Letter to the editor...John Walker-Smith

http://www.thelancet.com/journal/vol359/iss9307/full/llan.359.9307.correspondence.20101.1

Autism, bowel inflammation, and measles

Sir--I was the senior clinician in the preliminary study of ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder reported in 1998.1 Apart from one letter after our report,(2) I have remained silent, except for coauthorship on several articles on this topic.(3,4)

I believe that serious medical and scientific debate should be based on published work in peer reviewed journals, and done in professional media. The latest evidence in this matter has now been published on the internet,5 precipitated by the BBC Panorama programme on Feb 3, 2002. Although I retired from my chair at Royal Free and University School of Medicine in September, 2000, and have seen no patients since then, I hope that my opinions might be of some use.

I belive that the published data in peer reviewed journals show two things. First, a highly selected group of children with developmental disorder (many with regressive autism) exists, who have an unusual gastrointestinal abnormality characterised by ileal-lymphoid-nodular hyperplasia and non-specific enterocolitis that is not classical inflammatory bowel disease. The immunopathology of this disorder has been studied by Furlano and colleagues,(4) who have established clear differences from chronic inflammatory bowel disease.

Second, in such highly selected children, Uhlmann and colleagues(5) have now provided new evidence that measles might be involved, by use of molecular techniques to show the presence of measles virus genomes in 75 of 91 children with ileal-lymphoid-nodular hyperplasia, enterocolitis, and developmental disorder, compared with five of 70 control children. Measles virus was mainly localised in dendritic cells in reactive follicular hyperplastic centres in the ileum. This localisation mirrors that of HIV-1.

Uhlmann and colleagues pose the question does measles virus play a part in the unusual inflammation already reported in children with developmental disorder. Surely there is now a high priority to do research to answer this question.

There has been much criticism of Wakefield and colleagues' work. His results have been said to be refuted. Much of this criticism has been epidemiological. Yet, as Morris and Aldulaimi (6) in their comment on the Dublin data state, "Epidemiology is a pretty blunt tool and the studies done do not rule out the possibility that there are at risk groups where a real link with [measles, mumps, rubella vaccine] MMR and autism/bowel inflammatory condition exists". It seems clear to me that what epidemiology has shown is that the MMR vaccine is safe in most children.

Furlano and colleagues' work on the inflammatory changes and the intestine in autism was reviewed in the Medical Research Council's 2001 report. Some criticisms were made but the work was certainly not refuted.

Now, anecdotally, my own observations are that there is grave concern felt by many parents of autistic children about the possible triggering role of MMR for autism and bowel disorders. This issue has been brought to the attention of a wider audience by television. I believe this issue must be addressed by discussion of the lead-up to the initial study and to the follow up publications.

As a paediatrican I am all too aware of the dangers of measles. I have seen the devastation it can cause in children in Africa, and in my new role as a medical historian, I am familiar with the mortality that has been caused by measles in this country. S Murch, in the Panorama programme, described how uncomfortable it is for a paediatrician to be associated with research that might affect vaccine uptake rates. I agree with this view. However, I have also been shocked to see the severity of autism in the children I used to see each week from 1995 to 2000 at the Royal Free, and I have listened to the views of the parents of these children.

I continue to support the MMR vaccine, as have all the Royal Free paediatricians in this research from the beginning. Three of my grandsons have received the MMR vaccination. Although I am very concerned about the current outbreak of measles, I am also concerned that further urgent research is needed to resolve the genuine concerns of parents who associate MMR with the onset of autism and to try to identify whether there are factors that may place a very small but important group of children at risk
of such a disorder.

I believe children have been badly served by the adversarial approach involved in the current legal action against manufacturers, and that adopted towards Andrew Wakefield and his work by some Department of Health officials. This attitude was typified by David Salisbury's mocking comments on Panorama, pouring scorn on Wakefield's work.

Am I too naive to ask all people of goodwill on both sides of this debate to speedily agree on an independent research agenda that will finally resolve this matter? Such an agenda must involve non-epidemiological research, focusing on the bowels of these children. It is self-evident that this whole question is going on far too long and is causing so much heart-ache in parents. Although the original observation has been extended and refined with additional evidence, resolution of this matter seems as far off as it did then. Studies reported lately provide evidence that measles virus might have a role. There is now a case to be answered. This study finding needs urgent confirmation and elaboration of its importance.

John Walker-Smith

Wellcome Trust Centre for History of Medicine at UCL, London NW1 1AD, UK (e-mail:johnwalker_smith@hotmail.com)

1 Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998; 351: 637-41. [Text]

2 Walker-Smith JA. Autism, inflammatory bowel disease, and MMR vaccine.  Lancet 1998; 351: 1356-57. [PubMed]

3 Wakefield AJ, Anthony A, Murch SH, et al. Enterocolitis in children with developmental disorders.  Am J Gastroenterol 2000; 95: 2285-95. [PubMed]

4 Furlano RI, Anthony A, Day R, et al. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr 2001; 138: 366-72. [PubMed]

5 Uhlmann V, Martin CM, Silva I, et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. http://mp.bmjjournals.com/cgi/content/full/ 54/6/DC1 (accessed on Feb 19, 2002).

6 Morris A, Aldulaimi D. New evidence for a viral pathogenic mechanism for new variant inflammatory bowel disease and developmental disorder? http://mp.bmjjournals.com/cgi/content/full/ 54/6/DC1 (accessed on Feb 19, 2002).