VALUE OF NECROPSY IN AIDS

508 around. It is difficult to find statistics for conservative management, but in one series of 89 children treated since 1979 the mortality was 37% by 1987.10 It has been the general experience of others that the younger the patient, and the fewer transfusions, the easier the transplant-and in such elective situations bone marrow teams can now achieve over 90% success."," With the growing problem of AIDS (in Africa 10% of blood units can be positive) and the knowledge now that even sero-negative blood has transmitted rapidly fatal disease, one can make a case for considering early transplantation as an ethical alternative to what can be achieved in some countries. Then there are the economic considerations-a transplant at under C20 000 versus transfusion/chelate therapy to the age of 20 years that can cost over c 100 000. This is especially important where health services are not free. The gene-transfer camp, as far as I am aware, has not yet managed to keep their tent up in a whole animal, and the latest understanding that maybe only one-eighth of bone marrow stem cells are ever in use at any given time suggests it is going to be very difficult to maintain an adequate transfection rate in primate bone marrow. Accepting Weatherall’s cautions in assessing severity with early diagnoses, one can also accept that nothing in medicine is perfect and that we can only advise what we consider is the best treatment for the patients at that time. Many parents, given the full picture, have opted for BMT, which, when successful, allows children to lead normal lives without the risks of life-long transfusions. Westminster Hospital,

J. R. HOBBS,

London SW1P 2AR

Chairman, Westminster Bone Marrow Team

1. Hobbs JR. Bone marrow transplantation for inborn errors. Lancet 1981; n: 735-39. ED, Buckner CD, Sanders JE, et al. Marrow transplantation for thalassaemia. Lancet 1982; ii: 227-29. 3. Ehrsson H, Hassan M, Ehrucbo M, et al. Busulfan kinetics. Clin Pharmacol Ther 1983; 34: 86-89. 4. Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with advanced thalassemia. N Engl J Med 1987; 316: 1050-55. 5. Shaw P, Hugh-Jones K, Hobbs JR, et al. Busulphan and cyclophosphamide caused little early toxicity during displacement bone marrow transplantation in fifty children. Bone Marrow Transpl 1986; 1: 193-200. 6. Hobbs JR, Hugh-Jones K, Shaw P, et al. Engraftment rates related to busulphan and cyclophosphamide dosage for displacement bone-marrow transplant in 50 children Bone Marrow Transpl 1986; 1: 201-08. 7. Steimuller D, Motulsky AG. Treatment of hereditary spherocytosis in Peromyscus by radiation and allogeneic bone marrow transplantation. Blood 1967; 29: 320. 8. Johnson FL, Look AT, Gockerman, et al. Bone marrow transplantation in a patient with sickle cell anemia. N Engl J Med 1984; 311: 780-83. 9. Bortin MM, Rimm AA. Treatment of 144 patients with severe aplastic anaemia using immunosuppression and allogeneic marrow transplantation: a report from the International Bone Marrow Transplant Registry. Transpl Proc 1981; 13: 227-29. 10 Giardina PJ, Ehlers K, Lesser M, et al. Improved survival in beta thalassaemia major. Pediat Res 1987; 21: 229A. 11. Storb R, Thomas ED, Buckner CD, et al. Marrow transplantation m thirty "untransfused" patients with severe aplastic anemia. Ann Intern Med 1980; 92: 30-36. 12. Hobbs JR. Displacement bone marrow transplantation and immunoprophylaxis for genetic diseases. Adv Intern Med 1988; 33: 81-118. 2. Thomas

UTERINE SIZE BEFORE AND AFTER TRIPTORELIN TREATMENT I

I

-

Results

as mean (SD) (and range). *n = 13; in 9 patients requiring hysterectomy follow-up to surgery was 5 9 (2-4) (3-11) months and uterine size at day of hysterectomy was 373 (273) (180-1000) ml.

In these 6 perimenopausal uterine size decreased during from 588 to 125 ml and remained that size during follow-up (table). None has required hysterectomy. In the premenopausal women uterine size decreased from 444 to 158 ml on average. In 9 outgrowth of fibroids was such (enlargement to 373 ml) that hysterectomy was necessary. This operation was done 6 months (mean) after treatment stopped. In the other 13 premenopausal patients almost no outgrowth of fibroids occurred during the post-treatment period and 3 of these 13 patients have been symptom-free for more than a year. In premenopausal patients oestradiol and osteocalcin levels returned to normal within 2 months of treatment. In perimenopausal patients with uterine fibroids, hysterectomy can be prevented by triptorelin while premenopausal patients remain at risk of needing surgery, though most will have a long treatment

symptom-free period after a short treatment course. Department of Gynaecology and Obstetrics, Rijnstaete EG Hospital, 6800EK Arnhem, Netherlands

