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Measles vaccination as a risk factor for inflammatory bowel disease
Letters to the Editor
Measles vaccination as a risk factor for inflammatory bowel disease
3
4
and colleagues (April 29, p 1071) report an association between measles vaccination and Crohn’s disease and ulcerative colitis, though they do not claim to have established a causal link. However, their study is flawed because of biases from differential loss to follow-up and case ascertainment in the vaccinated and unvaccinated cohorts. The vaccinated cohort included recipients of live measles vaccine in the 1964 measles vaccine trial who were followed by means of an annual postal questionnaire. The 3545 responders to the questionnaire about gastrointestinal disease represent only 26% of the 13 433 originally allocated to receive live vaccine, and 45% of the 7889 available for long-term follow-up.’ By contrast, the unvaccinated cohort included 11 407 of the 13 444 individuals actively traced in 1991 as part of the National Child Development Study, which originally recruited 17 414 individuals born in 1958. The unvaccinated group therefore includes 66% of the original cohort and 85% of those traced. The very different methods and rates of follow-up in the two cohorts are likely to introduce substantial bias, since disease rates cannot be assumed to be identical in responders and individuals lost to follow-up. However, in their assessment of response rates, Thompson and colleagues play down the large cumulative losses in the vaccinated group from lack of response to the annual questionnaires. Furthermore, their suggestion that ascertainment bias is not important because no significant difference was shown in the rates of coeliac disease is invalid, in view of the low power for this comparison. Indeed, the focus on gastrointestinal disease in the questionnaire to vaccinated individuals contrasts with the open-ended inquiry about chronic illness in the unvaccinated group, and is likely to result in differential ascertainment. Ulcerative colitis rates have slightly declined in the UK since measles vaccination was introduced in 1968, whereas rates of Crohn’s disease have increased.2 A large case-control study failed to find a link between ulcerative colitis or Crohn’s and measles vaccination.3 The rise of Crohn’s disease in the UK predates the introduction of mass vaccination against measles.4 The virological evidence linking Crohn’s disease with measles has been challenged.5 We conclude that methodological bias is the most likely explanation for the associations found by Thompson and
SiR-Thompson
colleagues. Paddy Farrington, *Elizabeth Miller Statistics Unit, Public Health Laboratory Service; and *Immunisation Division, Communicable Disease Surveillance Centre, London NW9 5EQ, UK
1
2
Measles Vaccine Committee. Vaccination against measles: clinical trial of live measles vaccine given alone and live vaccine preceded by killed vaccine. Second report to the Medical Research Council. BMJ 1968; i: 449-52. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983: marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut 1989; 30: 618-22.
1362
5
Gilat T, Hacohen D, Lilos P, Langman MJS. Childhood factors in ulcerative colitis and Crohn’s disease: an international co-operative study. Scand J Gastroenterol 1987; 22: 1009-24. Hermon-Taylor J, Ford J, Sumar N, Millar D, Doran T, Tizard M. Measles virus and Crohn’s disease. Lancet 1995; 345: 922-23. Iizuka M, Nakagomi O, Chiba M, Ueda S, Masamune O. Absence of measles virus in Crohn’s disease. Lancet 1995; 345: 199.
SiR-Since the highly effective measles rubella immunisation campaign of November, 1994, the transmission of measles virus in this country seems to have been interrupted: the last confirmed case indigenously acquired of measles had onset on Feb 24, 1995. Thompson and colleagues postulate a link between measles immunisation and inflammatory bowel disease (IBD). Before the campaign was launched, Wakefield (one of the authors of the report) alerted me to the anticipated outcome of his group’s study, which gave me the opportunity to seek advice from national and international experts on measles and IBD. Subsequently, my department organised a meeting of independent experts to hear about Wakefield’s work and about work that linked Crohn’s disease with other infectious agents. In view of the epidemiological and virological uncertainties, and after advice from a range of experts, I concluded that there was no indication to recommend changes in existing national immunisation policy and practice. In their April 29 commentary, Patriarca and Beeler draw attention to the epidemiological weaknesses and lack of biological plausibility in Thompson and co-workers’ report of the suggested association between measles immunisation and IBD. With the use of PCR with primers shown to be both sensitive and specific for the measles virus genome, Iizuka and co-workers (Jan 21, p 199) could not show evidence of measles viruses in small intestinal tissues from patients with Crohn’s disease, or those with ulcerative colitis, or from controls. Hermon-Taylor et al (April 8, p 922) have presented data from England, Wales, and Scotland suggesting that the reported rise in Crohn’s disease clearly antedated the introduction of measles immunisation. It would be most unfortunate if the publication of this controversial work led to public anxiety over the safety of measles vaccine. There is no dispute that measles immunisation prevents an enormous burden of morbidity and worldwide, measles is one of the foremost causes of death of young children. K C Calman Chief Medical Officer, Department of Health, Richmond House, London SW1A 2NS, UK
