Authors: Andrew J Wakefield MB,BS., FRCS., FRCPath and Carol Stott, PhD.

Response to: D'Souza et al. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics. 2006;118:1664-75.

Dear Sir,
The merit of D'Souza et al.'s use of a study of peripheral blood mononuclear cells to dismiss findings in intestinal biopsies is questionable.¹ A recent US study using nested PCR and sequencing confirmed the fidelity of the original Uhlmann F-gene primers in the detection of measles virus in intestinal biopsies from children with autism.² D'Souza et al. claim that, among other things, the "epidemiological burden of evidence against such an [causal] association between MMR and autism is overwhelming." They fail to reference the authoritative Cochrane review of this epidemiology³ which dismissed much of it as being of insufficient quality to merit consideration, including Fombonne's own work⁴ of which they said, "the number and possible impact of biases in this study was so high that interpretation of the results was difficult." Even the Cochrane review failed to note that another of Fombonne's studies using the UK General Practice database (GPRD)⁵ tested the wrong hypothesis and lacked sufficient power to detect an association between MMR and regressive autism.

So which studies are sufficient to overwhelm? Several have looked at age of exposure to MMR vaccine and risk of autism. Such a hypothesis is merited on the basis that younger age of exposure to measles virus is associated with an increased risk of adverse outcome including persistent infection and delayed disease. Richler et al. posed the question of whether there is an autism phenotype characterized by regression associated with significant intestinal symptoms following MMR vaccine, in a previously developmentally normal or near-normal child.⁶ Children meeting these criteria were compared with all other autistic children in their study cohort. In this, the only epidemiologic study to at least attempt to segregate this sentinel autism phenotype, age of exposure to MMR vaccine was significantly lower (mean age 14.38 months) when compared with the remaining autistic population (mean age 17.71 months; p<0.05). Strangely - and at odds with their own reported findings - the authors concluded that, "there was no evidence that onset of autistic symptoms or of regression was related to MMR vaccination."

Three further aspects of age of exposure to MMR and autism have been reported: DeStefano and colleagues performed a case-control study comparing age at first MMR vaccination in children from the Atlanta metro area.⁷ By 36 months of age, significantly more cases with autism (93%) had received MMR than controls (91%)(odds ratio 1.49; 95% confidence interval [CI] 1.04-2.14). This association was strongest in the 3 to 5-year age group with an odds ratio of 2.34. Due to diagnostic delay, a significant proportion of this group had yet to be diagnosed with autism, potentially underestimating this risk. Moreover, in a subgroup analysis looking at children with different disease characteristics, they found a significant association between MMR vaccination by 36 months and autistic children with no evidence of mental retardation (IQ>70; OR 2.54 [1.20-5.00]). The odds ratios were increased to 3.55 in a subgroup analysis adjusted for birth weight, multiple gestation, maternal age, and maternal education, thus strengthening the association between age of exposure to MMR and autism.

It is interesting that their 'regressive group' did not show this effect although the interpretation of this finding is severely constrained by their retrospective ascertainment of regression from medical records. First, regression did not form part of the diagnostic algorithm for autism, and second, the concept of regression conflicted, until very recently, with the beliefs of most autism diagnosticians. IQ, on the other hand, is an objective measure and a normal IQ appears to be an increasingly common feature among recent cohorts of affected children.⁸ An IQ within the normal range may well reflect a period of normal cerebral development and, in this instance, be a better marker of the late-onset phenotype than retrospective record review. Having tested a hypothesis and found a significant association between autism and age of first MMR exposure, the authors, somewhat curiously, ascribe this effect to an "artifact of immunization requirements for pre-school special education attendance in case children." Such an interpretation would only possibly be valid if the immunization mandate for normal pre-school children were different from that of special education children; it is not. Moreover, the special education group, with a likely excess of contraindications to MMR vaccination such as seizures, should have a lesser exposure to MMR. In addition, if there were no true association, lower exposure in the special education group would be expected in light of higher levels of parental concern and consequent rates of abstention in this group, a possibility that could have been easily checked by comparing the proportions of exemption filings held by law in all state schools. This notwithstanding, the data of DeStefano et al. are not consistent with the author's post hoc rationalization.

