HOSPITAL MEDICAL STAFFING: HOPE AT LAST?

140

CYCLOSPORIN FOR DIABETES? INSULIN-DEPENDENT diabetes is caused by destruction of the insulin-secreting 0 cells of the pancreas. At diagnosis, such diabetics show immune changes in the peripheral blood, notably increased levels of activated T lymphocytes and autoantibodies to islet cells and insulin.1-3 These immune changes and the presence of inflammatory cells in the pancreatic islets have led to the suggestion that damage to the 0 cell is mediated by an autoimmune process.4 Another explanation is that the immune changes are the consequence of cellular damage rather than its cause. Damage to the 0 cell could be mediated by viruses which can activate lymphocytes and, in certain instances (eg, glandular fever and viral hepatitis), lead to the production of autoantibodies. In either event, the islet-cell damage would be associated with immune changes which could be treated with immunosuppression.

recently diagnosed insulin-dependent immunosuppression were first made nearly ten years ago, with inconclusive results.5,6 Subsequent studies with cyclosporin A, a potent suppressor of T-cellmediated immunity, suggested an effect .^1,8 However, the studies were uncontrolled and interpretation was complicated by the normal and frequent occurrence of a "honeymoon period"-a fall or even disappearance of insulin requirement within the first two years after diagnosis, followed by relapse.9 Two controlled studies of cyclosporin treatment were started, one in Canada, Denmark, and Germany, and the other in France. The first report of the French study by Dr Feutren and his colleagues appears in this issue (p 119). The results are interesting if not dramatic. 122 recently diagnosed insulin-dependent diabetics entered a doubleblind controlled study; at six months, insulin treatment was not required in 25% of patients treated with cyclosporin by comparison with 19% of the placebo group, while at nine months, 24% of the cyclosporin group but only 6% of the placebo group remained off insulin. Thus cyclosporin seems to have prolonged the honeymoon period in no more than a fifth of patients. These observations are consistent with the hypothesis that insulin-dependent diabetes is an autoimmune disease and that the islet-cell damage is, at least in part, mediated by Attempts

to treat

diabetics with

immune process. It remains to be determined whether cyclosporin will be of any therapeutic benefit. The French group speak of a "complete remission" when their patients are off insulin, yet the patients remained hyperglycaemic whilst on a diet. Difficult questions will therefore arise if the present trend towards a beneficial effect is sustained beyond the honeymoon period and if it is confirmed by the Canadian study. The aim must surely be to cure diabetes, which neither this nor previous studies have achieved. Is it an

1.

Alviggi L, Johnston C, Hoskins PJ, et al. Pathogenesis of insulin-dependent diabetes: A role for activated T-lymphocytes. Lancet 1984; ii: 4-6. 2. Bottazzo GF, Dean BM, Gorsuch AN, Cudworth AG, Doniach D. Complementfixing islet-cell antibodies in type-1 diabetes: Possible monitors of active beta-cell damage. Lancet 1980; i: 668-72. 3. Palmer JP, Asplin DM, Clemons P, et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983; 222: 1337-39. GF, McDevitt HO. Insulin-dependent diabetes mellitus: The initial lesion. N Engl J Med 1981; 304: 1454-65 5. Leslie RDG, Pyke DA, Denman AM. Immunosuppressive therapy in diabetes. Lancet 1985; i: 516. 6. Elliott RB, Crossley JR, Berryman CC, Jones AG Partial preservation of &bgr;-cell function in children with diabetes. Lancet 1981; ii: 1-4. 7. Stiller CR, Dupre J, Gent M, et al. Effects of cyclosporin immunosuppression m insulin-dependent diabetes mellitus of recent onset. Science 1984; 223: 1362-67. 8. Assan R, Feutren G, Debray-Sachs M, et al. Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus Lancet 1985; i: 67-71. 4. Cahill

sufficient to convert an insulin-dependent diabetic into a non-insulin-dependent diabetic? The patient would be glad not to need insulin injections but we do not know whether risks of diabetic complications would be reduced. Furthermore, if effective, cyclosporin might have to be continued indefinitely; pancreas transplanted from the unaffected to the diabetic member of pairs of identical twins can still be immunologically attacked years after the onset of diabetes. to

