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
510
high that no further test is needed, unless there are reasons to doubt the result. If this rule were applied to confirmatory testing virtually all genuinely positive specimens could be rapidly identified and important savings made. It would be an added advantage if it were found that other pairs of cheap, methodologically independent assays (eg, particle agglutination and competitive ELISA) fulfilled the
same
role. Resources could then be concentrated
on
the
investigation of those specimens that gave discrepant results. Developing countries in particular need straightforward and inexpensive confirmatory procedures. The use of appropriate pairs of assays might be adopted there for confirmatory testing for anti-HIV. Virus Reference Laboratory, Central Public Health Laboratory, London NW9 5HT
ANDREW DAY PHILIP P. MORTIMER
1. Mortimer PP, Parry JV, Mortimer JY. Which anti-HTLV screening and confirmatory testing? Lancet 1985; ii: 873-77.
III/LAV
assays for
NO CLINICAL SIGNS 14 YEARS AFTER HIV-2 TRANSMISSION VIA BLOOD TRANSFUSION
SIR,—The incubation period from infection to clinical disease with HIV-1 has been assessed by studies on transfused patients for whom the date of infection is known.’ Although very few cases of HIV-2 infection have so far been diagnosed2 the incubation period does seem to be different. A Portuguese man, still alive, was reported with AIDS due to HIV-2 in 1985. It was assumed that he had been infected between 1966 and 1969 in Guinea Bissau, indicating an incubation of 16-19 years. He said that he had been a regular blood donor from 1973 (when he emigrated to France) to 1983. We have been trying to trace recipients and nine have been identified. Four died soon after transfusion, two were lost to follow-up, and three were located. Serum samples from two of these three recipients have now been obtained. They had been transfused with the Portuguese donor’s whole blood in July, 1974, and September, 1982. Both are seropositive for HIV-2 by specific western blot and spot tests with
specific HIV-1/HIV-2 synthetic peptides (Diagnostics Pasteur, peptides from Genetic Systems4). With HIV-1 assays, ELISA (’ELAVIA’, Diagnostics Pasteur; Abbott second generation) and western blot (DuPont), clear cross-reactivity was observed with the serum from the 1974 recipient whereas the other recipient was negative by ELISA and had only a weak p24 band on western blot. These two women, born in 1926 and 1929, respectively, had no risk factors for HIV infection other than transfusion. Neither has any clinical manifestation of HI V infection. To our knowledge these are the first published cases of HIV-2 transmission by blood transfusion. The timing of infection is certain (and it confirms the long-standing infection of the Portuguese man). These cases (and others5,6) confirm a long incubation period for HIV-2-at least 16 years (1969-85) in the blood donor and 14 years or more in the woman transfused in 1974 who is still symptom-free. Blood Transfusion Centre, Hôpital de Melun Institut National de Transfusion rue A. Cabanel, 75015 Pans, France
GÉRARD DUFOORT Sanguine,
6
ANNE-MARIE COUROUCÉ
SIR,—The efficacy of serotoninergic agents in reducing disruptive behaviour in demented patients has been reported with tryptophan, trazadone, 1-3 and buspirone.4,5 We have used buspirone to reduce disinhibition, morbid jealousy, and aggression (though not memory loss) in an elderly man, which precluded long-term institutional
ROSEMARY ANCELLE-PARK
care.