H. A. I. M. VAN LEUSDEN

1. Van Leusden HAIM.

Rapid reduction of uterine myomas after short-term treatment microencapsulated D-Trp6-LHRH. Lancet 1986; ii: 1213. 2. Coddington CC, Collins RL, Shawker TH, et al. Long-acting gonadotropin-releasing hormone analog used to treat uteri. Fertil Steril 1986; 45: 624-29. 3. Lumsden MA, West CP, Baird DT. Goserelin therapy before surgery for uterine with

fibroids. Lancet 1987; i: 36-37. R, Lemay A, Merat P. Use of intranasal luteinizing hormone-releasing hormone agonist m uterine leiomyomas. Fertil Steril 1987; 47: 229-33. 5. West CP, Lumsden MA, Lawson S, et al. Shrinkage of uterine fibroids during therapy with goserelin (Zoladex) a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot: Fertil Steril 1987; 48: 45-51. 6. Friedman AJ, Barbieri RL, Benacerraf BR, et al. Treatment of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin-releasing hormone agonist. Fertil Steril 1987; 48: 560-64. 7. Friedman AJ, Barbieri RL, Doubilet PM, et al. A randomized, double-blind trial of a gonadotropin releasing hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uten. Fertil Stenl

4 Maheux

1988; 49: 404-09. 8. Kessel B, Liu J, Mortola J, et al. Treatment of uterine fibroids with agonist analogs of gonadotropin-releasing hormone. Fertil Steril 1988; 49: 538-41. 9. Van Leusden HAIM, Dogterom AA. Rapid reduction of utenne leiomyomas with

TRIPTORELIN TO PREVENT HYSTERECTOMY IN PATIENTS WITH LEIOMYOMAS

SIR,-In a letter in The Lancetl in 1986 I reported the rapid shrinkage of uterine myomas during a short (4 month) treatment course with monthly injections of triptorelin (’Decapeptyl’; Ferring, Sweden). At that time one could only speculate whether hysterectomy could be postponed or even avoided in this way. Since then several other publications have appeared,2-9 but none answers the prevention/postponement question. I now report on 28 patients with intramural leiomyomas who have been treated with triptorelin for 4-6 months and then followed up for 2-19 months. Data on 16 of the patients (but not on the follow-up) have been published.l,9 Triptorelin (4 mg in biodegradable microcapsules) was injected once a month; the first injection was given on the 21st day of the cycle. Before and during treatment, 1 month after the last injection, and during follow-up the size of the uterus was measured ultrasonographically. Of the 28 patients 6 entered the menopause during or shortly after treatment, as defmed by amenorrhoea and hormone measurements.

monthly injections of D-Trp6-GnRH. Gynecol Endocrinol 1988; 2: 45-51.

VALUE OF NECROPSY IN AIDS

SIR,-Dr Wilkes and colleagues’ analysis (July 9, p 85) fails to examine several important aspects when evaluating a new but terminal disease. With any new disease, a learning curve develops among clinicians treating such a disorder. By including such a wide period from 1981 to 1987 in their analysis, many of their "necropsy only" diagnoses may have occurred in the initial slow learning phase. It would be important to compare only "necropsy proven" cases over time to see if diagnoses improved, as would be expected with new clinical information, increased numbers of patients with AIDS, and improved diagnostic techniques. AIDS infections are rarely "single" and most AIDS viral, parasitic, and fungal infections are "rarely curable".1 Knowing this, many clinicians, although alerted to diagnostic possibilities, are reluctant to pursue diagnoses which do not result in cures or even short-term remissions. Therefore, given the terminal nature of the

509 disease and the inability to treat a variety of infectious or neoplastic disorders,2 there is little incentive to make accurate diagnoses. Also the techniques available to make defmitive diagnoses after empiric therapy has failed, such as brain or open-lung biopsy, have significant morbidity and are often associated with false-negative results. Since necropsy did not change the cause of death in this retrospective study, it remains to be seen prospectively whether early diagnosis or treatment of co-infections or neoplasms alters the morbidity and mortality of the disease. With these important caveats, I agree with Wilkes and colleagues’ conclusions that clinicians should still continue to request necropsies and learn about the protean nature of this disease. School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6094, USA

TERRY A.

AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988; 318: 1439-48. 2. Knowles DM, Chamulak GA, Subar M, et al. Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 198: 744-53.

SIR,—Dr Wilkes and colleagues demonstrate a very high incidence of undiagnosed infection in terminally ill patients with AIDS. Although many homosexual men with AIDS have previously been infected with syphilis, there was no mention of it in Wilkes and colleagues’ series. In primary and secondary syphilis, Treponema pallidum may be present in the cerebrospinal fluid (CSF), but treatment of early syphilis with conventional doses of penicillin produces subtreponemicidal levels in CSF.1 Treponemelike forms consistent with T pallidum have been demonstrated in aqueous humour and CSF from immunocompetent patients following such treatment.2 We are concerned that syphilis might recrudesce in patients who subsequently become immunosuppressed, and the serological tests used for diagnosis would be unreliable. There have been several reports of patients with HIV and syphilis in whom neurological relapse occurred within months of treatment with penicillin.3-5 Secondary syphilis with negative serological tests in a patient with concurrent HIV infection has also been reported.’ If T pallidum infection of the central nervous system were to recur in a patient with AIDS it might be expected to present atypically. It would therefore be very interesting to know if there were any findings suggestive of neurosyphilis in Wilkes and colleagues’ series. Was T pallidum looked for with silver stains, immunofluorescence, or other techniques? It is important that another potentially treatable infection is not added to the list of missed diagnoses in patients with AIDS. P. E. HAY N. FRANCIS S. M. FORSTER D. GOLDMEIER

