I'll defend doctors to the end on this point. They are a convenient front line for those agencies to hide behind -- it's just shameful."

The theory that live virus immunizations could trigger autism first arose in 1998 in Britain, when gastroenterologist Dr. Andrew Wakefield published a paper suggesting a possible association between childhood MMR immunization, bowel disease and regressive autism.

The premise: Interaction between viruses -- scientifically known as immune interference -- could depress a susceptible child's immune system, lead to persistent infection by the measles virus in the GI tract and possibly the nervous system itself, and trigger autism-inducing brain damage. While the case has not been proven, it gains plausibility from the fact that naturally occurring measles infection is known to cause delayed brain damage in a small percentage of children, proponents of the theory say.

Wakefield's study, and his plea in Britain to separate the component measles, mumps and rubella (German measles) vaccines and administer them a year apart to reduce possible risk, caused an uproar. Co-authors subsequently repudiated part of the paper, conflict-of-interest allegations emerged, and the prestigious Lancet, which originally published the study, issued a statement calling it "fatally flawed."

Wakefield was asked to leave his medical job in Britain and is now doing research in Austin, Texas.

After the Olympia cases were described to him by UPI in March, Wakefield met with several of those parents at an autism conference in Portland, Ore. He also read studies Merck cites as central to the FDA approval of ProQuad.

"It's actually heartbreaking, listening to these parents, because you're staring into an abyss," Wakefield said afterwards. "You're listening to stories which reflect the fundamental misconception of vaccine manufacturers of what viruses are and what they do. The whole perception of these people is dangerously naïve."

In contrast to the United States, British health authorities have not recommended chickenpox immunization. But an MMR-chickenpox shot was under discussion there at one point, and Wakefield said he warned its developers that putting four live viruses in one shot was a bad idea.

He says the Olympia cases show why.

"As far as I'm concerned, you are further increasing the likelihood of persistent infection and delayed disease, which they are never looking for and therefore they will never find if it does occur, as it did clearly in a relatively short space of time with some of these children, and it's never ascribed to an adverse reaction to the vaccine."

On its Web site, the CDC says such concerns -- and Wakefield's studies in particular -- are not based on good science.

"Current scientific evidence does not support the hypothesis that MMR vaccine, or any combination of vaccines, causes the development of autism, including regressive forms of autism," the CDC says.

"The existing studies that suggest a causal relationship between MMR vaccine and autism have generated media attention. However, these studies have significant weaknesses and are far outweighed by epidemiological studies ... that have consistently failed to show a causal relationship between MMR vaccine and autism."


Dr. Jeff Bradstreet, a family practitioner in Florida who treats 3,000 autistic children and has worked with Wakefield, said he believes the risk of autism rises the earlier and closer together that live-virus vaccines are administered. He warned the Institute of Medicine in 2004 that it was ignoring the possibility that younger children are more vulnerable because their immune and neurological systems are immature.

"There's definitely been an association of kids getting MMR at 12 months and crashing (becoming autistic)," Bradstreet said.

He said adding 10 times the standard dose of chickenpox virus, called varicella-zoster, to the MMR shot and administering it to 1-year-olds is playing with fire.

"We think putting varicella with MMR is just nuts."

British researcher Paul Shattock sees another reason to be concerned with combining the four viruses: He suspects that children who get wild -- or naturally occurring -- chickenpox too close in time to the MMR shot face a higher risk for autism. That scenario parallels the one Olympia parents noticed with the chickenpox vaccination.

Shattock, director of the Autism Research Unit in the School of Sciences at the University of Sunderland, said he noticed that autistic British children whose parents blame the MMR for triggering the disorder had a pattern of "undisclosed viral illness" around the time of the shot.

He studied the records of 100 of those children, compared to 100 children whose parents did not cite the MMR as the trigger, to see if there was a higher incidence of chickenpox cases three months before or after the MMR immunization.

"Now, there was," Shattock said in an interview while attending an autism conference this month in Washington, D.C. "It wasn't statistically significant at the 95 percent level -- but enough to make you think that if it was a huge study, it might be."

His concern about adding chickenpox to the MMR shot: "I'm worried about it because of the interference of the vaccines, mainly because it depresses the immune system by yet another mechanism."

A Merck scientist discussed that issue at a CDC meeting in 2004, the year before ProQuad was approved, according to agency minutes. Dr. Florian Schodel "confirmed the possibility" that the chickenpox virus component of ProQuad was "causing a local immune suppression and an increase in measles virus replication. ...

"The current hypothesis is that the varicella and measles virus are co-infecting the same or proximate areas of the body and engaging in a specific interaction, but how that works is as yet unknown."

He said the interference appeared to involve only the chickenpox and measles viruses -- "there is no such effect for the mumps or rubella vaccines administered locally at the same time."

At the same meeting, Merck's Dr. Barbara Keller said the amount of chickenpox virus in ProQuad is "about a log" -- or 10 times -- higher than Merck's standalone chickenpox vaccine, Varivax, in order to overcome immune interference.

Both Wakefield and Shattock said the Olympia families' unusual histories with chickenpox are worrisome because their children might have inherited problems coping with the vaccine.

"There's no doubt the immune response to viruses is determined by our genetic constitution," Wakefield said. "It may well be there is a genetically determined predisposition to abnormal handling of chickenpox virus, at least in children.

"This kind of phenomenon has been shown to (play a role in) measles. The immune response to measles is determined by your genetic profile. It's certainly consistent with what is known about the immune response to viruses."

ProQuad is likely to be widely adopted by healthcare professionals who previously administered separate MMR and Varivax shots.

"Use of licensed combination vaccines, such as (ProQuad), is preferred to separate injection of their equivalent component vaccines," says the new edition of the CDC's authoritative "Pink Book" on vaccine-preventable diseases.

"When used, (the immunization) should be administered on or after the first birthday, preferably as soon as the child becomes eligible for vaccination."

This series of articles, based on reporting in Olympia in February and March, tells the families' stories, looks at the scientific controversy and examines implications for the autism-vaccine debate.


Next: "He has gone backward mentally ... "



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