SiR-Patriarca and Beeler’s commentary and other discussion seem to accept that persistence of measles virus in the gut in IBD has been convincingly demonstrated. In fact no virus has been reported to be isolated from such tissues, and attempts to detect viral sequences by PCR under conditions in which contamination can be ruled out (see Iizuka and colleagues, Jan 21, p 199 and March 11, p 660; Wakefield and Pounder, March 11, p 660) have failed to reveal measles-specific nucleic acid. The evidence for the presence of persistent measles virus in IBD is partly derived
electronmicroscopy’ in which certain morphological thought to be measles related, on the basis of morphological features. However, diagnosis based on morphology alone can and has been misleading, and the structures presented closely resemble normal cellular elements including cellular fibrils, glancing sections of nuclei
from
structures were
and normal inclusion bodies in natural killer cells. Further from in-situ derives evidence hybridisation,’ and immunohistochemistry,’ immunogold staining,2 which are all subject to problems of specificity, even in the most careful hands when used at high sensitivity. Other recent studies3,4 have demonstrated the presence of antigens from listeria, Escherichia coli, and streptococcus in Crohn’s lesions, while specifically failing to detect measles and a range of other antigens. Until measles-virus-specific nucleic acid can be positively identified by sequence determination the presence of the virus should be regarded as unproven.
Philip D Minor Division of Virology, National Institute for Biological Standards and Controls, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK
1 Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn’s disease. J Med Virol 1993; 39: 345-53. 2 Lewin J, Dhillon AP, Sim R, et al. Persistent measles virus infection of the intestine: confirmation by immunogold electron microscopy. Gut 1995; 36: 564-69. 3 Liu Y, van Kruiningen HJ, West AB, et al. Immunocytochemical evidence of Listeria, Escherichia coli and Streptococcus antigens in Crohn’s disease. Gastroenterology 1995; 108: 1396-404. 4 Brown WR. Listeria: the latest putative pathogenic microorganism in Crohn’s disease. Gastroenterology 1995; 108: 1589-90.
and colleagues had previously suggested disease was caused by multifocal infarction secondary to granulomatous gastrointestinal vasculitis. 1,2 Controls such as intestinal tuberculosis or granulomatous ileitis secondary to neutrophil dysfunction were not studied. Searching for an agent that would cause vasculitis, the same group then produced evidence that measles virus was present in granulomas and vascular endothelium in most Crohn’s patients but in only a few ulcerative colitis and control patients.3 Controls such as those with sarcoidosis were not studied, although two patients with intestinal tuberculosis, details unspecified, were given limited examination and proved negative. On the basis of these data, they speculated that there was a possible role for measles in the pathogenesis of Crohn’s disease, but, implicitly, not of ulcerative colitis, since this served as the inflammatory control for the viral identification studies.3 This conclusion was supported by studies showing that perinatal measles infection was a slight risk factor for Crohn’s disease, but not ulcerative colitis.4 In the meantime the same group published data of an association between herpesvirus 6 and/or cytomegalovirus or Epstein-Barr virus and ulcerative colitis.s Substantiation of the notion that Crohn’s disease is associated with measles3 would require the rejection of the null hypothesis that there is no difference between the frequency of Crohn’s disease and ulcerative colitis in measles vaccinated individuals. Thompson and colleagues’ fails to reject this null hypothesis since epidemiological study there is no difference in the frequency of Crohn’s disease and ulcerative colitis in measles vaccinees. Thus the findings of the original study3 suggesting an involvement of measles virus in the pathogenesis of Crohn’s disease (which used ulcerative colitis as the principal control group) are not supported by these data. The relative risk of measles vaccinees developing inflammatory bowel disease compared with unvaccinated individuals (relative risk 2-5-3-0) should
SIR—Thompson
that
Crohn’s
be
seen
subjects 5-0).