Second, Edwardes and Baltzan⁹ reanalyzed the California autism data of Dales and colleagues¹⁰, confirming that the age of MMR immunization became younger between 1981 and 1993. The ratio of children immunized before age 17 months to those immunized between age 17 and 24 months increased 200% from 1981 to 1993, and the rate of early MMR immunization is correlated with the incidence of autism. This is an important factor in light of DeStefano et al.'s observation of a greater statistically significant association between autism and MMR vaccination by 36 months in more recent birth cohorts.¹¹

Third, Suissa pointed out that according to the Danish data of Madsen et al., the rates of autistic disorder by age at vaccination are 18.9, 14.8, 24.6, and 26.9 per 10⁵ per year respectively for ages <15, 15-19, 20-24, 25-35, falling to 12.0 per 10⁵ with age at vaccination >35 months, compared with the overall rate of 11.0 for the reference group of no vaccination, over all ages.¹² Suissa considered it somewhat implausible for the age-adjusted rate ratio to fall below 1 (as presented), unless the risk profile by age in the unvaccinated is vastly different than in the vaccinated. Thus, rather than an apparent association between exposure and outcome being a spurious result of confounding, this would actually represent effect modification. The data support the hypothesis of an association between exposure and outcome, modified rather than confounded by age of exposure.

While an effect of age of exposure to MMR vaccine on autism risk is evident from these studies, the nature of that risk is not known. Aside from the issue of age of exposure, Taylor et al. found a significant clustering of parental concern within six months of MMR vaccination (p=0·03)¹³ and, as was later pointed out, a step-up in number of autism diagnoses associated with the introduction of MMR vaccination in the UK¹⁴. A similar step up in the autism rate with introduction of MMR was observed in Denmark.¹⁵

Overwhelmed, D'Souza et al. claim that the hypothesized link between MMR and ASD is spurious. With respect, we disagree.

Andrew J Wakefield MB,BS., FRCS., FRCPath and Carol Stott Ph.D

Potential conflicts.
The authors have acted as paid experts in the UK MMR vaccine litigation. AJW is a named inventor on two viral diagnostic patents.

1. D'Souza Y, Fombonne E, Ward BJ. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics. 2006;118:1664-75.
   
   
2. Walker SJ, Hepner K, Segal J, Krigsman A. Persistent ileal measles virus in a large cohort of regressive autistic children with ileocolitis and lymphnodular hyperplasia: re-visitation of an earlier study [abstract]. International Meeting for Autism Research (IMFAR) 2006, www.cevs.ucdavis.edu/Cofred/Public/Aca/WebSec.cfm?confid=238&webid=1245.
   
   
3. Cochrane. Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children (Review) The Cochrane Library. John Wiley & Sons, Ltd. 2005, Issue 4. http://www.thecochranelibrary.com.
   
   
4. Fombonne E, Chakrabarti S. No evidence for a new variant of measles-mumps-rubella-induced autism. Pediatrics 2001;108:E58.
   
   
5. Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues L, Smith P, Hall A. MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 2004, 364:963-969.
   
   
6. Richler J, Luyster R, Risi S, Hsu Wan-Ling, Dawson G, Bernier R, et al. Is there a 'regressive phenotype' of autistic spectrum disorder associated with the measles-mumps-rubella vaccine? a CPEA study. Autism Dev. Dis. 2006, 36:299-316.
   
   
7. DeStefano F, Bhasin TK, Thompson WW, Yeargin-All¬sopp M, Boyle C. Age at first measles-mumps-¬rubella vaccination in children with autism and school-mat¬ched control subjects: a population-based study in metro¬politan Atlanta. Pediatrics 2004, 113:259–266.
   
   
8. Autistic Spectrum Disorders: changes in the California caseload. An update: 1999 through 2002. California Department of Developmental Services. A Report to the Legislature, Department of Developmental Services. Sacramento, Calif.: www.dds.ca.gov. Accessed Oct, 2006.
   
   
9. Edwardes M, Baltzan M. MMR Immunization and Autism. JAMA 2001, 285:2852-2853.
   
   
10. Dales L, Hammer SJ, Smith NJ. Time trends in autism and MMR immunization coverage in California. JAMA 2001, 285:1183-1185.
    
    
11. DeStefano F, Bhasin TK, Thompson WW, Yeargin-All¬sopp M, Boyle C. Age at first measles-mumps-¬rubella vaccination in children with autism and school-mat¬ched control subjects: a population-based study in metropolitan Atlanta. Pediatrics 2004, 113:259–266.
    
    
12. Madsen MK, Hviid A, Vestergaard M, Schendel D, Wohlfarht J, Thorsen P, et al. A population-based study of measles mumps rubella vaccination and autism. NEJM 2002, 347:1478-1482.
    
    
13. Taylor B, Miller E, Farrington CP, Petropoulos MC, Favot-Mayaud I, Li J, Waight PA. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet. 1999 Jun 12;353(9169):2026-9.
    
    
14. Wakefield AJ.MMR vaccine and autism. Lancet. 1999;354:950-951.
    
    
15. Stott CA; Blaxill M, Wakefield AJ. MMR and Autism in Perspective: the Denmark Story. J Am Phys Surg. 2004;9:89-91.

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