Volume 363, Number
9417 17 April 2004
MMR--responding to retraction
Sir--Almost 6 years have passed
since AJW disclosed in a letter published
in The Lancet1 that he was undertaking a
pilot study on behalf of the Legal Aid
Board (later to become the Legal Services
Commission), a study that sought to
examine the merits of parental claims of
an association between their children's
exposure to the measles, mumps, and
rubella (MMR) vaccine and subsequent
autistic regression and intestinal
symptoms. He wrote on May 2, 1998, 3
months after the original paper:
"Only one author (AJW) has agreed to
help evaluate a small number of these
children on behalf of the Legal Aid
Board."
There was no
attempt at any stage to conceal the fact
that the viral study was ongoing before
the publication of the paper in The
Lancet in 1998. Almost 6 years have
passed during which The Lancet and our
co-authors have had the opportunity to
seek further details and consider their
position with respect to perceived
conflicts of interest. We read the
absence of any comment as implying tacit
acknowledgment of lack of such conflict,
as stated by AJW at the time. The Lancet
requires that the funding source for a
study be declared; our report conformed
to this requirement since there was no
external funding for the work relevant to
this report. The Lancet disclosure policy
also required that the authors declare
anything that would embarrass an author
if it were to emerge after publication.
This is, of course, a subjective
definition and we can confirm that this
is not an issue which causes us
embarrassment; we are, however, dismayed
by the way in which events have been
misrepresented.
Conflict of
interest is created when involvement in
one project potentially could, or
actively does, interfere with the
objective and dispassionate assessment of
the processes or outcomes of another
project. We cannot accept that the
knowledge that affected children were
later to pursue litigation, following
their clinical referral and
investigation, influenced the content or
tone of the 1998 paper which was a
description of a possible new syndrome in
the classical mode. We emphasise that
this was not a scientific paper but a
clinical report. The laboratory support
funded by Legal Aid for a separate viral
detection study had no bearing on the
original paper.
No Legal Aid money
was used in the preparation of the 1998
paper, and the viral study could not then
and indeed, does not now, influence the
"objective and dispassionate
assessment" of the veracity of the
original paper, which we reiterate simply
reported a novel clinical syndrome. There
was no conflict of interest. When the
viral study is published, the Legal Aid
Board (now Legal Services Commission)
funding will be duly acknowledged.
Various claims were
made by agents of the Sunday Times of Feb
22, 2004, against those of us involved in
the Lancet 1998 report. These claims
included inappropriate patient referral,
inappropriate use of Legal Aid funding,
lack of ethics approval, unmerited
clinical investigation, and keeping
secret for 6 years the involvement of the
Legal Aid Board in a separate study. All
of these claims have been investigated
and we know they are unfounded and
vigorously deny them.
It is worth
reiterating that all of the first 12
children reported in the Lancet study
were referred to the Royal Free Hospital
exclusively for the investigation of
their intestinal symptoms at a time when
none was involved in Legal Aid
litigation. Their pathological findings
were interpreted and reported by
clinicians who could have had no
knowledge of any future legal claim. The
report itself was a description of the
history as reported to us, and the
relevant clinical findings. No claim of a
causal association with MMR was ever
made. The opinion on choice of single
vaccines pending scientific resolution of
any possible association, expressed by
AJW at the press briefing, was based not
on the findings in these children alone,
but on a detailed investigation of the
history of MMR vaccine and its safety.
AJW's opinion, then and now, has been
restated in Jefferson and colleagues'
subsequent 2003 Cochrane Review2--ie,
that "the design and reporting of
safety outcomes in MMR vaccine safety
studies, both pre- and post-marketing,
are largely inadequate", and
furthermore, that Jefferson and
colleagues "found limited evidence
of safety of MMR compared to its
single-component vaccines from low risk
of bias studies".
Nonetheless we
regret the furore and polarisation of
opinion that ensued from that press
briefing for which AJW bears some
responsibility. Richard Horton is
reported to have stated that he would not
have published the paper, had he known
about the MMR litigation. As reported,
this clearly has major implications for
the valid scientific investigation and
reporting of possible iatrogenic injury
in patients who may also be seeking legal
redress. It is notable that subsequent to
the aforementioned Legal Aid pilot study,
other university-based studies have been
funded by the Legal Services Commission,
and reported in the British Medical
Journal.3
On March 6, 2004,
some of our ex-colleagues issued a
"retraction of an
interpretation", not a retraction of
the factual content of the paper, as
widely inferred. Since no interpretation
of the possible MMR/autism link was
offered in the original 1998 Lancet
report, other than to state that the data
did not constitute evidence of an
association and suggest that further
research was required, it is difficult to
know quite what has been retracted,
particularly in light of Richard Horton's
current plea for further research funding
for autism, a plea that we welcome
wholeheartedly.
Let us be clear
that parents reported gastrointestinal
symptoms in their children that many
medical professionals denied and refused
to investigate. Some parents were
referred to social services and false
claims of Munchausen's syndrome by proxy
were levied. The parents were right;
their children have an inflammatory
intestinal disease.
The medical
profession was wrong, in some cases
shamefully so. In light of this lesson it
is imperative that rather than relying on
endless reviews of epidemiological data
which fail to even address the original
hypothesis,4 parental claims should be
taken seriously and their children should
be investigated on an individual basis.
