ACE inhibitors and myocardial infarction

493

Differentiated thyroid carcinoma incidence around the French nuclear power plant in Chooz S]R,—A significant increase in thyroid carcinoma incidence has been reported in Belarus since the Chemobyl accident. If this increase is real and not due to the effects of more intensive screening after the accidentit suggests that the effect of radioiodine, and particularly that of short-lived isotopes such as 1331 which have a life about 10 times shorter than that of 1311, is faster than previously suggested. Because these isotopes are also released during the normal activity of nuclear power plants,3 we studied thyroid cancer incidence around a nuclear power plant. The plant at Chooz, north Ardennes, is one of the oldest in France, and was operated from October, 1966, to December, 1991. Data on new cases of differentiated thyroid carcinomas around the plant were obtained from the Champagne-Ardennes thyroid cancer registry’ which covers the two "departements" of Mame and Ardennes. Information was available on histology and the tumour-nodemetastasis (TNM) stage and on age, sex, and place of residence of cases between 1979 and 1991. All the "communes" (electoral wards) within 40 km of the plant were included. Four geographical zones were considered: under 10, 10-19, 20-29, and 30-39 km from the plant. Each commune was classified in one of these zones according to the distance between its main city or village and the plant. The rest of the registry catchment area (>40 km from the plant) was considered the reference population. National cancer incidence data do not exist in France and the incidence rates obtained from the Champagne-Ardennes specialised registry were higher than those in other French general cancer registries 4 Census data by commune for the years 1975, 1982, and 1990 were obtained from the Institut National de la Statistique et des Etudes Economiques. The populations at risk each year from 1979 to 1990 in each commune were estimated from these data by linear interpolation, and that of 1991 by extrapolation of the variation recorded from 1982 to 1990. To test the possible existence of an increase in differentiated thyroid carcinoma incidence around Chooz’s nuclear power plant, we compared the observed incidence in the four geographical zones to that expected in the reference population. Four standardised incidence ratios (SIRs) were thus obtained. A linear trend test was applied to the SIRs to test whether an increase could be associated with a smaller distance from the plant.6 1852 140 person-years of observation were accrued from the 71 communes in the four geographical zones from 1979 to 1991. During this period, 77 cases of differentiated thyroid carcinoma were diagnosed (63 in women and 14 in men) (table). No significant relation was found between a younger age at diagnosis and proximity to the plant: the mean age at diagnosis was, respectively, 53,60,45, and 45 years. No relation was found between TNM stage and distance from the plant: the frequency of node involvement was 1/9, 2/8, 0/10, and 8/50 in the four areas, and the frequency of metastases at initial diagnosis was 0/9, 1/8, 0/10, and 5/50. The table shows the size of the population at risk, the observed and expected number of cases, and the SIR per geographical zone. No significant increase was recorded in the SIRs near Chooz (p = 0-9). The power of the study was 74% to detect a linear increase in the SIR from 100% in the furthest geographical zone up to 200% in NUMBER OF PERSON-YEARS AND OBSERVED AND EXPECTED NUMBER OF DIFFERENTIATED THYROID INCIDENT CASES BY GEOGRAPHICAL ZONE

"(OlE) 100.

the

nearest zone,

and 94%

to

show

an

increase up

to

250% in the

Although the power was reasonable, our study did not show an increase in the SIR of differentiated thyroid carcinoma around the Chooz nuclear plant in France. The cases diagnosed near the plant were not younger, and their disease was not more extended, than in others further afield. The mean annual release of radioactivity in the atmosphere by the Chooz nuclear plant during its activity was about 0-1 GBq for 1311 and 0-02 Gbq for 1331 (M. Bertin, personal communication). nearest zone.

U351 INSERM, Department of Biostatistics and Epidemiology, Institute Gustave Roussy, 94805 Villejuif, France, and Department of Nuclear Medicine, Institute Jean Godinot, Reims

CLAIR REKACEWICZ FLORENT DE VATHAIRE MARIE JOËLLE DELISE, on behalf of the Groupe de Pathologie Thyroidienne Tumorale de Champagne-Ardennes

1. Kazakov VS, Demidchik EP, Astakhova LN. Thyroid cancer after Chernobyl. Nature

1992; 359: 21-22. 2. Ron E, Lubin J, Schneider AB. Thyroid cancer incidence. Nature 1992; 360: 113. 3. UNSCEAR. Ionising radiation: sources and biological effects. New York: United Nations, 1986. 4. Delisle MJ, Gibold C. Exploitation épidémiologique du registre de ChampagneArdenne. Chalons sur Marne: ORS, 1989. 5. Benhamou E, Laplanche A, Wartelle M, et al. Incidence des cancers en France 1978-1982. Paris: INSERM, 1990. 6. Breslow NE, Day NE. The design and analysis of cohort studies. Lyon: IARC, 1987.