in perspective: Crohn’s disease is more whose first house had a hot water tap
common
in
(odds ratio
Thomas T MacDonald Department of Paediatric Gastroenterology, Medical College of St Bartholomews Hospital, London EC1A 7BE, UK
Wakefield AJ, Sawyer AM, Dhillon AP, et al. Pathogenesis of Crohn’s disease: multifocal gastrointestinal infarction. Lancet 1989; 334: 57-62. 2 Wakefield AJ, Sankey EA, Dhillon AP, et al. Granulomatous vasculitis in Crohn’s disease. Gastroenterology 1991; 100: 1279-87. 3 Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn’s disease. J Med Virol 1993; 39: 345-53. 4 Ekbom A, Wakefield AJ, Zack M, Adami HO. Perinatal measles infection and subsequent Crohn’s disease. Lancet 1994; 344: 508-10. 5 Wakefield AJ, Fox JD, Sawyer AM, et al. Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn’s disease using the nested polymerase chain reaction. J Med Virol 1992; 38: 183-90. 1
SIR-The
by Patriarca and Beeler that and colleagues’ report, directs attention to several cogent questions about the adequacy of the epidemiological methods used and their consequences for the validity of the conclusions drawn. Of particular concern is the possibility that differences in the methods commentary
accompanied Thompson
used to ascertain histories of IBD in the measles vaccinated group compared with controls might have led to a biased underestimation of the prevalence of IBD in the National Child Development Study (NCDS) control group. This possibility is underlined by comparison of findings from NCDS-4 and NCDS-5 in which Thompson and co-workers found evidence that life-long prevalence rates of peptic ulcer derived from histories given by subjects in the NCDS were unreliable. We do not accept Thompson’s suggestion that a diagnosis of IBD is necessarily more rigorous, nor do we believe that subjects’ recall and reporting of IBD is likely to be any more reliable than for peptic ulcer. Thus, could a comparison similar to that made for histories of peptic ulcer be used to test the reliability or otherwise of a history of IBD in the NCDS group? We would be interested to see an analysis of the frequencies of IBD histories given by the same individuals in NCDS-4 and NCDS-5. *David Miller, Adrian Renton Academic Department of Public Health, St London W2 1PG, UK
Mary’s Hospital Medical School,
SIR—In their commentary, Patriarca and Beeler raise several questions about the epidemiological methods that Thompson and colleagues use which limit the inferences that can be drawn from the findings. We believe that, in addition to these methodological issues, the study design used to test the measles/inflammatory bowel syndrome hypothesis was inappropriate. Crohn’s disease and ulcerative colitis are rare conditions. In studies that aim to explore the aetiology of such conditions, by searching for differences in previous exposure of cases and controls to a range of suspected agents or factors, a case-control study method is 1
preferred.’ The hypothesis linking measles virus and inflammatory bowel syndrome is biologically plausible and needs further exploration. In the interests of the broader public health, such investigations should be scientifically rigorous and be designed to answer the question raised. *Tony Baxter, John Radford Department of Public Health, Doncaster Health, White Rose House, Doncaster DN4 5DJ, UK
1
Altman DG. Practical statistics for medical research. London: Chapman and Hall, 1991.
1363
Authors’reply SIR-For the past 7 years our objective has been to identify the factors that result in the development of IBD. Our working hypothesis is that, in genetically susceptible individuals, persistent measles virus infection is associated with a mesenteric granulomatous vasculitis that presents as Crohn’s disease.’ Other factors must also be involved. Hermon-Taylor and colleagues (April 8, p 922) superimposed two sets of independent data to "exclude both wild-type measles virus and the vaccine strain as primary causative agents in Crohn’s disease". This simplistic epidemiological approach is flawed, because it fails to understand the nature of persistent viral infection. Exposure to measles virus in early life seems to increase the risk of later developing Crohn’s disease.2Until the 1920s many young British children died from acute measles infection, but the death rate then fell strikingly probably because of improving social conditions such as hot water in the home. Crohn’s disease appeared with increasing frequency after the 1930s. We postulate that these patients are some of the surviving infants of earlier measles epidemics, and that they continue to be infected with wild measles virus. Does measles vaccination protect against Crohn’s disease? Protection seemed unlikely even before we undertook the study, since we knew that some British children with Crohn’s disease had received live measles vaccine. We reported the measles vaccination study for discussion by the scientific community, not only with many qualifications about its epidemiological aspects but also with great care not to excite media over-reaction. Indeed, we were commended by the UK Department of Health for our responsible attitude. Our data record a prevalence of IBD in 31-year-old vaccinees of 1 in 140. We realised that the measles vaccination programme is of great