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to believe that plasma exchange would do any more than

temporarily lower the serum concentration of any IgG antibodiesby about 20%, a useless contribution when the antibody is probablybeing synthesised within the CNS compartment. I am not in theleast surprised that the participants in this debate found no value inthese procedures-I am a bit surprised that they even thought theywere worth studying.

I know of only two treatments that can deal with establishedsecondary immune responses (T-cells and B-cells). One is totalbody irradiation followed by a bone-marrow transplant. To justifythat, one would have to be certain that the patients’ disease wasgoing to cripple them, and then make that decision before it was toolate-and this is one of the biggest difficulties in multiple sclerosis.The alternative is the "Gorski manoeuvre" (after the

immunologist in the Polish team who conceived it and established itin mice with severe autoimmune disease’). This procedure reducesa mean serum antibody level of around 130 units down to about 6.My own team have lowered IgM anti-B or anti-A titres from 256 to2-4 in three separate patients by this manoeuvre. The conceptinvolves a series of plasma exchanges (eg, for IgM one will do; forIgG three in 3 days) to achieve a 70-90% reduction of antibodies,which will remove negative feedback and encourage the memoryclones of committed lymphocytes to go into division. Even then, ifcyclophosphamide alone is used, it is still not possible to achieve alarge enough elimination. The Polish team followed the last of theexchanges with a dose of immunomodulator; they chose a thymicfactor extract and we have used this too because these extracts makeCD4 helper T-cells release activators for B-cells. This requires thatsuch T-cells should be uninhibited, so no corticosteroids,cyclosporin, or other immunosuppressives should be active for 4-72hours while the T-cytokines are being released and acting. In futurewe might be able to use a combination of interleukins 4 and 6. Theeffect is to increase recruitment in the number of specific memorycells that would go into division, and exactly 24 hours after thethymic extract quite acceptable doses of cyclophosphamide can begiven such as 20 mg/kg, and again at 48 hours. These doses willcatch the lined-up lymphocytes at a crucial moment during theirpreparation for division and synthesis and result in a sharpreduction in antibody concentrations. In some patients remissionsof up to one year without any need for other treatments have beenachieved in myasthenia gravis and similar diseases. Nevertheless,even with such clever manoeuvres, it still remains almost impossibleto delete all reactive clones and almost always their products willreturn. The beauty of the Gorski manoeuvre is that it is repeatable,provided skin testing is done for whichever immunomodulator isused a second time.

Department of Immunology,Charing Crossand Westminster Medical School,

London SW1 P 2AP, UK J. R. HOBBS

1. Gorski A, Podobinski R, Nowaczyk M, Korczak-Kowalska G. Immunomodulatoryeffects of thymic factor (TFX) on the interactions between T- and B-cells and theirsensitivity to immunosuppressive agents. In: Byrom NA, Hobbs JR, eds. Thymicfactor therapy. New York: Raven, 1984: 103-12.

Megadose methylprednisolone or IVIG foridiopathic thrombocytopenic purpura

SiR,—Ozsoylu et all reported the successful use of megadosemethylprednisolone (MDMP) for chronic idiopathicthrombocytopenic purpura (ITP) in a 7-year-old boy after thefailure of the usual dose of prednisone and intravenous

gammaglobulin (IVIG). We disagree with some aspects of thisreport.

First, no clear difference was shown between acute and chronicITP. According to Ozsoylu et al, both have a favourable outlook.We think this is not so. Acute ITP in children has an 80-85%

spontaneous remission rate, whereas chronic ITP in children, as inadults, rarely remits without treatment.2

Second, they say that with IVIG almost all patients haveside-effects, mentioning haemolysis3.4 This notion differs from thegeneral experience that IVIG is safe with a very low frequency ofmajor side-effects.5 Haemolysis associated with the use of IVIG is

very rare. Furthermore, IVIG has been proposed as a therapeuticoption in autoimmune haemolytic anaemia.6 We do not think that ahigh frequency of side-effects is good reason to choose MDMPinstead of IVIG.