ACE inhibitors and

myocardial infarction

SiR,—Iwas gratified to see that Dr McMurray and Dr Dargie (Dec 19/26, p 1547) now accept as fact "the remarkable effect of angiotensin-converting-enzyme (ACE) inhibitors on myocardial infarction". In their response to my editorial in the Journal of Hypertension (1991; 9: 385-92) about the cardioprotective potential of ACE inhibitors, they felt that this hypothesis had "still to be tested in humans". Now that it is tested and proven to be true, their only objection remains that "the experimental evidence ... is inconsistent and difficult to relate to the clinical picture", their reference to this statement being their response to my editorial. I find intriguing this obstinate resistance to admit that my experimental data published in The Lancet 20 years ago opened the way to subsequent clinical and molecular studies, each one adding another piece to the evidence in support of the original idea. What does it take to convince a scientist that there is a point beyond which what might have been originally healthy scepticism can now sound more like lack of good faith? True, there may be many additional mechanisms of action of ACE inhibitors yet to be explored, but this does not negate the obvious ones proposed earlier. The fact is, the recent clinical results of the SAVE and SOLVD trials are perfectly consistent with the earlier experimental evidence. Hypertension and Atherosclerosis Section, Boston University School of Medicine, Boston, Massachusetts 02118, USA

HARALAMBOS GAVRAS

Authors’reply SiR,—In his editorial1 Professor Gavras did

not

mention

prevention of myocardial reinfarction and unstable angina as a potential secondary preventive benefit of ACE inhibitors. We are, of course, well aware of and impressed by, Gavras’ pioneering work, carried out in Glasgow.2 It is still, however, unclear to us how this work relates to the findings of SAVE and the prevention arm of SOLVD.3,4 Undoubtedly, very high concentrations of angiotensin II can cause diffuse focal myocardial necrosis, as demonstrated by Gavras and others. 2,5 This explanation is not, however, an "obvious" one for a reduction in episodes of unstable angina. Nor are the contrasting results of CONSENSUS II (acute phase, high circulating angiotensin II levels) and SAVE/SOLVD (subacute/chronic phase, less renin-angiotensin system activation) in keeping with the experimental evidence.6.7 There are other reasons, as set out in our letter of Dec 19/26, to believe that the results of the SAVE/SOLVD clinical trials are not "perfectly consistent" with the experimental evidence. There seems little doubt that ACE inhibitors are of benefit in the subacute phase of myocardial infarction and in patients with

494

CLINICAL DETAILS

established left ventricular dysfunction. We believe, however, that even Gavras would concede that much more work needs to be done before we fully understand the mechanisms of action of these drugs in individuals with coronary artery disease. Department of Cardiology, Infirmary, Glasgow G11 6NT, UK

Western

J. MCMURRAY H. J. DARGIE

H, Gavras I Cardioprotective potential of angiotensin converting enzyme inhibitors. Hypertension 1991; 9: 385-92. 2. Gavras H, Brown JJ, Lever AF, Macadam RF, Robertson JIS. Acute renal failure, tubular necrosis and myocardial infarction induced in the rabbit by intravenous angiotensin II. Lancet 1971; ii: 19-22. 3. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1. Gavras

1992; 327: 669-77. 4. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-91. 5. Tan L-B, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 6. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction-results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992; 327: 678-84. 7. McAlpine HM, Morton JJ, Leckie B, Rumley A, Gillen G, Dargie HJ. Neuroendocrine activation after acute myocardial infarction. Br Heart J 1988; 60: 117-24.

Persistent arthritis after human B19 infection

parvovirus

SIR,-Infection with human parvovirus B19 can cause acute arthropathy in 50% of affected adults (women more often than men).1,2 Symptoms are preceded by an influenza-like illness and erythematous rash, although joint symptoms may be the only manifestation. The arthropathy usually resolves rapidly. Klouda et onset