importance to the community and the public health of the nation, but it would have been unethical to suppress this result because its preliminary conclusions were uncomfortable or inconvenient. Even if all the lost subjects for the vaccine trial are healthy, 1 in 316 of this sample of 7889 Britons aged 31 years would have IBD. Surely this should not be overlooked? A case-control study would be helpful, but the patients in the cited study were of an age that few would have been vaccinated. Such a study would have to address recall bias if retrospective data were used. A detailed investigation of IBD patients born around the time of introduction of measles vaccination might clarify the situation. Measles vaccination was introduced in Britain in 1968 with an initial uptake above 50%, but there will be social differences between vaccinated and unvaccinated patients that would also introduce bias. We agree with Minor that independent fullyreported studies are needed to examine whether measles virus (wild-strain or vaccine-strain) can be detected in tissues from IBD patients. At the moment the reports are equal-one confirmation3 and one rebutta1.4 MacDonald summarises some of our papers, noting that hitherto we have not implicated measles virus in the pathogenesis of ulcerative colitis. We have maintained scientific integrity, publishing results that both support (March 18, p 688) and opposes the working hypothesis. Work continues, others will investigate the hypothesis, and in due course it will be known whether measles virus is an epiphenomenon of limited relevance or an element in the development of IBD. Between 1988 and 1992, 1882 patients died from IBD in England and Wales. We believe that the Department of Health should be supporting research into ulcerative colitis and Crohn’s disease. N P Thompson, S M Montgomery, *R E Pounder, A J Wakefield, Inflammatory Bowel Disease Study Group, *Royal Free Hospital School of Medicine, London NW3 2PF, UK; and Social Statistics Research Unit, City University, London
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1
2 3
4
5
Wakefield AJ, Ekbom A, Dhillon AP, Pittilo RM, Pounder RE. Crohn’s disease: pathogenesis and persistent measles virus infection. Gastroenterology 1995; 108: 911-16. Ekbom A, Wakefield AJ, Zack M, Adami HO. Perinatal measles infection and subsequent Crohn’s disease. Lancet 1994; 344: 508-10. Miyamoto H, Tanaka T, Kitamoto N, Fukuda Y, Shimoyama T. Detection of immunoreactive antigen, with a monoclonal antibody to measles virus, in tissue from a patient with Crohn’s disease. J Gastroenterol 1995; 30: 28-33. Liu Y, van Kruiningen HJ, West AB, et al. Immunocytochemical evidence of Listeria, Escherichia coli and Streptococcus antigens in Crohn’s disease. Gastroenterology 1995; 108: 1396-404. Thompson NP, Pounder RE, Wakefield AJ. Perinatal and childhood risk factors for inflammatory bowel disease: a case-control study. Eur J Gastroenterol Hepatol 1995; 7: 385-90.
Intraoperative cerebral infarction after desmopressin administration in infant with end-stage renal disease is considered to be a safe drug there have been reports of cerebral and myocardial infarction after its use in adults.’-3 We report a case of intraoperative cerebral infarction associated with the use of desmopressin in an infant. A 7-month-old girl with chronic renal failure associated with congenital nephrotic syndrome and bilateral Wilms’ tumour (Denys Drash syndrome) was admitted for bilateral nephrectomy and left internal jugular vein and peritoneal dialysis catheter placement. She was maintained preoperatively on peritoneal dialysis and her hypertension was treated with captopril and propranolol. Her generalised tonic-clonic seizure disorder was well controlled with
SiR-Although desmopressin
phenobarbitone. Preoperative albumin, haemoglobin, partial thromboplastin time, prothrombine time, and platelet count were normal. She was dialysed the day before surgery and received intravenous crystaloids. She gained little in weight in the preoperative period. Bleeding time was 675 s (normal 174-560). Desmopressin acetate 0-3 g/kg (2 flg total) was given intravenously over 15 min at the start of the operation. The operation itself was uneventful with normal blood pressure and arterial oxygen saturation throughout. Central pressures were 9-11 cm water. The estimated blood loss was 100 mL and the infant was given 160 mL packed red cells to bring her haemoglobin to 11-6g/dL. At the end of the operation a pronounced asymmetry in limb movement was noted: the left extremities were immediately strong and moved vigorously, whereas the right leg was initially immobile, then slowly recovered some spontaneous movement. A right ptosis was also noted. The right arm remained flaccid. Respiratory efforts and gag reflexes were adequate and extubation was uneventful. On the first postoperative day magnetic resonance imaging revealed an area of ischaemia/infarction in the superolateral aspect of the left frontal lobe with a second focus of infarction posteriorly near the motor strip. An echocardiogram was normal, with no evidence of right to left shunting. The right ptosis and leg weakness resolved completely after a few hours and the right arm regained some voluntary activity over the ensuing week when physiotherapy was started. The mechanism leading to the vascular injury in this infant is obscure. Volume depletion, either due to peritoneal dialysis or vascular compartment contraction associated with hypoalbuminaemia, may have been a predisposing factor but the adequate volume status preoperatively and the normal range of haemodynamic indices during surgery makes this mechanism unlikely. Desmopressin increases the circulating levels of factor VIII procoagulant, von Willebrand factor, and tissue plasminogen activator activity. Arterial atherosclerosis has been postulated as contributing to the development of cerebral thrombosis in elderly patients, by venous
