913

ANTI-HCV RESULTS IN IMPLICATED AND NON-IMPLICATED DONORS

conventional smallpox vaccine were a new product it would be unlikely to get a product licence for general use. The results reported by Cooney et al may aid our understanding of the factors that determine the human virulence of vaccinia virus. Animal studies have shown that vaccinia recombinants which have the foreign gene inserted into the vaccinia thymidine kinase gene, and which are therefore TK-, tend to be attenuated.3.4However, the recombinant used by Cooney et al was also TK - ,sand produced results in man similar to that of the conventional TK+ vaccine. In fact in the two subjects tested who had not previously had smallpox vaccine the effect if anything was more severe than the conventional vaccine. Thus, whatever its attenuating effect in animals, it seems that inactivation of the thymidine kinase gene of vaccinia does not necessarily attenuate the virulence of the virus for man. University of Liverpool, Department of Medical Microbiology, Liverpool L69 3BX, UK

DERRICK BAXBY

1. Fenner F, Henderson DA, Arita I, et al. Smallpox and its eradication. Geneva: WHO, 1988 2. Buller RML, Smith GL, Cremer K, et al. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative

phenotype. Nature 1985; 317:

i

I

I

I

i

*Upper limrt of normal 40 U/I, ALT= alanine transferase t4-RIBA testing done on follow-up samples 20-35 mo postdonation +=pos!tMe,-=negat!ve

(structural) region of the HCV genome, have been coated in bands on nitrocellulose strips in addition to the 5-1-1 and C-100 antigens present in the first generation RIBA. The antigen band intensities are compared with weak positive and moderate positive control bands, and a response of 1 + or greater (up to 4 + ) to any two or more HCV antigens is interpreted as a positive result. We have tested samples from 9 implicated donors in our prospective post-transfusion hepatitis study,* each of whom was associated with 1 of the 9 post-transfusion HCV cases. In addition, 26 non-implicated C-100 ELISA positive donations, not associated with recipient hepatitis, were analysed. All 26 non-implicated ELISA-positive donor samples were non-reactive for the antigens C33c and C22 in 4-RIBA (table). All the implicated donors, however, showed reactivity for both antigens, including donors 2, 5, and 8, who were not detected by ELISA and were non-reactive for antigens 5-1-1 and C-100 in RIBA. In view of our experience, antibodies to the new antigens C33c and C22 seem to predict infectivity with high sensitivity, and their addition in the primary HCV screening assay is important. FREJA EBELING Finnish Red Cross Blood Transfusion Service, SF-00310 Helsinki, Finland

RUTH NAUKKARINEN GUNNAR MYLLYLÄ JUHANI LEIKOLA

1. Ebeling F, Naukkarinen R, Leikola J. Recombinant immunoblot assay for hepatitis C virus antibody as predictor of infectivity. Lancet 1990; 335: 982-83.

813-14.

3. Buller RML, Moss B Genetic basis for vaccinia virus virulence. In: Quinnan GV Jr, ed. Vaccinia viruses as vectors for vaccine antigens. New York: Elsevier, 1985: 37-46. 4. Rodriguez D, Rodriguez J-R, Rodriguez JF, et al. Highly attenuated vaccinia virus mutants for the generation of safe recombinant viruses. Proc Natl Acad Sci USA 5. Hu

1989; 86: 1287-91. S-L, Kosowski SG, Dallrymple JM. Expression of AIDS virus envelope gene in recombinant vaccinia viruses. Nature 1986; 320: 537-40.

Exacerbations of asthma in salmeterol

patients on

SIR,-Sears and colleagues’ paper on the effects of regular fenoterol’ has prompted concern about the safety of long-term use of regular p-agonists. On the basis of a small crossover trial Sears et al proposed that long-term treatment with regular fenoterol led to a deterioration in asthma and its control. They also suggested that such an effect might apply to other p-agonists. On the basis of data on over 2000 patients during the clinical development of salmeterol, a long acting inhaled &bgr;z-agonist, we drew different conclusions (Jan 5, p 43). Nevertheless it is pertinent that these concerns are raised now, since guidelines are being drawn up worldwide for the management of asthma, coinciding with the advent of new longer acting inhaled &bgr;z-agonists. Because salmeterol controls symptoms so effectively there is a possibility that it might mask any underlying deterioration. If so, the number of exacerbations would be a useful indicator of disease control. For the purpose of this study, an exacerbation was defined as any worsening of an asthma symptom recorded as an adverse event. Serious exacerbations were defined as those that caused death, were life-threatening, or resulted in hospital admission. In several large controlled clinical trials during the development of salmeterol the number of serious exacerbations was less in patients treated with salmeterol (12%,n 4658) than in those on control treatments such as other 0-agonists or theophyllines (2%; =

n = 3466).