all

reported an increased frequency of HLA DR4 in patients with persistent arthritis associated with parvovirus B19, whereas others’°5 found no such association. HLA DRl was absent in all adults tested who had persistent joint symptoms for more than 2 months. Between December, 1991, and June, 1992, we have seen 7 women with acute parvovirus B 19 infection and acute polyarthritis (table). All were positive for parvovirus B19 IgM antibodies by radioimmunoassay. None had previous inflammatory arthritis or spondylitis. Rheumatoid factor and antinuclear antibodies were negative. Radiography of the sacroiliac joints was normal. The arthritis persisted for 9 months in 3 patients who were HLA B27 positive. When the arthritis eventually settled there was no evidence of any joint deformity or radiological changes in the affected joints. The arthropathy resolved in 10-14 days in the other 4. We also saw a 35-year-old man with severe relapse of spondylitic symptoms after a febrile illness with a generalised erythematous rash (his 8-year-old daughter was recovering from the "slapped cheek" syndrome). He was also HLA B27 positive. The febrile illness proved to be parvovirus B19. His spondylitic symptoms were functionally disabling and he needed to take a non-steroidal anti-inflammatory for the first time in 15 years and was unable to do his exercises. The symptoms lasted 13 weeks. Erythrocyte sedimentation rate returned to normal after 20 weeks (97 mm/h in April, 43 in July, and 13 in September). Thus HLA B27 status may be associated with persistent arthritis in adult women after infection with human parvovirus B19. This link was also supported by findings in the man with ankylosing spondylitis. Most patients with ankylosing spondylitis (95%) or reactive arthritis (80%) express HLA B27, an allele found in only 7% of the general population.s Only bacteria and chlamydia have been shown to cause reactive arthritis. There are at least three common features among the microorganisms causing reactive arthritis: they mainly cause infections on mucosal areas, they live intracellularly, and they have a lipopolysaccharide outer membrane.6 The first two features apply to parvovirus B 19. During the acute illness, the virus may be detected in respiratory tract secretions, and virus replication in the respiratory tract may be associated with sore throat; hence the picture may be of an influenza-like illness.7 Parvovirus contains no

lipids, carbohydrates, histone-type proteins or either cellular or virus coded enzymes? Possibly, similar to microorganisms that cause reactive arthritis, during or after acute parvovirus infection the viral antigens persist in HLA B27 positive patients. Chase Farm Hospital, The Ridgeway, Enfield, Middlesex EN2 8JL, UK

ALI S. M.

JAWAD

1. White

DG, Mortimer PP, Blake DR, et al. Human parvovirus arthropathy. Lancet 1985; i: 419-21. 2. Woolf AD, Campion GV, Chiswick A, et al. Clinical manifestation of human parvovirus B19 in adults. Arch Intern Med 1989; 149: 1153-56. 3. Klouda PT, Corbin SA, Bradley BA, Cohen BJ, Woolfe AD. HLA and acute arthritis following human parvovirus infection. Tiss Antigens 1986; 28: 318-19. 4.

Dykmans BAC, Breedveld FC, de Vries RR. HLA antigens in human parvovirus arthropathy. J Rheumatol 1986; 13: 1192-93. 5. Brewerton DA, Caffrey M, Hart FD, James DCO, Nicholls A, Sturrock RD. Ankylosing spondylitis and HL-A27. Lancet 1973; i: 904-07. 6. Granfors K. Do bacterial antigens cause reactive arthritis? Rheum Dis Clin North Am 1992; 18: 37-48. 7. Anderson MJ. Parvoviridae. In: Parker MT, Collier LH, eds. Topley & Wilson’s principles of bacteriology, virology and immunity, vol 4. Virology. 8th ed. London. Edward Arnold, 1990: 546-57.

Increased frequency of CMV infection in HLA-DR7 matched renal allograft recipients SIR,-Blancho et al,l in a retrospective study, showed that HLA-DR7-matched renal allograft recipients are more susceptible to cytomegalovirus (CMV) disease. In a prospective study in recipients of a kidney allograft, transplanted between May,1990, and July, 1992, we can confirm and extend these findings. Samples of blood and urine were collected pre-operatively and post-operatively during admission (weekly) and in the outpatient clinic (monthly). Infection was defined as a positive culture (virus isolation by rapid coverslip culture method with a monoclonal antibody to immediate early antigen2 and/or conventional culture based on the cytopathic effect) and/or seroconversion (latex agglutination and/or detection of specific CMV IgM by enzymelinked immunoabsorbent assay), or at least a four-fold rise of IgG titre (by complement binding antibodies). The criteria for the diagnosis of CMV disease were the same as those used by Blancho et al.l Acute rejection (in the first 6 months after grafting) was assessed clinically and confirmed histologically by needle-core biopsy. HLA typings of donor and recipient were done at least twice with standard serological methods. Data were mostly analysed with general linear regression and, in some instances, with nonparametric statistics. 82 consecutive recipients on cyclosporin-based immunesuppression were enrolled. 5 needed transplantectomy in the first week after grafting and were excluded. 23 (30%) needed rejection treatment. 25 of the 77 recipients (32%) had CMV infection. Infection occurred in 10 of 18 HLA-DR7-positive recipients (56%) and in 15 out of 59 HLA-DR7-negative recipients (25%) (p < 002). There were no significant correlations between CMV infection and other HLA antigens. HLA-DR7 was significantly correlated with CMV infection (r = 0-08, p=0003). Almost all recipients with HLA-DR7 received an HLA-DR7-positive allograft, so no further differentiation can be made about whether HLA-DR7 of recipient, or donor, or the matching for HLA-DR7 is the important factor involved in the increased risk for CMV infection. No significant correlation was found between HLA-DR7 and rejection treatment