Measles vaccination as a risk factor for inflammatory bowel disease
3
4
and colleagues (April 29, p 1071) report an association between measles vaccination and Crohn’s disease and ulcerative colitis, though they do not claim to have established a causal link. However, their study is flawed because of biases from differential loss to follow-up and case ascertainment in the vaccinated and unvaccinated cohorts. The vaccinated cohort included recipients of live measles vaccine in the 1964 measles vaccine trial who were followed by means of an annual postal questionnaire. The 3545 responders to the questionnaire about gastrointestinal disease represent only 26% of the 13 433 originally allocated to receive live vaccine, and 45% of the 7889 available for long-term follow-up.’ By contrast, the unvaccinated cohort included 11 407 of the 13 444 individuals actively traced in 1991 as part of the National Child Development Study, which originally recruited 17 414 individuals born in 1958. The unvaccinated group therefore includes 66% of the original cohort and 85% of those traced. The very different methods and rates of follow-up in the two cohorts are likely to introduce substantial bias, since disease rates cannot be assumed to be identical in responders and individuals lost to follow-up. However, in their assessment of response rates, Thompson and colleagues play down the large cumulative losses in the vaccinated group from lack of response to the annual questionnaires. Furthermore, their suggestion that ascertainment bias is not important because no significant difference was shown in the rates of coeliac disease is invalid, in view of the low power for this comparison. Indeed, the focus on gastrointestinal disease in the questionnaire to vaccinated individuals contrasts with the open-ended inquiry about chronic illness in the unvaccinated group, and is likely to result in differential ascertainment. Ulcerative colitis rates have slightly declined in the UK since measles vaccination was introduced in 1968, whereas rates of Crohn’s disease have increased.2 A large case-control study failed to find a link between ulcerative colitis or Crohn’s and measles vaccination.3 The rise of Crohn’s disease in the UK predates the introduction of mass vaccination against measles.4 The virological evidence linking Crohn’s disease with measles has been challenged.5 We conclude that methodological bias is the most likely explanation for the associations found by Thompson and
SiR-Thompson
colleagues. Paddy Farrington, *Elizabeth Miller Statistics Unit, Public Health Laboratory Service; and *Immunisation Division, Communicable Disease Surveillance Centre, London NW9 5EQ, UK
1
2
Measles Vaccine Committee. Vaccination against measles: clinical trial of live measles vaccine given alone and live vaccine preceded by killed vaccine. Second report to the Medical Research Council. BMJ 1968; i: 449-52. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983: marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut 1989; 30: 618-22.
1362
5
Gilat T, Hacohen D, Lilos P, Langman MJS. Childhood factors in ulcerative colitis and Crohn’s disease: an international co-operative study. Scand J Gastroenterol 1987; 22: 1009-24. Hermon-Taylor J, Ford J, Sumar N, Millar D, Doran T, Tizard M. Measles virus and Crohn’s disease. Lancet 1995; 345: 922-23. Iizuka M, Nakagomi O, Chiba M, Ueda S, Masamune O. Absence of measles virus in Crohn’s disease. Lancet 1995; 345: 199.
SiR-Since the highly effective measles rubella immunisation campaign of November, 1994, the transmission of measles virus in this country seems to have been interrupted: the last confirmed case indigenously acquired of measles had onset on Feb 24, 1995. Thompson and colleagues postulate a link between measles immunisation and inflammatory bowel disease (IBD). Before the campaign was launched, Wakefield (one of the authors of the report) alerted me to the anticipated outcome of his group’s study, which gave me the opportunity to seek advice from national and international experts on measles and IBD. Subsequently, my department organised a meeting of independent experts to hear about Wakefield’s work and about work that linked Crohn’s disease with other infectious agents. In view of the epidemiological and virological uncertainties, and after advice from a range of experts, I concluded that there was no indication to recommend changes in existing national immunisation policy and practice. In their April 29 commentary, Patriarca and Beeler draw attention to the epidemiological weaknesses and lack of biological plausibility in Thompson and co-workers’ report of the suggested association