African trypanosomiasis: more aggressive treatment or more aggressive research?

250

10 ml plasma from each donor were retested twice by RT-PCR on separate samples. Of the first 127 units tested 92 had a midrange ALT value (45-89 IU/1), for which units are discarded but donors not deferred, and 35 had a high ALT (> 90 IU/1), resulting in permanent deferral of the donors. 64 of these units were screened only by C 100-3 anti-HCV enzyme immunoassay (EIA) (HCV EIA 1-0) and 63 were screened by c22, c200 based EIA (HCV EIA 2-0, Ortho Diagnostics). Only 1 unit (midrange ALT) was repeatedly positive for HCV RNA by RT-PCR on multiple samples. This donation was confirmed anti-HCV negative by both EIA 1-0 and 2-0. Sugitani’s and our results demonstrate that PCR can detect HCV infections in units with raised ALT that are missed by the best antibody-screening tests, and therefore support the value of continued ALT testing in blood banks, to complement routine anti-HCV screening. However, Sugitani’s recommendation for automated PCR as an additional routine screening method in blood banks would need further studies on ALT-normal units to find how many HCV infections are missed by both anti-HCV and ALT

pools,

screening tests.

Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA

-

TIMOTHY SANKARY JOSEPH ROMEO PAUL ULRICH MICHAEL BUSCH GIRISH H. VYAS

hospital laboratory. To rule out relapse or re-infected CATT-positive subjects were checked for parasite in blood, saliva, or CSF, according to clinical presentation. We found that proportion of CATT-positive individuals in a population of formerly treated trypanosomiasis cases decreased over time (figure). However, about half the subjects who were seen 24-36 months after treatment remained CATT positive. Thus, interpretation of CATT screening might pose problems in areas of active transmission, when a proportion of the population has already been treated for trypanosomiasis. Here, serological screening will not differentiate infected individuals from old cases. When testing is for case-finding, this might increase the number of patients false-positive by CATT and thus decrease specificity. If population testing is done for surveillance, it might lead to an overestimate of the,prevalence rates and hinder inferences from the

the Moyo cases,

observed trends. This investigation received financial support from the UNDP/World Bank/WHO special programme for research and training in tropical diseases.

Epicentre, 8 rue St Sabin, 75011 Paris, France

CHRISTOPHE PAQUET THIERRY ANCELLE

Médecins Sans Frontières, Paris

MARC GASTELLU-ETCHEGORRY JORGE CASTILLA IRENA HARNDT

1.

T, Van Meirvenne NA. Card-agglutination test with stained (CATT) for the serological diagnosis of T.b. gambiense trypanosomiasis. Ann Soc Belg Med Trop 1978; 58: 169-76. Cattand P. Diagnosis of African human trypanosomiasis. WHO Expert Committee on Trypanosomiasis. Geneva’ WHO, 1985 TRY/EC/WP/85.21 Van Nieuwenhove S, Declercq J Mass serodiagnosis and treatment of serological positives as a control strategy in trypanosomiasis gambiensis. Proceeding of a symposium on sleeping sickness screening. Antwerp; Nov, 1983. 47-50

Magnus E,

Vervoort

trypanosomes

1. Ulrich PP, Romeo JM, Lane PK, Kelly I, Daniel LJ, Vyas GN. Detection, semiquantitation, and genetic variation in hepatitis C virus: sequences amplified from the plasma of blood donors with elevated alanine aminotransferase. J Clin Invest 1990; 86: 1609-14.

Persistence of antibodies to Trypanosoma brucei gambiense after treatment of human trypanosomiasis in Uganda SIR,-Most of the control programmes in areas affected by Trypanosoma brucei gambiense use the card agglutination trypanosomiasis test (CATT).1 Affected villages are visited regularly by mobile teams with the objective of testing the entire population?,3 In north-west Uganda, the human African trypanosomiasis prevalence is up to 30% in some parts, and the high rate of transmission prompted repeat screening visits within short periods. Therefore, many already treated individuals are probably screened at each visit. Thus, it is important to document the course of the serological response in treated cases. From January to March, 1992, we surveyed with CATT former trypanosomiasis patients treated at Moyo Hospital, Uganda, during the past 3 years. All had had a positive CATT (wet blood and/or diluted serum) at diagnosis, associated with evidence of the parasite in blood, saliva, or cerebrospinal fluid (CSF). Recruitment was from patients attending scheduled follow-up over 2 years. Since attendance at follow-up decreased over time, we also selected former patients from hospital records and searched for the people still living in Moyo and its surrounds. 457 subjects were recruited (follow-up 3-36 months after initial diagnosis). CATT was done in

2.

3.