Third, the therapeutic approaches in acute and chronic ITP arealso different. In acute disease, treatment, when necessary, tends torapidly raise the platelet count to avoid haemorrhage. In this senseIVIG and MDMP have shown their usefulness. In chronic disease,treatment (eg, prednisone, splenectomy, immunosuppressives)tends to produce sustained recovery of platelets. In children over 6years old with chronic ITP, splenectomy is an alternative thatshould be considered after the failure of normal-dose prednisone.

Haematology Department,Hospital Britanico DE BS. AS,Perdriel 74 (1280),Capital Federal,Argentina

G. R. STEMMELINC. M. SHANLEY

J. M. CERESETTOE. O. BULLORSKY

1. Özsoylu S, Hicsonmez G, Duru F. Megadose methylprednisolone for chronicidiopathic thrombocytopenic purpura. Lancet 1990; 336: 1078-79.

2. Williams W, Beutlher E, Erslev A, Lichtman MA. Thombocytopenia due to enhancedplatelet destruction by immunologic mechanisms. In. Hematology, 4th edToronto: McGraw-Hill, 1991: 137-98.

3. Nakamura S, Yoshido T, Ohtake S, Matsuda T. Hemolysis due to high doseintravenous gammaglobulin treatment for patients with idiopathicthrombocytopenic purpura. Acta Haematol 1986; 76: 115-18.

4. Kim HC, Park CL, Cowan JH III, et al. Massive intravascular hemolysis withintravenous immunoglobulin in bone marrow transplant recipients. Am J PediatrHematol Oncol 1988; 10: 69-74.

5. Berkman SA, Lee ML, Gale RP. Clinical uses of intravenous immunoglobulins. AnnIntern Med 1990; 112: 278-92.

6. Bussel JB, Cunningham-Runaldes C, Abraham C. Intravenous treatment ofautoimmune hemolytic anemia with very high-dose gammaglobulin. Vox Sang1986; 41: 264

Long-term safety and tolerability ofintravenous immunoglobulin

SIR,-Intravenous immunoglobulins (IVIG) have been usedsince the late 1970s to treat patients with primaryhypogammaglobulinaemia and more recently for autoimmunediseases.1 Several commercial preparations have been licensed bythe regulatory authorities in the UK, most having passed formalclinical trials to show that they are well tolerated and do not transmithepatitis viruses. However, a brief look at the history of IVIGtherapy over the last decade suggests that we should not be

complacent. There were two major and two minor outbreaks ofnon-A, non-B hepatitis associated with four different IVIG

preparations during the 1980s, and during the last year there hasbeen a small cluster of cases in Italy associated with a licensedpreparation.2-4 Most experts agree that the manufacturing methodsused for these "second generation" preparations are on the edge ofsafety, and much depends on the standard of management of thefactory and on the degree of viral contamination in the plasma poolsthat provide the starting material. This concern has led to the recentintroduction of specific antiviral steps in the process, providing"third generation" IVIGs.We summarise our experience with a second-generation IVIG in

patients with primary hypogammaglobulinaemia, providing a

useful yardstick with which to compare new preparations. 42patients (6 X-linked, 36 common variable) had liver function testedat routine clinic visits; all patients had exclusively received’Sandoglobulin’, at doses of 200-400 mg/kg every two weeks for upto 8 years (mean 3 years). In 10 patients, transient minor increases(< 100 IU/1) in serum aspartate transaminase and/or alaninetransferase developed, but there was no evidence of chronic liverdisease on formal assessment in 1989. 1 patient had chronic liverdisease with splenomegaly and persistently raised serum

transaminases associated with chronic inflammatory bowel disease.Tolerability was generally satisfactory, although minor reactions

were common. The following data relate to records keptprospectively by 28 patients (5 X-linked, 23 common variable)receiving 1385 infusions of IVIG. There were fifty-five reactions(none in 15 patients, one [all mild] in 6, two to five in 3, and over fivein 4). The main symptoms during reactions were shivering and/orheadache 44, nausea/vomiting 6, tightness in chest 3, faintness 1,and aching of joints 1.