between measles immunisation and IBD. With the use of PCR with primers shown to be both sensitive and specific for the measles virus genome, Iizuka and co-workers (Jan 21, p 199) could not show evidence of measles viruses in small intestinal tissues from patients with Crohn’s disease, or those with ulcerative colitis, or from controls. Hermon-Taylor et al (April 8, p 922) have presented data from England, Wales, and Scotland suggesting that the reported rise in Crohn’s disease clearly antedated the introduction of measles immunisation. It would be most unfortunate if the publication of this controversial work led to public anxiety over the safety of measles vaccine. There is no dispute that measles immunisation prevents an enormous burden of morbidity and worldwide, measles is one of the foremost causes of death of young children. K C Calman Chief Medical Officer, Department of Health, Richmond House, London SW1A 2NS, UK
SiR-Patriarca and Beeler’s commentary and other discussion seem to accept that persistence of measles virus in the gut in IBD has been convincingly demonstrated. In fact no virus has been reported to be isolated from such tissues, and attempts to detect viral sequences by PCR under conditions in which contamination can be ruled out (see Iizuka and colleagues, Jan 21, p 199 and March 11, p 660; Wakefield and Pounder, March 11, p 660) have failed to reveal measles-specific nucleic acid. The evidence for the presence of persistent measles virus in IBD is partly derived
electronmicroscopy’ in which certain morphological thought to be measles related, on the basis of morphological features. However, diagnosis based on morphology alone can and has been misleading, and the structures presented closely resemble normal cellular elements including cellular fibrils, glancing sections of nuclei
from
structures were
and normal inclusion bodies in natural killer cells. Further from in-situ derives evidence hybridisation,’ and immunohistochemistry,’ immunogold staining,2 which are all subject to problems of specificity, even in the most careful hands when used at high sensitivity. Other recent studies3,4 have demonstrated the presence of antigens from listeria, Escherichia coli, and streptococcus in Crohn’s lesions, while specifically failing to detect measles and a range of other antigens. Until measles-virus-specific nucleic acid can be positively identified by sequence determination the presence of the virus should be regarded as unproven.
Philip D Minor Division of Virology, National Institute for Biological Standards and Controls, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK
1 Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn’s disease. J Med Virol 1993; 39: 345-53. 2 Lewin J, Dhillon AP, Sim R, et al. Persistent measles virus infection of the intestine: confirmation by immunogold electron microscopy. Gut 1995; 36: 564-69. 3 Liu Y, van Kruiningen HJ, West AB, et al. Immunocytochemical evidence of Listeria, Escherichia coli and Streptococcus antigens in Crohn’s disease. Gastroenterology 1995; 108: 1396-404. 4 Brown WR. Listeria: the latest putative pathogenic microorganism in Crohn’s disease. Gastroenterology 1995; 108: 1589-90.
and colleagues had previously suggested disease was caused by multifocal infarction secondary to granulomatous gastrointestinal vasculitis. 1,2 Controls such as intestinal tuberculosis or granulomatous ileitis secondary to neutrophil dysfunction were not studied. Searching for an agent that would cause vasculitis, the same group then produced evidence that measles virus was present in granulomas and vascular endothelium in most Crohn’s patients but in only a few ulcerative colitis and control patients.3 Controls such as those with sarcoidosis were not studied, although two patients with intestinal tuberculosis, details unspecified, were given limited examination and proved negative. On the basis of these data, they speculated that there was a possible role for measles in the pathogenesis of Crohn’s disease, but, implicitly, not of ulcerative colitis, since this served as the inflammatory control for the viral identification studies.3 This conclusion was supported by studies showing that perinatal measles infection was a slight risk factor for Crohn’s disease, but not ulcerative colitis.4 In the meantime the same group published data of an association between herpesvirus 6 and/or cytomegalovirus or Epstein-Barr virus and ulcerative colitis.s Substantiation of the notion that Crohn’s disease is associated with measles3 would require the rejection of the null hypothesis that there is no difference between the frequency of Crohn’s disease and ulcerative colitis in measles vaccinated individuals. Thompson and colleagues’ fails to reject this null hypothesis since epidemiological study there is no difference in the frequency of Crohn’s disease and ulcerative colitis in measles vaccinees. Thus the findings of the original study3 suggesting an involvement of measles virus in the pathogenesis of Crohn’s disease (which used ulcerative colitis as the principal control group) are not supported by these data. The relative risk of measles vaccinees developing inflammatory bowel disease compared with unvaccinated individuals (relative risk 2-5-3-0) should
SIR—Thompson
that
Crohn’s
be
seen
subjects 5-0).