More than 6 years
on, the original Lancet report should be
viewed in the context of the emerging
laboratory and clinical evidence of
intestinal pathology,5-10 measles virus
persistence in diseased tissues,11,12 and
abnormal measles immunity13-15 in this
specific subset of children with autistic
spectrum disorder. It would be
inappropriate to interpret the events of
the past month as exonerating MMR vaccine
as a possible cause of autism.
Andrew J
Wakefield (AJW), *Peter Harvey, John
Linnell
c/o 134 Harley Street, London W1G 7JY, UK
1 Wakefield AJ.
Autism, inflammatory bowel disease, and
MMR vaccine. Lancet 1998; 351: 1356-1356.
[PubMed]
2 Jefferson T, Price D, Demicheli V, et
al. Unintended events following
immunization with MMR: a systematic
review. Vaccine 2003; 21: 3954-60.
[PubMed]
3 Paul A, Cunningham J, Dhanesha U,
Ballard M, Thompson J, Marsh J.
Disturbance of cerebral function in
people exposed to drinking water
contaminated with aluminium sulphate:
retrospective study of the Camelford
water incident. BMJ 1999; 319: 807-11.
[PubMed]
4 Wakefield AJ, Montgomery SM. Autism,
viral infection and measles-mumps-rubella
vaccination. Isr Med Assoc J 1999; 1:
183-87. [PubMed]
5 Wakefield AJ, Anthony A, Murch SH, et
al. Enterocolitis in children with
developmental disorders. Am J
Gastroenterol 2000; 95: 2285-95. [PubMed]
6 Horvath K, Papadimitriou JC, Rabsztyn
A, Drachenberg C, Tildon JT.
Gastrointestinal abnormalities in
children with autistic disorder. J
Pediatrics 1999; 135: 559-63. [PubMed]
7 Furlano R, Anthony A, Day R, et al.
Quantitative immunohistochemistry shows
colonic epithelial pathology and -T cell
infiltration in autistic enterocolitis. J
Pediatrics 2001; 138: 366-72. [PubMed]
8 Torrente F, Machado N, Ashwood P, et
al. Enteropathy with T cell infiltration
and epithelial IgG deposition in autism.
Mol Psych 2002; 7: 375-82. [PubMed]
9 Horvath K, Perman A. Autistic disorder
and gastrointestinal disease. Curr Opin
Pediatr 2002; 14: 583-87. [PubMed]
10 Ashwood P, Murch SH, Anthony A, et al.
Intestinal lymphocyte populations in
children with regressive autism: evidence
for extensive mucosal immunopathology. J
Clin Immunol 2003; 23: 504-17. [PubMed]
11 Uhlmann V, Martin CM, Shiels O, et al.
Potential viral pathogenic mechanism for
new variant inflammatory bowel disease.
Mol Pathol 2002; 55: 84-90. [PubMed]
12 Sheils O, Smyth P, Martin C, O'Leary
JJ. Development of an 'allelic
discrimination' type assay to
differentiate between the strain origins
of measles virus detected in intestinal
tissue of children with ileocolonic
lymphonodular hyperplasia and concomitant
developmental disorder. J Pathol 2002;
198 (suppl): 5A.
13 Singh VK, Lin SX, Yang VC. Serological
association of measles virus and human
herpesvirus-6 with brain autoantibodies
in autism. Clin Immunol Immunopathol
1998; 89: 105-08. [PubMed]
14 Singh VK, Lin SX, Newell E., Nelson C.
Abnormal measles-mumps-rubella antibodies
and CNS autoimmunity in children with
autism. J Biomed Sci 2002; 9: 359-64.
[PubMed]
15 Singh VK, Jensen RL. Elevated levels
of measles antibodies in children with
autism. Pediatr Neurol 2003; 28: 292-94.
[PubMed]
Editor's
reply
We do not accept
Andrew Wakefield and colleagues'
interpretation of the letter published in
The Lancet on May 2, 1998,1 which was, in
any event, only published 3 months after
the original 1998 Lancet paper. This
letter was written in response to a
letter from Dr A Rouse,2 published in the
same issue. Dr Rouse's letter raised
concerns about whether children
investigated in the 1998 paper had been
referred to the authors by the Society
for the Autistically Handicapped, and
simply mentioned that his concerns arose
out of a fact sheet produced by a firm of
solicitors.
Although the letter
made it clear that Dr Wakefield "has
agreed to help evaluate" some
children for the Legal Aid Board, it does
not indicate that in fact such work had
been commissioned and was being
undertaken well before the 1998 paper was
published. In the light of this, the
natural and ordinary meaning to be drawn
from Dr Wakefield's letter at the time
was that following the publication of the
1998 paper he had agreed to complete
evaluations of children reported in the
1998 paper for the Legal Aid Board. We
understood the letter to mean that,
although Dr Wakefield agreed to undertake
an evaluation for the Legal Aid Board,
the evaluation had not taken place before
the 1998 paper's publication.
In the light of
this, and Dr Wakefield's express
statement that no conflict of interest
existed, we had no reason to investigate
the position further, until the editors
were notified for the first time that Dr
Wakefield's relationship with the Legal
Aid Board predated the publication of the
1998 paper by some considerable time.
Richard
Horton
The Lancet, 32
Jamestown Road, London NW1 7BY, UK
1 Wakefield AJ. Autism, inflammatory
bowel disease, and MMR vaccine. Lancet
1998; 351: 1356-1356. [PubMed]
2 Rouse A. Autism, inflammatory bowel
disease, and MMR vaccine. Lancet 1998;
351: 1356-1356. [PubMed]