Safety of recombinant vaccinia vaccines SIR,-Dr Cooney and colleagues’ report (March 9, p 567) of a trial of a recombinant vaccinia vaccine is of great interest for at least two reasons other than the fact that the vaccine expresses an HIV

antigen. Their conclusion that the recombinant vaccine is safe is based on direct comparison of the effects of the vaccine and conventional smallpox vaccine; both vaccines gave similar results. Thus for the recombinant to be considered safe it follows that Cooney et al regard conventional smallpox vaccine as safe-a conclusion with which many will disagree. The side-effects of smallpox vaccination are well known,’ and most workers interested in the development of recombinant vaccinia vaccines have emphasised the need for the vector to be attenuated further if such vaccines are to gain acceptance 2’ It is not altogether fanciful to suggest that if

a

A more detailed analysis of exacerbation rates in patients treated with salmeterol has been done for one of the pivotal development studies in which inhaled salmeterol 50 Ilg twice daily (n 361) was compared with salbutamol (n 358) over one year in patients with =

=

NUMBER OF PATIENTS WITH ASTHMA EXACERBATIONS

914

rhesus incompatibility was established. Serum bilirubin concentrations were monitored at 6 h intervals. Exchange transfusions were undertaken if serum bilirubin concentrations exceeded the modified curves of Polacek2 by more than 2 mgjdJ. The two groups were not significantly different with respect to birth weight, age, haemoglobin, and bilirubin concentrations on admission. Two patients, one in the control and one in the treatment group, were excluded from the final evaluation because of protocol violations. Results from 32 children were analysed. Of 16 children who received HDivGG, only 2 (12-5%) required exchange transfusion, while 11of 16 (69%) required transfusion in the control group (xl-test with Yates’ correction; p < 0-005). No side-effects were observed. The two treatment failures may be attributable to suboptimum management. In one, phototherapy was discontinued on day 2 without closely monitoring further bilirubin concentrations. This child required exchange transfusion on day 4. In the other child, HDivGG was given at 12 h when the bilirubin concentration was already 2 mg/dl below the exchange curve defmed by the protocol. The time available for HDivGG to act was probably too short because exchange transfusion was begun 2 h after administration of HDivGG. These preliminary data indicate that the frequency of exchange transfusion can be significantly reduced by combining conventional phototherapy with HDivGG. However, HDivGG is only effective if given early after a positive direct Coombs’ test result is obtained. HDivGG will not influence the elimination of bilirubin, but probably prevents its production by interaction with the reticuloendothelial system Fc receptors. A similar process may take place in patients with immune thrombocytopenia who are also treated with HDivGG.3,4 Since rhesus antibodies do not fix complement, antibody-coated red blood cells are probably eliminated via antibody dependent cellular cytotoxicity. The optimum dose of HDivGG, the number of infusions, and the best preparation remain to be determined. soon as

mild to moderate reversible airways obstruction. Exacerbations in the salmeterol patients were grouped according to the 3-monthly visit structure (although during the first 3 months visits also took place at 2, 4, and 8 weeks). The frequency of patients having 0, 1, 2, 3, or 4 exacerbations during each 3 month period were tabulated and the time in days for the first exacerbation to occur was analysed with an actuarial life-table method (table, figure). The total number of patients decreased during the study since not all completed 12 months. Patients who withdrew as a result of asthma exacerbation are included at the relevant time points. Those withdrawn for reasons other than asthma exacerbation are included until the time of the withdrawal. If long-term treatment with salmeterol leads to a deterioration in asthma and its control, we would expect to see an increase in the frequency of exacerbations during the study and an increase in the change, between time points, in the cumulative percentage of patients having their first exacerbation. The frequency of exacerbations in patients taking salmeterol was clearly higher in the first 3 month period but this almost certainly reflects the frequency of study visits during that time. The number of patients reporting several exacerbations in a 3 month period, during the last 9 months of the study, remained constant. The rate at which first exacerbations occurred did not increase during the trial, with changes in the cumulative percentage of patients with an exacerbation of 66%, 81%, and 7-8% between months 3 and 6,6 and 9, and 9 and 12, respectively. Improvements in lung function, as monitored during the first 3 months by increase in morning and evening peak expiratory flow rates, reduction in diurnal variation, and reduction in noctural symptoms, were maintained throughout the 12 month treatment