in perspective: Crohn’s disease is more whose first house had a hot water tap
common
in
(odds ratio
Thomas T MacDonald Department of Paediatric Gastroenterology, Medical College of St Bartholomews Hospital, London EC1A 7BE, UK
Wakefield AJ, Sawyer AM, Dhillon AP, et al. Pathogenesis of Crohn’s disease: multifocal gastrointestinal infarction. Lancet 1989; 334: 57-62. 2 Wakefield AJ, Sankey EA, Dhillon AP, et al. Granulomatous vasculitis in Crohn’s disease. Gastroenterology 1991; 100: 1279-87. 3 Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn’s disease. J Med Virol 1993; 39: 345-53. 4 Ekbom A, Wakefield AJ, Zack M, Adami HO. Perinatal measles infection and subsequent Crohn’s disease. Lancet 1994; 344: 508-10. 5 Wakefield AJ, Fox JD, Sawyer AM, et al. Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn’s disease using the nested polymerase chain reaction. J Med Virol 1992; 38: 183-90. 1
SIR-The
by Patriarca and Beeler that and colleagues’ report, directs attention to several cogent questions about the adequacy of the epidemiological methods used and their consequences for the validity of the conclusions drawn. Of particular concern is the possibility that differences in the methods commentary
accompanied Thompson
used to ascertain histories of IBD in the measles vaccinated group compared with controls might have led to a biased underestimation of the prevalence of IBD in the National Child Development Study (NCDS) control group. This possibility is underlined by comparison of findings from NCDS-4 and NCDS-5 in which Thompson and co-workers found evidence that life-long prevalence rates of peptic ulcer derived from histories given by subjects in the NCDS were unreliable. We do not accept Thompson’s suggestion that a diagnosis of IBD is necessarily more rigorous, nor do we believe that subjects’ recall and reporting of IBD is likely to be any more reliable than for peptic ulcer. Thus, could a comparison similar to that made for histories of peptic ulcer be used to test the reliability or otherwise of a history of IBD in the NCDS group? We would be interested to see an analysis of the frequencies of IBD histories given by the same individuals in NCDS-4 and NCDS-5. *David Miller, Adrian Renton Academic Department of Public Health, St London W2 1PG, UK
Mary’s Hospital Medical School,
SIR—In their commentary, Patriarca and Beeler raise several questions about the epidemiological methods that Thompson and colleagues use which limit the inferences that can be drawn from the findings. We believe that, in addition to these methodological issues, the study design used to test the measles/inflammatory bowel syndrome hypothesis was inappropriate. Crohn’s disease and ulcerative colitis are rare conditions. In studies that aim to explore the aetiology of such conditions, by searching for differences in previous exposure of cases and controls to a range of suspected agents or factors, a case-control study method is 1
preferred.’ The hypothesis linking measles virus and inflammatory bowel syndrome is biologically plausible and needs further exploration. In the interests of the broader public health, such investigations should be scientifically rigorous and be designed to answer the question raised. *Tony Baxter, John Radford Department of Public Health, Doncaster Health, White Rose House, Doncaster DN4 5DJ, UK
1
Altman DG. Practical statistics for medical research. London: Chapman and Hall, 1991.
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Authors’reply SIR-For the past 7 years our objective has been to identify the factors that result in the development of IBD. Our working hypothesis is that, in genetically susceptible individuals, persistent measles virus infection is associated with a mesenteric granulomatous vasculitis that presents as Crohn’s disease.’ Other factors must also be involved. Hermon-Taylor and colleagues (April 8, p 922) superimposed two sets of independent data to "exclude both wild-type measles virus and the vaccine strain as primary causative agents in Crohn’s disease". This simplistic epidemiological approach is flawed, because it fails to understand the nature of persistent viral infection. Exposure to measles virus in early life seems to increase the risk of later developing Crohn’s disease.2Until the 1920s many young British children died from acute measles infection, but the death rate then fell strikingly probably because of improving social conditions such as hot water in the home. Crohn’s disease appeared with increasing frequency after the 1930s. We postulate that these patients are some of the surviving infants of earlier measles epidemics, and that they continue to be infected with wild measles virus. Does measles vaccination protect against Crohn’s disease? Protection seemed unlikely even before we undertook the study, since we knew that some British children with Crohn’s disease had received live measles vaccine. We reported the measles vaccination study for discussion by the scientific community, not only with many qualifications about its epidemiological aspects but also with great care not to excite media over-reaction. Indeed, we were commended by the UK Department of Health for our responsible attitude. Our data record a prevalence of IBD in 31-year-old vaccinees of 1 in 140. We realised that the measles vaccination programme is of great importance to the community and the public health of the nation, but it would have been unethical to suppress this result because its preliminary conclusions were uncomfortable or inconvenient. Even if all the lost subjects for the vaccine trial are healthy, 1 in 316 of this sample of 7889 