London W2 1PG

1 Dunlop EMC Survival of treponemes after treatment: comments, clinical conclusions and recommendations Genitour Med 1985; 61: 293-301. 2 Rice NSC, Dunlop EMC, Jones BR, et al. Treponeme-like forms untreated early syphilis Br J Vener Dis 1970; 46: 1-9.

m

treated and

3 Tramont EC Syphilis in the AIDS era. N Engl J Med 1987; 316: 1600-01. 4 Berry CD, Hooton TM, Collier AL, Lukehart SA. Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection.

N Engl JMed 1987; 316: 1587-89 5 Johns DR, Tierney M, Felsenstem D. Alteration m the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus N Engl J Med 1987, 316: 1569-72. 6 Hicks CB, Benson P, Lupton GP, Tramont EC Seronegative secondary syphilis in a patient infected with HIV with Kaposi’s sarcoma Ann Intern Med 1987; 107: 492-95.

ZIDOVUDINE OVERDOSE

SIR,--Overdose of zidovudine has been reported only once before,’ when no adverse effects were noted. We describe a 34-year-old man with AIDS who took a hundred 200 mg tablets of zidovudine with temazepam 6 h before admission. He had been started

on

zidovudine 2 weeks earlier

at a

*Relative to day of overdose Normal ranges in parentheses. NK = not known.

JACOBSON

1 Glatt

Departments of Genito-Urinary Medicine and Pathology, St Mary’s Hospital Medical School,

HAEMATOLOGICAL DATA

dose of 200 mg 4-hourly.

On admission he was drowsy but otherwise well. Blood levels of zidovudine and its 5’-gluconuride 12 h after the overdose were very high, at 185 and 114 µmol/1, respectively. Steady state levels of zidovudine for doses of 250 mg every 4 h are 0.6-4.4 µmol/1, and the concentration found in this patient is the highest ever recorded at the Wellcome Research Laboratories, who kindly did the assays. Zidovudine was discontinued. The patient remained well. The slight fall in haemoglobin (table) may be attributable to the drug, the subsequent rise is probably related to stopping the drug. At no stage did the patient become leucopenic or thrombocytopenic. Liver function tests and electrolytes were normal. The adverse effects of long-term zidovudine include dose-related bone-marrow suppression, nausea, myalgia, and insomnia.2 Serious neurotoxicity has been suggested in case-reports.3-5 Neither our patient nor the previous one with zidovudine overdose1 had marrow toxicity. A regimen of intermittent high-dose zidovudine to avoid marrow

toxicity warrants investigation.

Departments of Medicine and Haematology, St Stephen’s Hospital, London SW10 9TH

M. HARGREAVES G. FULLER C. COSTELLO B. GAZZARD

1. Pickus OB. Overdose of zidovudine. N Engl J Med 1988; 318: 518. 2. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in

the treatment of

patients with AIDS and AIDS related complex. N Engl JMed

1987; 317: 192-97. 3. Hagler DN, Frame PT. Azidothymidine neurotoxicity Lancet 1986; ii 1392-93. 4. Davtyan DG, Vinters HV. Wernicke’s encephalopathy in AIDS patients treated with zidovudine. Lancet 1987; i: 919-20. 5 Harris PJ, Caceres CA. Azidothymidine in the treatment of AIDS. N Engl J Med 1988; 318: 250

SIMPLIFIED CONFIRMATORY HIV TESTING

SIR,—Confirmatory testing for anti-HIV can mean costly blot and other assays. During more than three years of confirmatory testing our impression has been that almost all truly positive sera have given positive reactions by both an indirect (eg, Elavia, Abbott, Dupont) and a competitive (eg, Wellcome, Behring, Organon) ELISA, which led us to wonder if further testing of specimens that give two such anti-HIV positive reactions is necessary, or whether this in itself indicates a true positive. We have investigated our data on all specimens received between Jan 1, 1986, and March 15, 1988, and tested for anti-HIV by Elavia or Abbott, and ’Wellcozyme’ or wellcozyme monoclonal ELISA: most of these specimens had been referred to our laboratory for confirmatory tests. Of the 3623 specimens, 1969 were confirmed as anti-HIV positive in multiple assays (indirect ELISA, competitive and capture radioimmunoassay, Serodia particle agglutination, western blot1), with where necessary tests on follow-up specimens. 1959 (99-5%) of these positive specimens were indirect assay positive and competitive assay positive, 9 were positive/negative, and 1 was negative/positive. None of the 1654 negative sera were positive/positive, though 12 were positive/negative, and 316 were western

negative/positive or negative/equivocal. Thus the probability of any serum that is positive in both indirect and competitive assays being truly anti-HIV positive is so