African trypanosomiasis: treatment or more

aggressive aggressive research? more

SIR,-Dr Hunter and colleagues (April 18, p 956) present findings suggesting that subcurative chemotherapy is an important cause of post-treatment reactive encephalopathy (PTRE) in mice infected with Trypanosoma brucei brucei and recommend that patients with African trypanosomiasis should receive more aggressive treatment. Their argument is similar to that of Jennings et al,’ who speculated that subcurative chemotherapy results in a rapid disappearance of trypanosomes from the bloodstream, but in their persistence in the central nervous system (CNS). The immune system might "concentrate" on the surviving parasites in the CNS, thereby causing meningoencephalitis. In a report of 598 patients with sleeping sickness due to T brucei gambiense, who were treated with melarsoprol, we provided some arguments against this hypothesise We emphasise that the relevance to human medicine of this new study, done in a small number of mice, is doubtful. Pentamidine and suramin sodium, drugs that cross the blood-brain barrier poorly (and which would thus be thought subcurative and, according to Hunter et al, more likely to induce PTRE) do not cause such an encephalopathy in man, even when used in patients with abnormal cerebróspinal fluid (CSF) fmdings. Diminazene, one of the subcurative drugs used in their experiments, although never licensed for human use for commercial reasons, has been widely used in thousands of patients in Zaire (some of whom certainly had a few trypanosomes in the CNS despite normal CSF white blood cell count) during shortages of pentamidine, and it has never been reported to induce PTRE. Melarsoprol, a highly curative and trypanocidal drug, which is still the standard treatment for patients with CNS involvement, frequently ’induces PTRE, whereas eflornithine, a drug which is trypanostatic and kills trypanosomes slowly, rarely, if ever, induces this condition. We recognise that the mouse model is useful to study potential new trypanocidal drugs or combinations of these drugs, and that the contribution of the Glasgow group in that field has been outstanding. However, this model has some limits. For instance, eflornithine (DFMO) monotherapy was not very effective in murine trypanosomiasis,3yet it has proved curative in more than 90% of patients .4

251

Nor are Hunter and colleagues’ PCR data convincing. It would have been surprising not to find trypanosomal DNA in the brain of patients who died only 3-19 days after initiation of therapy, and these workers have no arguments supporting their contention that this implies the presence of live trypanosomes. It was shown four decades ago that in T brucei rhodesiense sleeping sickness, graded dosing of melarsoprol decreases the frequency of PTRE.5 This has not yet been proved in gambiense trypanosomiasis, and it is still standard practice to initiate treatment with the full dose on the first injection (3-6 mg/kg), to reduce the risk of treatment failures. The minimum effective dose of melarsoprol is not known, and studies with another animal model have suggested that 0-9 to 1 -8 mg/kg daily may be sufficientso that the currently used daily dose may already be overcurative. This finding highlights that what is urgently needed is more aggressive research, with properly designed trials involving large numbers of patients, to answer these very simple questions. As clinicians who have treated more than 1500 patients with gambiense trypanosomiasis, we are very well aware that melarsoprol treatment is much like playing Russian roulette. We believe that the more aggressive treatment regimens that Hunter et al propose would be equivalent to increasing the number of bullets in the cylinder-perhaps killing the parasites more rapidly but at what cost to the patient? Université de Montréal, Montréal, Québec, H 1 N 1A2 Canada

FRANÇOIS MILORD

Université de Sherbrooke Sherbrooke, Québec

JACQUES PEPIN

1 Jennings FW, McNeil PE, Ndung’u JM, Murray M. Trypanosomiasis and encephalitis: possible aetiology and treatment. Trans R Soc Trop Med Hyg 1989; 83: 518-19.

Pepin J, Milord F. African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis. Trans R Soc Trop Med Hyg 1991; 85: 222-24. 3. Clarkson AB, Bienen EJ, Bacchi CJ, et al. New drug combination for experimental late-stage African trypanosomiasis: DL-alpha-difluoromethylonithine (DFMO) with suramin. Am J Trop Med Hyg 1984; 33: 1073-77. 4. Hardenberg J, Claverie N, Tell GP. Eflomithine (Ornidyl) treatment of Trypanosoma brucei gambiense sleeping sickness; report of 711 patients treated up to March 1991 (Presented at the 21st meeting of the International Scientific Council for Trypanosomiasis Research and Control, Yamoussoukro, Cote d’Ivoire, October, 1991). 5 Apted FIC Four years’ expenence of melarsen oxide/BAL in the treatment of late-stage Rhodesian sleeping sickness. Trans R Soc Trop Med Hyg 1957; 51: 2.