195

These patients receive large quantities of IVIG over a longperiod, and provide important information on the safety of IVIGs.Our data confirm the general impression that sandoglobulin hasenjoyed a long record of safety,s although we need to exclude thepossibility that small rises in liver enzymes are due to transientsub-clinical hepatitis C virus infection, with perhaps the occasionalpatient acquiring chronic HCV hepatitis. Tolerance to infusions is aless important issue, but there may be differences between

preparations. It will be useful to compare our data with that fromsurveys of other IVIGs in the future.

Immune Deficiency Research Group,MRC Clinical Research Centre,Harrow HA1 3UJ, UK

M. HANYA. RYANA. D. B. WEBSTER

1. Imbach P, ed. Immunotherapy with intravenous immunoglobulins. London:Academic Press, 1991.

2. Intravenous gammaglobulin for immunodeficiency; report from the European Groupof Immunodeficiencies (EGID). Clin Exp Immunol 1986; 65: 683-90.

3. Williams PE, Yap P-L, Gillon J, et al. Transmission of non-A, non-B hepatitis bypH4-treated intravenous gammaglobulin. Vox Sang 1989; 57: 15-18.

4 Quinti K, Guerra E, Scala E, et al. Anti-HCV antibodies in gammaglobulin forintravenous use. In: Chapel HM, Levinsky RJ, Webster ADB, eds. Progress inimmunodeficiency III. London: Royal Society of Medicine Services, 1991: 150.

5. Cunningham-Rundles C. Immunoglobulin replacement therapy. In. Webster ADB,ed. Immunodeficiency and disease. London: Kluwer Academic, 1988: 43-60.

Monoclonal anti-CD25 for acute rejectionafter liver transplantation

SIR,-Antibodies to interleukin-2 receptors (CD25) represent anovel approach to the prevention of acute allograft rejection.l-4 Lastyear we reported a pilot study with the monoclonal CD25 antibodyBT 563 (Biotest-Pharma) in liver transplantation.s This study hasnow been extended to 19 consecutive transplantations, withmodification of both dose of antibody and the basic

immunosuppressive regimen.In a historical control group (n = 6, mean age 51)

immunosuppression consisted of methylprednisolone 1 ’5 mg/kgtapered down to 0 1 mg, cyclosporin (blood concentration 300-400ng/ml [monoclonal] for 2 weeks, thereafter 100-200 ng/ml), andazathioprine 1 ’5 mg/kg for 2 months. Three regimens with BT 563have been used: (A) n = 6, mean age 43, 10 mg BT 563 per 24 h for10 days by continuous infusion and 10 mg by intravenous bolusevery other day until day 20, plus additional immunosuppressivedrugs as in controls; (B) n = 3, mean age 40, 5 mg BT 563 per 24 hfor 10 days and 5 mg every other day until day 20, plusadditional immunosuppression as in controls; and (C) n = 10, meanage 44, 10 mg BT 563 per 24 h for 12 days, plus additionalimmunosuppressive treatment reduced to 50% of that in controls.The primary diagnoses, which were comparable in the four

groups, were hepatoma 7, chronic hepatitis 8, primary biliarycirrhosis 4, alcoholic cirrhosis 4, fulminant liver failure 1, andechinococcosis 1. The controls had had a biopsy if clinicallyindicated whereas the patients on BT 563 had planned biopsies ondays 7,14, and 21. For histological grading we used the Hannoverc1assification.6 An increase in bilirubin and a concomitant rise inaminotransferase activity with histopathological proof of rejectionwas defmed as "complete" rejection. However, even though thistriad was incomplete some patients were treated for rejection.Of the 25 patients, 22 are alive and well 4-13 months

postoperatively; 3 died from recurrent tumour 4-5 months after thetransplant. BT 563 did not cause side-effects such as fever, rash, or

NUMBER OF REJECTIONS DURING AND AFTER PROPHYLACTICTREATMENT WITH BT 563

other symptoms of acute serum sickness. The rate of infection was

comparable in controls and BT 563 treated patients; there were fiveepisodes in 3 controls and nine episodes in 7 patients on BT 563.Episodes of complete and incomplete rejection among controls andpatients who received BT 563 are shown in the table. All but twoepisodes were easily controlled with methylprednisolone 3 x 0-5 g;the two steroid-resistant episodes were controlled with OKT3.Even when conventional immunosuppression was much reduced(C) the rate of rejection remained remarkably low among patientswho received BT 563. In 15 of the 56 protocol biopsies, histologicalsigns of rejection were noted but they were not accompanied byclinical signs or laboratory abnormalities.

