MORBIDITY OF VERY-LOW-BIRTHWEIGHT INFANTS

729

LONG-TERM HEPATOTOXICITY OF TACRINE

SiR,—The use of oral tacrine (tetrahydroaminoacridine, THA) long-term palliation in Alzheimer’s disease was described in 1986.1 In January, 1987, we reported the first two cases of apparent hepatotoxicity to the US Food and Drug Administration, and there for

has been concern about this issue ever since.2,3We report here our further experience with THA and toxicity. 48 patients with undifferentiated dementia were studied between June 14, 1981, and Feb 1, 1988. No-one was excluded becauses concomitant medical diagnoses or the use of vitamiricor medications.’ All were asked to take more than eight capsuies of lecithin daily. The daily dose of THA was individually determined and fell between 75 and 200 mg. If improvement was noted the patient was advanced to the double-blind phase in an outpatient setting. If the patient improved on oral THA (vs placebo) he or she was offered long-term THA, with monthly laboratory check-ups. In this report "liver-function tests" refer to aspartate and alanine aminotransferases (AST, ALT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), and total bilirubin. Normal ranges were established as the median of seven reference standards. We use medians and interquartile ranges to display the data plus the highest outlier. Analysis was confined to 30 months (only 2 patients were on THA for longer). Of the 48 patients 3 were not given THA. In the 45 who took the drug the maintenance dose was 75-200 mg daily. 14 were dropped from the study before 3 months but not because of side-effects. The remaining 31 took oral THA for 3-44 months (mean 18; figure). Of the original 45 patients, 8 had abnormal liver-function tests, 6 within 8 weeks of the start of therapy. 6 of the 8 subjects were on

drugs known to be hepatotoxic and m only 2 cases was THA s copped because ut an apparent adverse liver effect of this drug; in 5 of the other 6 cases removal of a concomitant offending drug and/or reduction of I HA dose resulted in acceptable lowering of liver t’ther

function ll.Ò1U’,s

Hepanc ’ uf "’iJ’;obtained in 4 cases (biopsy 2, necropsy 2). All 4 showed " ai in on’’nuclear cell inflammation scattered with occasion;.. eosinuphils There was no evidence of non-caseating epnhr’’ granulomatous reactions3 or cholestasis,’ and the hepatic ar~4; :f.cure was

fully preserved.

THA has been said to be severely hepatotoxic.2.5 We disagree. Although 8 (18%) of the 45 patients had any abnormality in liver function tests only 2 were removed from the study for this reason, and in those exposed to THA for 18 months on average there was no trend towards cumulative toxicity. The hepatotoxicity of THA seems to resemble that of benign hepatic reactions to

cWorpromazine.6 Should THA be continued in the face of moderate increases in is a fatal illness, and it seems reasonable not to discard THA until a more promising agent can be developed. However, we do not allow transaminases to drift above

hepatic indices? Alzheimer disease

200 IU/1 before intervening.’ We currently recommend weekly monitoring of liver function during the first 10 weeks. An

AST/ALT level of 120 IU/I may prove to be a reasonable risk/benefit boundary-provided there is improvement in the patient’s dementia. Solo Research, Arcadia, 91006 California, USA

WILLIAM K. SUMMERS

Department of Pathology, Huntingdon Memorial Hospital, Pasadena, California

ARTHUR L. KOEHLER

Department of Biostatistics, University of Pittsburgh

GARY M. MARSH

Department of Psychiatry, K. TACHIKI Sepulveda VA Hospital, ARTHUR KLING Sepulveda, California 1. Summers WK, Majovski LV, Marsh GM, et al Oral tetrahydroaminoacridine m long term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241-45 2. Marx JL. Alzheimer’s drug trial put on hold Science 1987; 238: 1041-42 3. Ames DJ, Bhathal PS, Davies BM, et al. Hepatotoxicity of tetrahydroacridine Lancet

1988; i: 887 HJ. Hepatotoxicity New York: Appelton-Century-Crotts. 1978:3-31,

4. Zimmerman

349-69. 5. Katzman R. The mystery of Alzheimer’s disease. Exec Health

6. Ockner RK

Drug induced liver diseases. In. Zakin Philadelphia: Saunders, 1982: 691-722.