An 80-year-old divorced man had multi-infarct dementia for 8 years. He had lived alone in a home for single men for 3 months, after separating from a female friend of 3 years. He was brought for assessment because of increasingly intolerable behaviour over 2 years which had alienated him from his children and previously supportive friends, and from others at the home. He was agitated, garrulous, sexually disinhibited, irritable, and liable to jealous rages, especially about women. His memory was failing and self-care deteriorating. Local services had recommended him for long-term institutional care. He had a history of systemic hypertension treated with nifedipine and a cerebrovascular accident 2 years ago with a brief period of aphasia. He was distressed and anxious about his decreasing ability to cope but not depressed. There was no history of unipolar or bipolar affective disorder, alcohol abuse, or psychotropic drug use, and his condition was unchanged during a week of inpatient assessment and support. A trial of buspirone 5 mg thrice daily was started. Within 5 days a dramatic change occurred. He became calm, more socially appropriate, and his sexually disinhibited behaviour ceased. Irritability decreased, the jealous rages stopped, his attention and concentration improved, self-care improved, and he considered his memory was better, though he acknowledged continuing memory problems. His family said he was like their father of old, and his female friend re-established her relationship with him. Despite this clinical improvement, psychological test results (Wechsler adult intelligence scale and memory-for-designs tests6) were essentially unchanged. He left hospital to stay briefly with a daughter and then, being more settled, was accepted back to the home where he found he could cope. Improvement has continued for a month off buspirone after 6 weeks’ treatment. These results with low-dose buspirone alone, without neuroleptics, are consistent with 5HTIA receptor activity as previously postulated. The maintained improvement after stopping buspirone is consistent with the stabilising effect reported for this drug. Placebo-controlled trials of buspirone for disinhibition in the elderly are needed, considering short-term as well as longer term use. This case-report also suggests a possible additional use for buspirone in morbid jealousy. Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital,
J. W. G. TILLER J. A. DAKIS
Victoria
J. M. SHAW
3050, Australia
Greenwald BS, Mann DB, Silverman SM Serotoninergic treatment of screaming and banging in dementia. Lancet 1986, n: 1464-65. 2. O’Neil M, Page N, Adkins WN, Eichelman B Tryptophan-trazadone treatment of aggressive behaviour Lancet 1986; ii: 859-60 3. Simpson DN, Foster D. Improvement in organically disturbed behaviour with trazadone treatment Gen Clin Psychiatry 1986, 47: 192-93 4 Smith LM, Peroutka SJ. Differential effects of 5-hydroxytryptamine1Aselective drugs on the 5-HT behavioural syndrome. Pharmacol Biochem Behav 1986, 24: 1513-19 5. Colenda CC III. Buspirone in treatment of agitated demented patient Lancet 1988, i: 1.
1169 6. Graham
WHO
Collaborating Centre on AIDS, Hôpital Claude Bernard, Paris
SHORT-TERM BUSPIRONE TREATMENT IN DISINHIBITION WITH DEMENTIA
FK, Kendall BS. Memory for designs Skills 1960; 11: 147-88.
test:
revised
general
manual
Percep
Motor
Hôpital Pitié-Salpêtrière, Paris
OLIVIER BLETRY
Castagliola D, Downs AM. Incubation time for AIDS Nature 1987, 328: 582 Horsburgh CR, Holmberg SD. The global distribution of human immunodeficiency virus type 2 (HIV-2) infection Transfusion 1988; 28: 192-95. 3. Ancelle R, Bletry O, Baglin AC, et al. Long incubation period for HIV2 infection.
1 2.
Lancet 1987; i: 688-89. MC, Poulain M,, Delagneau JF, et al Dual HIV1 and HIV2 infection in West-Africa supported by site direction serology AIDS Res (in press). 5 Burin des Roziers N, Bruet A, Leger JP, et al. Infection par le virus HIV-2 avec longue période d’incubation. Presse Méd 1987, 16: 1981 6. Bryceson A, Tomkins A, Ridley D, et al HIV-2 associated AIDS in the 1970s. Lancet 1988; ii: 221
4 Cot
BACTERIAL ANTIGENIC CROSS-REACTIONS AND HAEMOLYTIC URAEMIC SYNDROME
SIR,-Escherichia coli producing verocytotoxin (VTEC) have been associated with haemorrhagic colitis (HC)’ and haemolytic uraemic syndrome (HUS)2 in the UK. Strains of VTEC belonged to several serogroups but 0157 was the most common (94%,’ 81%2). In both studies DNA probes provided a sensitive method whereby VTEC could be detected in faeces even when they represented less than 1 % of the coliforms, and testing faeces for verocytotoxin provided further evidence of VTEC involvement.