Against the hypothetical benefit of cyclosporin must therefore be set the considerable risks of taking the drug. After nine months’ treatment the French group observed a significant rise in creatinine and a significant fall in haemoglobin. It is also disconcerting that patients with anterior uveitis, an autoimmune disease, have been reported to show structural renal tubular and glomerular damage after cyclosporin treatment for an average of only two years-the kidney is an organ that we would be trying to protect from damage by the diabetic process." It is therefore far too soon to judge whether cyclosporin will provide adequate benefits to insulin-dependent diabetics to outweigh the significant risks. Nothing less than a cure of diabetes will ultimately be acceptable; any approach which gives hope of achieving that goal is worth pursuing. At present, immunosuppression should not be used in the treatment of diabetes except as part of a controlled clinical trial. HOSPITAL MEDICAL STAFFING: HOPE AT LAST? SOME of the manpower difficulties in the National Health Service look as though they may be nearing a solution at long last. The Minister for Health, Mr Barney Hayhoe, is doing more than any of his predecessors to secure a just solution to an ill which has vexed the NHS for many years. One reason for our midsummer optimism is that part of the proposed solution (see p 174), first published in 1973,1 has worked well in practice for general surgery for the past 14 years in part of the South-East Region. The distinction between registrar and senior registrar was then abolished and a new grade of surgical trainee was introduced. Each pair of surgeons had one trainee, half of whose time was spent in several of six district general hospitals and half at teaching hospitals. Of the total number of 20 trainees half were from overseas, making a ratio of permanent trainees to consultants of 1 to 4 (including 3 lecturers to help in the teaching of the 120 medical students and 80 dental students). An advantage of this scheme is that it is clearly fair, trainees being shared out among all the hospitals. Mr Hayhoe’s scheme treads very carefully on the issue of abolishing the distinction between senior registrar and registrar grades; and the hope is that this distinction will eventually fade away. It is, in fact, crucial that the distinction be removed as early as possible, not only to share out junior staff more equitably but also to attract overseas trainees who need higher training for their own College’s training requirements. What should now be avoided is a long debate on what to do with each registrar post. An across-the-board arrangement (one trainee for J, Selam JI, Pham JC, Mendoza F, Orsetti A. Sustained insulin-induced juvenile diabetes by means of an external artificial pancreas. Diabetologia 1978; 14: 223-27. 10. Sutherland DER, Sibley R, Chinn P, et al. Twin-to-twin pancreas transplantation: Reversal and reenactment of the pathogenesis of type 1 diabetes. Clin Res 1984; 32: 9. Mirenze

remission of

561A. 11. Palestine AG, Austin HA, Barlow JE, et al. Renal histopathologic alteration in

patients

treated with cyclosporin for uveitis. N Engl J Med 1986; 314: 1293-98. 1. McColl I. Comprehensive surgical training programme. Lancet 1973; i: 254-55. 2. Surgical supply and demand: RCS concerned at widening gap. Lancet 1986; i: 1511.

141

pair of consultants) specialties. each

would be

a

fair decision in

some

consultative document also puts forward a "pump-priming" scheme aimed at the creation of new consultant posts in acute specialties, and supplying an additional 15 000 per year per post as a contribution to related expenses. The proposal was unfortunately rejected in 1982. It has now been particularly welcomed by the Royal College of Surgeons of England, whose mournful report on general surgical manpower appeared last month.2 One part of the new deal which will worry many is the creation of a sub-consultant grade under a new name. The "intermediate level service grade" will lead to confusion and argument: for instance, what sort of operations should he or she do?; and under whose charge will this post lie? Apart from this defect, the proposals should achieve a balance which is infinitely more acceptable than the present shambles. The

new

ENERVATING ILLNESS AND EPSTEIN-BARR VIRUS

Epstein-Barr-virus-induced infectious mononucleosis is accompanied by a wide variety of humoral and cellular immune responses. In the acute phase of infection, serum antibodies are directed against a number of specific viral antigens, including the viral capsid antigen (VCA) which is a structural component of the virus particle, and the early antigen complex (EA), which is associated with viral enzymes. During convalescence, antibodies to nuclear antigen (NA) appear in the serum; at this stage latent Epstein-Barr virus (EBV) infection becomes established in a small proportion of B lymphocytes and viral DNA is incorporated into the host cell. Latently infected B lymphocytes show a potential for unlimited proliferation in vitro: after primary EBV infection, healthy subjects possess memory T lymphocytes which are cytotoxic for these infected B cells and cause regression of proliferating B cells in cultured In patients with infectious mononucleosis, VCA and NA antibodies continue to be synthesised after recovery whereas antibodies to EA, mostly to the restricted component, slowly declined A few patients with infectious mononucleosis fail to recover completely and suffer from what has become known as the chronic mononucleosis syndrome. The illness is difficult to define, but the main features include fatigue, malaise, low-grade fever, myalgia, lymphadenopathy, and pharyngitis. Symptoms sometimes persist or recur for several years.3-6 Heterophil antibody and atypical lymphocytosis may appear during exacerbations. Treatment of symptoms is all that can be offered, and patients often have a poor record of attendance at school and work. There is now persuasive evidence that patients with the chronic syndrome have aberrant immune responses to their EBV infection when compared with healthy controls. Persistent illness is accompanied by raised VCA IgG 1 Rickinson AB, Moss DJ, Pope JH, Ahlberg N. Long-term T-cell-mediated immunity to Epstein-Barr virus in man. IV Development of T-cell memory m convalescent infectious mononucleosis patients. Int J Cancer 1980; 25: 59-65. 2 Horwitz CA, Henle W, Henle G, Rudnick H, Latts E Long-term serological follow-up of patients for Epstein-Barr virus after recovery from infectious