Rep

1988. 25: 1-4

D, Boyer ID. eds Hepatology

MORBIDITY OF VERY-LOW-BIRTHWEIGHT INFANTS

SiR,—From Professor Pharoah’s comments (March 4, p 499) it appears that we were not clear enough m our report on morbidity of very-low-birthweight infants in the Netherlands (Feb 4, p 253) The use of the term handicap was deliberate. The word implies disturbance of normal life,’ placing the impairment or disability in social context. Handicap was used throughout in that way, looking the probability of a child going to a normal school and at interference with normal life. Pharoah correctly mentions the problem of interobserver variability, as we did. Precisely because of possible differences in allocating cases to the minor or major handicap category, we did not analyse these categories separately. Thus we stated that no relation between total handicaps and gestational age or birthweight could be found. We also stated that multivariate analysis, adjusting for other perinatal risk factors, was required to establish the importance of each factor. Therefore, logistic regression was done with gestational age and birthweight as exposure (independent) variables, total handicaps as outcome (dependent) variable, and eleven perinatal risk factors as potential confounders (socioeconomic class, pre-existing maternal a

at

Serial AP and AST activities in 31 patients on THA.

(A fuller illustration, with LDH activities and white-blood-cell counts is obtainable from The Lancet.)

disease, infants’ sex, maternal hypertension, congenital malformation, multiple pregnancy, antenatal transport, tocolysis, maternal glucocorticoid administration, fetal presentation, intrauterine growth retardation). From this analysis, there again appears to be no systematically increasing or decreasing relation

730

patient. The diagnosis of HPV infection was established by finding specific anti-HPV IgM in serum. Three days later, petechial purpura appeared; haemoglobin 12 g/dl, white cell count 2-3 x 109/1, and platelets 15 x 109/1. During the following days,

between handicap and gestational age (odds ratio 0 97 per additional week of gestational age, 95% confidence interval 086-1 09) or birth weight (0-98 per additional 100 g birthweight, O’90-l 08), after adjusting for risk factors. The results of this analysis strengthen our previous conclusion: handicap at the corrected age of 2 years is unrelated to gestational age or birthweight in this geographically defmed cohort of very preterm and very-low-birthweight infants. Some ol the other perinatal risk factors, however, were found to be significantly associated to later outcome. These findings will be reported

this

separately.3

anaemia).

POPS

blood count returned to its usual value. The severity of the thrombocytopenia in these two cases may be explained by a combination of the two mechanisms mentioned by Evans. The first case shows that intense thrombocytopenia can occur in HPV infection without acute anaemia (aplastic crisis is clinically apparent only in patients with chronic haemolytic

Study Centre,

Department of Neonatology and Paediatrics, University Hospital, 2300 Leiden, Netherlands

THEA M. VAN ZEBEN-VAN DER AA S. PAULINE VERLOOVE-VANHORICK RONALD BRAND

Institut National de Transfusion

Sanguine,

Alexandre-Cabanel, 75015 Paris, France rue

J. J. LEFRÈRE A. M. COUROUCÉ C. KAPLAN

JJ, Couroucé AM, Bertrand Y, Girot R, Soulier JP. Human parvovirus and aplastic crisis in chronic hemolytic anemias. a study of 24 observations. AmJ

1. Lefrère 1. WHO International classification of impairments, disabilities, and handicaps. Geneva: WHO, 1980. 2. Bax M. Looking at learning disorders. Dev Med Child 1982; 24: 731-32. 3 van der Bor M, van Zeben-van der Aa ThM, Verloove-Vanhorick SP, Brand R, Ruys JH. Hyperbilirubinemia in very preterm infants and neurodevelopmental outcome at 2 years of age: results of a national collaborative study. Pediatrics (in press).

PARVOVIRUS-ASSOCIATED THROMBOCYTOPENIC PURPURA

SiR,—The reports of Dr Foreman and colleagues (Dec 17, p 1426) and Dr Lefrere and colleagues (Feb 4, p 279) indicate that

thrombocytopenia may be associated with parvovius infection. It would be interesting to know if the thrombocytopenia is due to a direct depressing effect on the bone marrow, specific to parvovirus, or to a non-specific immunological reaction that follows infection with many other pathogens, amongst which we must now include the parvovirus. Foreman and colleagues’ patient was unwell for three weeks, which suggests that the second mechanism applied. This is further supported by the fact that the patient took six weeks to recover whereas recovery from an acute bone marrow suppression associated with viraemia would be expected to be more rapid. Could Lefrere and colleagues tell us more about their patients? Were the patients ill before thrombocytopenia developed? Did the platelet count recover rapidly? acute

Department of Pathology, Booth Hall Children’s Hospital, Blackley, Manchester M9 2AA

