PROGNOSTIC VALUE OF CYTOMEGALOVIRUS IgM ANTIBODY IN TRANSPLANT RECIPIENTS

1157 the fact that terminal care is not just a good and kind but both an art and a science. The challenge of developing the skills and services needed by the terminally ill has been met so far by people from all sorts of backgrounds (including those with impeccable qualifications and training) and their rich and varied experience has lent itself to an innovative approach to the work. But should this state of affairs be allowed to continue? As health authorities come under increasing pressure to provide good terminal care throughout their areas there will be greater need and demand for properly trained and experienced staff to look after patients directly in their care, to advise colleagues in hospital or general practice, and to teach. It seems essential that the excellent training opportunities now available in some hospices and continuing care units should be recognised and used fully for the benefit of staff and patients. So why not some rotations at senior registrar level? Doctors who intend to be full-time consultants/directors of units would certainly profit from experience acquired while still in training, rather than hasty arrangements made on an ad-hoc basis after appointment. Ideally this experience should be gained in an approved post in one of the bigger and well-established terminal care units with a teaching and research capacity. Some senior registrars whose chosen career is general medicine, oncology, or radiotherapy might also value experience in terminal care as a prelude to making their own contribution to caring for the dying from within the context of an NHS specialty and perhaps too as the consultant member of a symptom-control team. witness bedside

to

manner

St Christopher’s Hospice, 51-53 Lawne Park Road,

Sydenham,

GILLIAN FORD

London SE26 6DZ

CONSUMER VIEW OF RANDOMISED TRIALS OF CHORIONIC VILLUS SAMPLING

SIR,-Mr MacKenzie and colleagues’ letter (April 26, p 969) on the choices exercised by women wanting chorionic villus sampling (CVS) or amniocentesis highlights the dilemma facing those who wish to ensure proper evaluation of new medical procedures when faced with patients who have already decided. Responsible groups involved with maternity care have supported randomised controlled trials of CVS and recognise that while the trials are being conducted freedom of choice for individual women must be restricted. The randomised controlled trial of CVS is unique in that consumer groups were invited to become involved at an early stage. Following a meeting at the National Perinatal Epidemiology Unit, Oxford, one of the consumer representatives undertook to call a meeting of all the consumer groups interested in CVS, to discuss the proposals with the trial organisers, and to make recommendations. The meeting resulted in serious discussion of the issues and a broad consensus. The consumer representatives went back to their organisations with recommendations and a request for each organisation to endorse the Medical Research Council’s trial. The professionals involved returned with proposals and suggestions from the consumer groups, which were incorporated into the trial. Consumer groups were able and pleased to make suggestions at an early stage. One of the most important of those was an agreement that anyone entering the trial would be given written information which had been agreed and endorsed by the consumer groups. From the professional point of view one important feature of this trial is that, by enthusiastically entering into early discussion with the consumer groups, they have obtained consumer support. The Association for Improvements in the Maternity Services (AIMS) urged the trial organisers to restrict CVS to those women who were entered into the trial (except for women who already had a mid-trimester abortion because of a damaged child and women at very high genetic risk). Investigators in Canada and Denmark have also insisted on this and I am delighted to see that, in Britain, Oxford has responded to this suggestion. 21 Iver

Lane, Iver, Bucks SL0 9LH

BEVERLEY A. BEECH, Chair, AIMS

Hon

DRUG COMPANIES AND JOURNAL SUPPLEMENTS

SIR,-I agree with Professor Stavem (March 22, p 684) that anyone who becomes a full-time employee of a pharmaceutical company should not be the editor of an independent medical journal. His comment brought to mind the practice of a major US medical journal which publishes "supplements" of non-refereed articles at symposia sponsored by pharmaceutical companies. supplements have the same format as the normal journal, although they have no advertisements. In fact, the entire supplement is usually an advertisement for the drug company’s product and is subsidised by the drug company. The fact that this "independent medical journal" is owned by a for-profit corporation may explain this practice. In any case, for reasons similar to those given by Stavem, this practice should also be discontinued.