75-86. 6 Bouteille B, Darde ML, Pestre-Alexandre M, et al. Traitement de la trypanosomiase expérimentale du mouton à Trypanosoma brucei brucei: recherche d’une dose minimale active de melarsoprol. Bull Soc Pathol Exp Fil 1988; 81: 548-54.

Eosinophilia, clozapine, and pancreatitis SiR,-Clozapine has fewer extrapyramidal side-effects than conventional neuroleptics, although it has a particular spectrum of adverse reactions.l Acute pancreatitis associated with clozapine has been reportedWe report a second case of pancreatitis that also seems to have been caused by clozapine. A 17-year-old woman who continued to have psychotic symptoms despite treatment with conventional neuroleptic was started on clozapine. After 2 weeks at 100 mg per day, her psychotic symptoms diminished. Other medications were lithium, propranolol, haloperidol, and valproic acid. She had pyrexia, nausea, vomiting, right upper quadrant pain, and tachycardia. Gallbladder studies were normal. Leucocytes (18-5 x 109/1), eosinophils (19%), amylase (231 U/ml, normal = 16-108), alkaline phosphatase (147 IU/1, 0-41), and erythrocyte sedimentation rate (60 mm/h) were increased. We presumed clozapine-induced pancreatitis. Because of the association between valproic acid and pancreatitis,3 valproic acid was stopped with no change in her symptoms. Clozapine was then stopped and her somatic symptoms resolved within a few days. Her psychiatric status deteriorated and 30 days later, clozapine was restarted. Her somatic symptoms recurred within 2 weeks. Leucocyte count rose to 14-8 x’109/1 (no differential was done). Clozapine was stopped and her somatic symptoms resolved. The patient has been off clozapine for the past 2 years with no recurrence of pancreatitis. There was a temporal relation between the use of clozapine and two episodes of abdominal symptoms with pyrexia and increased

leucocyte count, with a clear "on-off-on" pattern. The patient also had an eosinophilia (which has been reported with clozapine)4 at the time of the first episode of pancreatitis, suggesting a possible

allergic aetiology. McLean

Hospital,

Belmont,

FRANCES R. FRANKENBURG

Massachusetts 02178-9106, USA

JUDY KANDO

1.

Baldessarini RJ, Frankenburg FR. Clozapine: anovelantipsychoricagent. N Engl J Med

1991; 324: 746. 2. Martin A. Acute pancreatitis associated with clozapine use. Am J Psychiatry 1992; 149: 714. 3. Murphy MJ, Lyon LW, Taylor JW, Mitts G. Valproic acid associated pancreatitis in an adult. Lancet 1981; i: 41-42. 4. Stricker BHC, Tielens JAE: Eosinophilia with clozapine. Lancet 1991; 338: 1520. 5. Tiihonen J, Paanila J. Eosinophilia associated with clozapine. Lancet 1992; 339: 488.

Hepatic injury associated with itraconazole SIR,-Liver enzyme may be slightly raised during treatment with antimycotic itraconazole.l,2 We describe three cases of symptomatic hepatic injury associated with this drug. Case 1 (62/F, itraconazole 100 mg twice daily for onychomycosis5 weeks later she complained of malaise, nausea, pain in right flank, pale stools, and dark urine. Itraconazole was stopped. There was no history of alcohol abuse, operations, or transfusions and she did not use other drugs. Laboratory values are shown in the table. Ultrasonography revealed a mildly enlarged liver. 2 weeks later she had pruritus, weight loss, and jaundice. Total bilirubin and conjugated bilirubin increased to 97 pmol/1 and 80 umol/l, respectively, whereas the other values gradually decreased. 2 months later all laboratory indices were normal. Case 2 (75/M itraconazole 200 mg twice daily for bronchopulmonary aspergillosis)--In the sixth week of treatment he was jaundiced. There was no history of transfusions or operations and he did not use other drugs. Itraconazole was discontinued. Echography of the liver and biliary tract showed the

abnormalities. Serum bilirubin increased to a maximum of 183 nmol/1. 10 weeks later all liver function tests were normal. Case 3 (57/F itraconazole 100 mg twice daily for chronic mycosis of soles and toe nails}-5 weeks later she had a temperature of 402°C, anorexia, headache, and insomnia. She used topical imidazole but no other drugs and there was no history of transfusions or operations. Itraconazole was stopped and the patient received 30 mg prednisone for 5 days, which resulted in disappearance of pyrexia and subjective symptoms. After discontinuation of itraconazole, alkaline phosphatase and y-GT increased slightly during 10 days to 392 U/1 and 275 U/1, respectively. 1 month later, laboratory data were almost normal. no

LABORATORY AND SEROLOGICAL INDICES I

I

I

y-GT=gamma-glutamyl transferase ND=notdone -=negative

I