D. I. K. EVANS

**Thisletter has been shown to Dr Lefrere and colleagues, whose reply follows.-ED. L. SIR,-The two mechanisms suggested by Dr Evans can be responsible for the thrombocytopenia sometimes observed in human parvovirus (HPV) infection. Besides its erythroblastopenic effect, HPV can sometimes cause a transient decrease in platelet count. A moderate thrombocytopenia of central origin, secondary to a hypoplastic effect on the megakaryocytes, seems common in HPV infection. An intense thrombocytopenia of peripheral origin, due to a non-specific immunological reaction (idiopathic thrombocytopenic purpura [ITP]) seems much rarer in this infection. Two cases of our series of ITP linked to HPV infection were as follows. Case1 (girl, aged five years, petechial purpura after upper respiratory tract infection).-The blood count revealed normal haemoglobin level (with reticulocytes below 5 x 109/1) and white cell count but a platelet count of 8 x 109/ 1. Bone marrow examination on admission revealed an increased number of megakaryocytes and erythroid precursors. The presence of antiHPV IgM in the serum demonstrated recent HPV infection. After five days of treatment (intravenous gammaglobulin, then corticosteroids), the platelet count returned to normal. Case 2 (boy, aged ten years. Chronic haemolytic anaemia with splenomegaly; blood transfusions every month since first year of life).-He was admitted with a temperature and severe anaemia (haemoglobin 3 g/dl) requiring immediate transfusion of 800 ml packed red cells, neutropenia (27x109/1), and thrombocytopenia (90 x 109/1) which, because of the hypersplenism, was normal for

Hematol 1986, 23: 271-75.

CD4 IS NOT THE MEMBRANE RECEPTOR FOR HHV-6

SIR,-Human herpesvirus type 6 (HHV-6) has a predominant tropism for CD4-positive T lymphocytes in vitro.1 CD4-positive cells also constitute the major target of human retroviruses, and for two of them (HIV-1 and HIV-2) the CD4 molecule itself is the major receptor structure on the membrane of susceptible cells. Our demonstration that individual T lymphocytes can be simultaneously and productively coinfected by HHV-6 and HIV- 12 raised the question whether HHV-6 makes use of the same receptor as HIV-1. This question may be important in light of the potential interactions between the two viruses in the pathogenesis of AIDS. Several lines of evidence indicate that CD4 is not implicated in the receptor mechanism for HHV-6. Firstly, unlike CD4, the putative HHV-6 receptor seems to be expressed on the surface membrane of activated, but not resting, T cells (unpublished). Secondly, we have done competition experiments with monoclonal antibodies (MoAb) directed to human CD4 (ie, OKT4, OKT4a, Leu3a) or the truncated, soluble form of the CD4 protein (sCD4) in an attempt to block viral infection. Normal, phytohaemagglutinin (PHA) activated, human cord blood mononuclear cells were pretreated for 1 h at 4°C with the MoAb (5 I1gjrnl) and exposed for 1 h to HHV-6 or HIV-1. The cells were then washed several times and cultured for up to 20 days. To test the activity of sCD4, virus stocks were preincubated with the protein (3 I1gjrnl) for 1 h at 4’C and then used to infect PHA-activated cells. The MoAb and sCD4 were maintained at the original concentration throughout the culture period. Virus expression was monitored by indirect immunofluorescence, titration of released virus, and antigen capture assays. No significant inhibition of HHV-6 expression was observed in any of the tests, while sCD4 and the OKT4a and Leu3a completely abrogated HIV-1infection. As further evidence for the use of different receptor structures by the two viruses, HHV-6 was found to superinfect human T-cell lines chronically harbouring HIV-1(eg, CEM), whose membrane CD4 is down-regulated or complexed with the gp120 envelope glycoprotein of HIV-1. We conclude that HHV-6 infection occurs via CD4-independent mechanism(s). The lack of interference between HHV-6 and HIV-1may be clinically relevant since the simultaneous presence of both viruses within the same target cell in vivo can permit HHV-6 to accomplish its documented trans-activation function on the HIV-1

regulatory sequences (LTR). Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, Maryland 20892, USA

PAOLO LUSSO ROBERT C. GALLO

Department of Cell Biology, Bionetics Research Inc, Rockville, Maryland

SUSAN E. DEROCCO PHILLIP D. MARKHAM

P, Markham PD, Tschachler E, et al. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J Exp Med 1988, 167: 1639-70. 2. Lusso P, Ensoli B, Markham PD, et al. Productive dual infection of human CD4 + T lymphocytes by HIV-1 and HHV-6. Nature 1989; 337: 370-73. 1. Lusso