Britons aged 31 years would have IBD. Surely this should not be overlooked? A case-control study would be helpful, but the patients in the cited study were of an age that few would have been vaccinated. Such a study would have to address recall bias if retrospective data were used. A detailed investigation of IBD patients born around the time of introduction of measles vaccination might clarify the situation. Measles vaccination was introduced in Britain in 1968 with an initial uptake above 50%, but there will be social differences between vaccinated and unvaccinated patients that would also introduce bias. We agree with Minor that independent fullyreported studies are needed to examine whether measles virus (wild-strain or vaccine-strain) can be detected in tissues from IBD patients. At the moment the reports are equal-one confirmation3 and one rebutta1.4 MacDonald summarises some of our papers, noting that hitherto we have not implicated measles virus in the pathogenesis of ulcerative colitis. We have maintained scientific integrity, publishing results that both support (March 18, p 688) and opposes the working hypothesis. Work continues, others will investigate the hypothesis, and in due course it will be known whether measles virus is an epiphenomenon of limited relevance or an element in the development of IBD. Between 1988 and 1992, 1882 patients died from IBD in England and Wales. We believe that the Department of Health should be supporting research into ulcerative colitis and Crohn’s disease. N P Thompson, S M Montgomery, *R E Pounder, A J Wakefield, Inflammatory Bowel Disease Study Group, *Royal Free Hospital School of Medicine, London NW3 2PF, UK; and Social Statistics Research Unit, City University, London
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Wakefield AJ, Ekbom A, Dhillon AP, Pittilo RM, Pounder RE. Crohn’s disease: pathogenesis and persistent measles virus infection. Gastroenterology 1995; 108: 911-16. Ekbom A, Wakefield AJ, Zack M, Adami HO. Perinatal measles infection and subsequent Crohn’s disease. Lancet 1994; 344: 508-10. Miyamoto H, Tanaka T, Kitamoto N, Fukuda Y, Shimoyama T. Detection of immunoreactive antigen, with a monoclonal antibody to measles virus, in tissue from a patient with Crohn’s disease. J Gastroenterol 1995; 30: 28-33. Liu Y, van Kruiningen HJ, West AB, et al. Immunocytochemical evidence of Listeria, Escherichia coli and Streptococcus antigens in Crohn’s disease. Gastroenterology 1995; 108: 1396-404. Thompson NP, Pounder RE, Wakefield AJ. Perinatal and childhood risk factors for inflammatory bowel disease: a case-control study. Eur J Gastroenterol Hepatol 1995; 7: 385-90.
Intraoperative cerebral infarction after desmopressin administration in infant with end-stage renal disease is considered to be a safe drug there have been reports of cerebral and myocardial infarction after its use in adults.’-3 We report a case of intraoperative cerebral infarction associated with the use of desmopressin in an infant. A 7-month-old girl with chronic renal failure associated with congenital nephrotic syndrome and bilateral Wilms’ tumour (Denys Drash syndrome) was admitted for bilateral nephrectomy and left internal jugular vein and peritoneal dialysis catheter placement. She was maintained preoperatively on peritoneal dialysis and her hypertension was treated with captopril and propranolol. Her generalised tonic-clonic seizure disorder was well controlled with
SiR-Although desmopressin
phenobarbitone. Preoperative albumin, haemoglobin, partial thromboplastin time, prothrombine time, and platelet count were normal. She was dialysed the day before surgery and received intravenous crystaloids. She gained little in weight in the preoperative period. Bleeding time was 675 s (normal 174-560). Desmopressin acetate 0-3 g/kg (2 flg total) was given intravenously over 15 min at the start of the operation. The operation itself was uneventful with normal blood pressure and arterial oxygen saturation throughout. Central pressures were 9-11 cm water. The estimated blood loss was 100 mL and the infant was given 160 mL packed red cells to bring her haemoglobin to 11-6g/dL. At the end of the operation a pronounced asymmetry in limb movement was noted: the left extremities were immediately strong and moved vigorously, whereas the right leg was initially immobile, then slowly recovered some spontaneous movement. A right ptosis was also noted. The right arm remained flaccid. Respiratory efforts and gag reflexes were adequate and extubation was uneventful. On the first postoperative day magnetic resonance imaging revealed an area of ischaemia/infarction in the superolateral aspect of the left frontal lobe with a second focus of infarction posteriorly near the motor strip. An echocardiogram was normal, with no evidence of right to left shunting. The right ptosis and leg weakness resolved completely after a few hours and the right arm regained some voluntary activity over the ensuing week when physiotherapy was started. The mechanism leading to the vascular injury in this infant is obscure. Volume depletion, either due to peritoneal dialysis or vascular compartment contraction associated with hypoalbuminaemia, may have been a predisposing factor but the adequate volume status preoperatively and the normal range of haemodynamic indices during surgery makes this mechanism unlikely. Desmopressin increases the circulating levels of factor VIII procoagulant, von Willebrand factor, and tissue plasminogen activator activity. Arterial atherosclerosis has been postulated as contributing to the development of cerebral thrombosis in elderly patients, by venous