mononucleosis. J Inf Dis 1985; 151: 1150-53. 3. Hamblin TJ, Hussain J, Akbar AN, et al. Immunological reason for chronic ill health after infectious mononucleosis Br Med J 1982; 287: 85-88. 4 Du Bois RE, Selley JK, Brus I, et al Chronic mononucleosis syndrome. South Med J 1984; 77: 1376-82.

antibodies 4,5and most researchers have documented raised titres of EA antibodies, with a variable pattern of fluorescent staining.4-7 Some patients lack the NA antibodies found in healthy EBV-infected individuals.5,6,8 More significantly, perhaps, abnormalities have been detected in cell-mediated immunity: four patients reported lately had T lymphocytes whose cytotoxicity for infected B cells was greatly impaired in a regression assay.6 The defect was probably EBV specific, since alloreactive T-cell responses were normal. Interestingly, mitogen-driven immunoglobulin synthesis by the patients’ B cells was reduced. Similar non-specific B-cell impairment has been shown, in other chronic mononucleosis patients, to be mediated by suppressor T cells 3,5,9 which are also active during the course of the acute illness .10-12 Does EBV induce the altered immune responses, or do these debilitated patients have a constitutional immune defect which is unmasked by the infection? Some of the immunological characteristics of the chronic mononucleosis syndrome have been encountered in a variety of

physiological and pathological conditions; in particular, both immunosuppressive therapy13.14 and the X-linked lymphoproliferative syndrome’ can cause failure of EBVtargeted cytotoxic T cells. These findings may imply some pre-existing impairment of host defences. Nevertheless, the features of mild immunodeficiency, such as lowered serum immunoglobulin levels, that have been found in some patients4,5 are just as likely to have followed the EBV infection as to have preceded it. The association between altered EBV responses and the chronic mononucleosis syndrome is impressive, but to what extent is it causal? Known chronic illnesses and infections have been sought and not found among such patients, but are difficult to exclude. The search must now encompass human immunodeficiency virus infection, which can produce glandular-fever-like illness and chronic ill-health, as well as abnormalities in cellular responses to EBV infection.15 A causal association is especially difficult to prove in patients with no history of acute illness or in those who have had infectious mononucleosis in the distant past, who nevertheless share the clinical, virological, and immunological features of the chronic syndrome.8,16,17 Included in this group are probably a number of EBVinfected individuals whose symptoms are caused by other undiagnosed infections and illnesses. A post-viral syndrome

5. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985; 102: 7-16. 6. Borysiewicz LK, Haworth SJ, Cohen J, et al. Epstein-Barr virus-specific immune defects in patients with persistent symptoms following infectious mononucleosis. Quart J Med 1986; 226: 111-21. 7. Masuci MG, Szigeti R, Emberg I, et al. Cellular immune defects of Epstein-Barr virus determined antigens in young males. Cancer Res 1981; 41: 4284-91. 8. Miller G, Grocan E, Fischer DK, et al. Antibody responses to two Epstein-Barr virus nuclear antigens defined by gene transfer. N Engl J Med 1985; 312: 750-55. 9. Tosato G, Straus S, Henle W, Pike SE, Blaese RM. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic IM). J Immunol 1985; 134: 3082-99. 10. Tosato G, Magrath I, Koski I, Dooleyn N, Blaese M. Activation of suppressor T cells during Epstein-Barr-Virus-induced infectious mononucleosis. N Engl J Med 1979; 301: 1133-37. 11. Johnsen HE, Madsen M, Kristensen T Lymphocyte sub populations in man: Suppression of PWM induced B cell proliferation by infectious mononucleosis T cells Scand J Immunol 1979, 10: 251-55 12. Haynes BF, Schooley RT, Payling-Wright CR, et al Emergence of suppressor cells of immunolglobulin synthesis during acute Epstein-Barr virus-induced infectious mononucleosis. J Immunol 1979, 123: 2095-101. 13. Crawford DH, Sweny P, Edwards JMB, Janossy G, Hoffbrand AV. Long-term T-cell-mediated immunity to Epstein-Barr virus in renal-allograft recipients receiving cyclosporin A Lancet 1981; i: 10-13. 14. Gaston JSH, Rickinson AB, Epstein MA Epstein-Barr-virus-specific T-cell memory in renal-allograft recipients under long-term immunosuppression Lancet 1982; i: 923-25