period. This study, of over 350 patients, is therefore at variance with Sears and colleagues’ suggestion. Similar analyses are under way for other studies. M. M.

JENKINS

C. J. HILTON J. C. DE KOCK J. B. D. PALMER

Glaxo Group Research Ltd, Greenford UB6 0HE, UK; and Glaxo Research Institute

German Rhesus Alloimmunisation Department of Paediatrics, University of Dusseldorf, D-4000 Dusseldorf, Germany

Study Group,

JOCHEN RUBO VOLKER WAHN

1 Rubo J, Wahn V. Versuch einer hochdosierten Gammaglobulm-therapie bei drei Kindern mit Hyperbilirubinamie bei Rhesusin-kompatibilitat Monatsschr Kinderheilkd 1990; 138: 216-20 2. Polacek K. Das universale Diagram zur Behandlung der Hyperbilirubinamie der Neugeborenen. Padiatr Prax 1984; 29: 1-3. 3. Derycke M, Dreyfus M, Robert JC, Tschernia G. Intravenous immunoglobulin for neonatal isoimmune thrombocytopenia. Arch Dis Child 1985; 60: 667-69. 4. Massey G, McWilliams N, Mueller D, Napolitano A, Maurer H. Intravenous immunoglobulin in treatment of neonatal isoimmune thrombocytopenia J Pediatr 1987; 111: 133-35

Warfarin

antagonism by avocado

SIR,-Warfarin antagonises vitamin-K-dependent coagulation factors, and resistance to its hypoprothrombinaemic effect caused by vitamin-K-rich vegetables has been reported.1-3 We present the warfarin-antagonising effect of avocado, which is low in vitamin K. A 15-year-old girl with antiphospholipid syndrome was being treated with warfarin for

1. Sears MR, Taylor DR, Print CG, et al. Regular inhaled bronchial asthma. Lancet 1990; 336: 1391-96.

beta-agonist

treatment m

High-dose intravenous gammaglobulin rhesus-haemolytic disease SIR,-We have completed

a

multicentre controlled trial

in to test

previously reported hypothesis1 that high-dose intravenous gammaglobulin (HDivGG) can reduce the frequency of exchange transfusions in newborn infants with Rhesus-haemolytic disease. After both ethical committee approval of our protocol and informed consent by parents, 34 children with a positive direct Coombs’test were randomly assigned to receive either conventional phototherapy alone or phototherapy with intravenous HDivGG (’Polyglobin N’, Cutter, Cologne, Germany) 500 mg/kg over 2 h, as our

a parieto-occipital brain infarct. She was adequately anticoagulated (international normalised ratio [INR] 2-5) for the first 6 weeks. Thereafter, while she was on the same dose of warfarin, the INR fell to 1 ’7. No other medications and no intercurrent illness were documented. At the time the patient was eating at least 100 g avocado every day. Once avocado was

eliminated from her diet, the INR returned to 2-5. 3 months later, despite advice, she started to eat avocado again and the INR fell to 17. A return to an avocado-free diet resulted in effective

anticoagulation once more. A 30-year-old woman in the 22nd gestational week of her sixth pregnancy was treated with heparin followed by warfarin because of pulmonary embolism. She was well anticoagulated, maintaining an average INR of 2-7. 2 months later she consumed 200 g avocado on two consecutive evenings, and her INR fell to 1-6. Elimination of

avodaco from her diet restored adequate anticoagulation. Avocado is low in vitamin K at 8 u.g per 100 g,4 compared

with

Exacerbations of asthma in patients on salmeterol.

913 ANTI-HCV RESULTS IN IMPLICATED AND NON-IMPLICATED DONORS conventional smallpox vaccine were a new product it would be unlikely to get a product...
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