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]