presented These

Montefiore Medical Center, East Elmhurst, New York 11370, USA

ROBERT L. COHEN

PROGNOSTIC VALUE OF CYTOMEGALOVIRUS ANTIBODY IN TRANSPLANT RECIPIENTS

IgM

infection in organ transplant and can be life-threatening or even fatal in primary infection, particularly when the virus is acquired from the donor organ.By contrast, reactivation of latent infection or reinfection is usually asymptomatic or associated with only mild illness. With the availability of foscarnet and B759U3,4 we need to be able to establish whether an immunosuppressed transplant recipient is experiencing a primary infection or reactivation or reinfection with CMV, so that early therapy can be given or the immunosuppression therapy modified when appropriate. We have studied 136 heart and heart-lung, 138 kidney, and 54 liver transplant recipients and have found serological evidence of CMV activity in 40%, 41%, and 48%, respectively. Primary infections were defined as those in which CMV antibody was not found by the complement fixation test (CFT) or competitive enzyme-linked immunosorbent assay (ELISA)5 in serum taken from patients either before or shortly after transplantation. Reactivation or reinfection was defined as a 4-fold or greater increase in CF titre after transplantation. Serum samples taken from patients after transplantation were tested for CMV-specific IgM by a p capture ELISAthat incorporated a peroxidase-conjugated anti-CMV monoclonal antibody.5 The wells of Falcon flexible enzyme immunoassay (EIA) plates (Becton Dickinson) were coated overnight at 4°C with 100 1 DAKO rabbit anti-human IgM antibody (diluted 1 in 2000 in carbonate/bicarbonate buffer, pH 9 -6). Plates were washed three times with 0-85% sodium chloride containing 0-8% ’Tween 20’. Then, 100 /1 of human test serum (diluted 1 in 100 in phosphate buffered saline [PBS]/tween 20) were added and the plates incubated at 37°C for 3 h. Serum dilutions were not placed in the top row of each plate. Reference control sera containing 100, 33, 10, 3-3, 1, 0 - 33, 0-1, and 0 arbitrary units per 0 -1 ml of CMV-specific IgM were included in each assay. The dilutions of antigen and conjugate were determined by chequerboard titrations. The plates were washed and 100 1 CMV antigen (Public Health Laboratory Service, Division of Microbiological Reagents and Quality Control, diluted 1 in 10 in PBS/tween 20 with 10% fetal calf serum) was added to each well which had contained serum. The plates were stored at 4°C overnight and then washed three times as previously, before 100 1 peroxidase-conjugated anti-CMV monoclonal antibody5 were added to all wells, except those in the top row. The plates were incubated at 37°C for 3 h then washed three times before 100 1 substrate solution (o-phenylenediamine 1 mg/ml and hydrogen peroxide 0 -41/ml in citric acid/phosphate buffer pH 5) were added to all wells. After incubation at room temperature for 30 min the reaction was stopped by adding 25 1 3 mol/1 sulphuric acid to each well. Absorbance was read at 492 nm in a ’Titertek Multiskan’ (Flow Laboratories). The top row of wells, coated with anti-human IgM and containing substrate and stop solution, provided blank

Six,-Cytomegalovirus recipients is usually

(CMV)

severe

1158

neurologist to differentiate between bouts and exacerbations provoked by either physical or psychological factors. It is well known that infections-particularly in connection with feverprovoke deteriorations which are indistinguishable from bouts but should not be counted as such. On the other hand, multiple sclerosis (MS) patients do not consult their doctors with each bout, and this might be more likely when sinusitis and a bout occur together. It is remarkable that the well-known higher frequency of bouts after childbirth has not been found in this study, although Gay and co-workers state that they looked at "medical procedures, or other medical disorders ... and their coincidence with episodes of the

demyelination". There is no information on treatment. MS patients are frequently receiving corticosteroids and/or immunosuppressive drugs and this medication might have favoured sinus infections. But even if we assume that Gay et al were aware of these pitfalls and considered them, the results bear other interpretations. Patients with a particular immunological make-up could be prone to coin

Amount of

CMV-specific IgM (arbitrary units)

found in

sera

from

heart, kidney, and liver transplant recipients experiencing

primary zit) and reactivated (0) CMV infection.

readings. The amount of CMV-specific IgM in serum was determined by reference to a standard curve plotted from the results obtained with the reference positive control series. The figure shows that primary CMV infections (as defined above) were associated with 1 to over 33 units of CMV IgM, while reactivation/reinfection produced 0-10 units of CMV IgM. While there is some overlap, sera from kidney and heart transplant recipients containing 3 - 3 units or more of CMV IgM and sera from liver transplant recipients containing 10 or more units of CMV IgM are much more likely to be associated with primary CMV infection than with reactivation/reinfection. Such a finding may thus be an important prognostic indicator of primary CMV infection, for which treatment regimens are becoming available. We have found similar results with the Northumbria Biologicals CMV IgM assay, although positive control sera with a range of arbitrary units are not provided in the kits. Our experience in closely monitoring the CMV IgM response in heart transplant recipients, however, indicates that if CMV IgM is found early in the course of infection, it is often present at high levels (10 units or more) in the absence of detectable CF antibody. Microbiology and Public Health Laboratory, Addenbrooke’s Hospital, Cambridge CB2 2QW Division of Microbiological Reagents and Quality Control, Central Public Health Laboratory, London NW9