Chirurgische Universitatsklinik Heidelberg,6900 Heidelberg, Germany

GERD OTTO

JOCHEN THIESTHOMAS KRAUSMARTIN MANNERCHRISTIAN HERFARTH

Pathological Institute,University of Heidelberg WALTER J. HOFMANN

Biotest-Pharma GmbH, Dreieich HELMUT SCHLAG

Department of Immunology,Deutsches KrebsforschungszentrumHeidelberg STEFAN MEUER

1. Herve P, Wijdenes J, Bergerat JP, et al. Treatment of acute graft-versus-host diseasewith monoclonal antibody to IL-2 receptor. Lancet 1988; ii: 1072-73.

2. Cantarovich D, Le Mauff B, Hourmant M, et al. Anti-IL2 receptor monoclonalantibody (33B3.1) in prophylaxis of early kidney rejection in humans: a randomizedtrial versus rabbit antithymocyte globulin Transpl Proc 1989; 21: 1769-71.

3. Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of amonoclonal antibody against the interleukin-2 receptor (33B3.1) as compared withrabbit antithymocyte globulin for prophylaxis against rejection of renal allografts.N Engl J Med 1990; 322: 1175-82.

4. Carpenter CB, Kirkman RL, Shapiro ME, et al. Prophylactic use of monoclonalanti-IL-2-receptor antibody m cadavenc renal transplantation. Am J Kidney Dis1989; 14: 54-57.

5. Otto G, Thies J, Manner M, et al. Monoclonal antibody to interleukin-2 receptor inliver graft rejection. Lancet 1990; 335: 1596-97.

6. Kemnitz J, Ringe B, Cohnert T, et al. Bile duct injury as a part of diagnostic criteria forliver allograft rejection. Hum Pathol 1989; 20: 132-43.

Cyclosporin analoguesSIR,-In considering candidate immunosuppressive drugs

which might replace cyclosporin in clinical practice, Professor Bach(July 6, p 59) is incorrect in describing rapamycin and

mycophenolic acid as cyclosporin analogues. Neither rapamycin(like FK 506, a macrolide) nor mycophenolic acid (like azathioprine,a purine synthesis inhibitor) is related structurally to cyclosporin, acyclic endecapeptide. Moreover, the three drugs have quite distinctmodes of action.2,3 Despite considerable effort, no cyclosporinanalogue, derivative, or metabolite has yet emerged with a highertherapeutic index than cyclosporin.Division of Transplantation,Department of Surgery,University of Pittsburgh,Pittsburgh, Pennsylvania 15261, USA A. W. THOMSON

1. Wood RP, Katz SM, Kahan BD. New immunosuppressive agents. Transplant Sci1991, 1: 34-46.

2. Sigal NH, Lin CS, Siekierka JJ. Inhibition of human T-cell activation by FK 506,rapamycin and cyclosporine A. Transplant Proc 1991; 23 (suppl 2): 1-5.

3. Allison AC, Almquist SJ, Muller CD, Eugui EM. In vitro immunosuppressive effectsof mycophenolic acid and an ester prodrug, RS-61443. Transplant Proc 1991; 23(suppl 2): 10-14.

Foodborne intoxication associated withseaweed

SIR,-We report preliminary information on a common-sourceoutbreak offoodbome intoxication associated with seaweed. Over a24 h period five people presented with vomiting, diarrhoea, stomachcramps, respiratory distress, muscle spasms, and numbness of theextremities and were admitted to hospital with a provisionaldiagnosis of ciguatera fish poisoning. Two patients with similarsymptoms but who were less seriously affected were briefly held forobservation; two additional patients were treated by privatephysicians as outpatients. These patients were from five households