MS bouts and sinusitis. To eliminate this possibility, matching for HLA-groups is warranted. Compston et al2 compared the frequency of infections in DR2 positive MS patients and DR2 positive controls; no difference could be found between the two. Although viruses seem to be better candidates in the aetiology and/or of MS, bacteria are far from being ruled out. Morris speculates, in a letter on Sibley’s report on frequent correlations between upper respiratory infections and bouts of MS,4 that viral infections might disturb the normal bacterial flora and lead to overgrowth of staphylococci, streptococci, or gramnegative bacilli. A cross-reaction between bacterial antigens and human brain proteins might precipitate MS bouts. That spirochaetes, however, are involved in nasopharyngeal infections and could act as such triggers is unlikely, although Gay et al mention immunological and pathological similarities between Lyme disease and MS. The clinical spectrum of Lyme disease is, as a rule, different from that ofMS and the authors cited by Gay et al report the typical

pathogenesis

5

picture of meningoradiculitis. There seems to exist a progressive encephalomyelitis caused by Ixodes ricinus-Borrelia,6but the frequency and significance of this event remains to be established. Epidemiology of I ricinus distribution and risk for MS show a different pattern, and we have thus far found no patient diagnosed as MS with local formation of antibodies against I ricinus-Borrelia in the cerebrospinal fluid (unpublished data), which would be a proof of borrelia as a causal agent of central nervous involvement. Neurological Department of Göttingen University, D3400 Göttingen, West Germany

SIGRID POSER

T. G WREGHITT

J. J. GRAY

C. CHANDLER

Cytomegalovirus infection in transplant patients Progr Med Virol 1982; 28: 44-64 2 Betts RF, Freeman RB, Douglas RG, Talley TE, Rundell B Transmission of cytomegalovirus infection with renal allograft. Kidney Int 1975; 8: 387-94 3. Klintmalm G, Lönnqvist B, Oberg B, et al. Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients ScandJ Infect Dis 1985; 17: 157-63. 4. Ringden O, Wilczek H, Lönnqvist B, Gahrton G, Wahren B, Lernestedt J-O. Foscarnet for cytomegalovirus infections. Lancet 1985; i: 1503-04. 5. Wreghitt TG, Hicks J, Gray JJ, O’Connor C. Development ofa competitive enzymelinked immunosorbent assay for detecting cytomegalovirus antibody. J Med Virol 1986, 18: 119-29 1. Betts RF.

MULTIPLE SCLEROSIS AND SINUSITIS

SIR,-Although Dr Gay and his colleagues (April 12, p 815) state that "general practice records, contrary to popular belief, are often well organised and comprehensive", it is doubtful whether the occurrence and exact timing of bouts can be accurately ascertained by this retrospective procedure. In most cases it is difficult even for

1. Poser S, Poser W. Multiple sclerosis and gestation. Neurology 1983; 33: 1422-27. 2. Compston DAS, Vakarelis BN, Paul E, McDonald WI, Batchelor JR, Mims CA. Viral

infection in patients with multiple sclerosis and HLA-DR matched controls Brain 1986; 109: 325-44. 3. Morris JA. Clinical viral infections and multiple sclerosis. Lancet 1985; ii: 273 4. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis Lancet 1985; i: 1313-15. 5 Steere AC, Malawista StE, Bartenhagen NH, Spieler PN, Newman JH, Rahn DW, et al. The clinical spectrum and treatment of Lyme disease Yale J Biol Med 1984, 57: 453-61. 6. Ackermann

R, Gollmer E, Rehse-Küpper Enzephalomyelitis Deutsch Med Wschr 1985; 110:

B.

Progressive

Borrelien-

1039-42.

SIR,-Permit me to suggest that the association between chronic sinusitis and multiple sclerosis exists because both result from a third factor. Both MS and Hodgkin’s disease are associated with chronic respiratory disease, as exemplified by a frequent history of childhood tonsillectomy. 1,2 Hodgkin’s disease has a bimodal ageincidence curve and the first peak coincides, around age 30, with the single peak in the curve for MS. Both conditions in young adults are concentrated in the temperate zones of North America, Europe, and Australasia. In each case the earliest manifestations tend to appear during the winter months. These facts, and the existence of timespace clusters of both conditions, have led to strong suspicions of slow virus infections acquired during late childhood or adolescence