450
of unrecognised infarcts during the next 5 years. The computer thus turned out to be the best predictor of subsequent unrecognised infarcts. Multivariate analysis of the 5-year incidence of unrecognised infarctions revealed that the most significantly related variables were age, left-axis deviation and left-ventricular hypertrophy on E.C.G., cigarette smoking, blood-pressure, and peripheral vascular disease. Some of the known risk factors for clinical infarct or angina, such as serumcholesterol, diabetes, anxiety, and psychosocial pro-
blems,
were
not
important
in
unrecognised
in-
farcts. Over the
7-year follow-up for mortality, the general study population had an average annual mortality-rate of 4-6/1000, whereas those with unrecognised infarcts had almost 4 times this rate In those with overt clinical infarcts 75/1000, 4y times the rate of the unrecognised infarcts and 16 times the rate of the infarct-free section of the population. This observation is at variance with those at Framingham,7 where subjects with unrecognised infarcts had the same mortality as those with clinical infarcts, but the Israeli workers regard the Framingham results
(17-3/1000).
the rate
was
as possibly misleading, since fatal cases were excluded from analysis. The American and Israeli studies suggest that for every clinical infarct detected there is probably as least one unrecognised one in the same population. Apparently the unrecognised infarct is a less severe episode of myocardial ischaemia than the clinically overt infarction, with a lower 7-year mortality-rate. These findings raise a number of issues-notably, concerning screening of populations at risk. Should one take frequent E.c.G.s for vague or suspicious symptoms, particularly in those with known risk factors such as hypertension or diabetes mellitus? In societies high in the world league-table for C.H.D., the social and financial consequences of regular E.c.G. surveillance of all middle-aged subjects with one or more risk factors and/or minor symptoms are frightening to contemplate. Despite the lack of conclusive evidence that removal of risk factors reduces the incidence of c.H.D., an attempt at prevention9 seems the only way out of the present epidemic.
Clinical
Immunology
CLINICAL immunology has developed at a brisk pace, both academically and in relation to the practice of medicine, since the late 1950s; and those associated with it enjoy the intellectual stimulus of a subject where the basic physiology is unravelling, often with prompt application to the elucidation of 9. Joint Working Party of the Royal College of Physicians of London and the British Cardiac Society. Jl.R. Coll. Physns. 1976, 10, 213. 10. Roitt, I. M. Essential Immunology. Oxford, 1974.
disorders hitherto obstinately obscure. Thus, ideas on the pathogenesis of pernicious anaemia have moved from the contemplation of the drinking of too much hot tea to the picture of an organ-specific autoimmune process against the specialised cells of the mucosa of the body of the stomach and to the recognition that the condition is one of the family of organ-specific autoimmune diseases, whose members are mainly endocrine disorders including juvenile-onset diabetes." Immune complexes and antibody to glomerular basement members are important in the causation and diagnosis of different types of glomerulonephritis; 12 and allergic reactions are the underlying mechanism in certain hitherto unexplained lung diseases.13 Other examples abound of the application of immunology to
medicine. 14 The fuller understanding of the immunodeficiency disorders that has emerged from the better appreciation of the physiology of the immune system has led to remarkable therapeutic achievements. The role of plasma exchange in Goodpasture’s syndrome and other conditions is becoming established. Prevention of haemolytic disease of the newborn is now routine by means of immunological techniques; and there is hope that immuno-suppression may achieve greater specificity than has so far been possible. The association between certain HLA phenotypes and immune-response genes is yielding exciting evidence about the linkage between genetics and the behaviour of the immune system and susceptibility to disorders linked with immunopathology. Again the immune mechanisms which may cause tissue damage are being more closely defined. The rapid establishment of Clinical and Experimental Immunology as a major publication within the past ten years, the much stronger representation of basic and applied immunology in undergraduate and postgraduate texts,ls-1’ and the popularity of the clinical immunology course for physicians and scientists held in Edinburgh each year all testify to the growth of the subject, especially within the United Kingdom. All the references we have cited so far are to British work. Although it is perhaps un-British to talk of this country’s achievements in thisarea, it is the needs of the subject in Britain which are the theme of the article by Dr REEVES on p. 459 this week. His paper, which emanates from the British Society for Immunology’s working party on clinical immu11. Irvine, W.
J. (editor) Autoimmunity in Endocrine Disease; vol. 4, no 2, of Endocrinology. London, 1975. 12. Peters, D. K., Williams, D. C. in Recent Advances in Renal Disease, edited by N. F. Jones), Edinburgh, 1975. 13. Pepys, J., Turner-Warrick, M. in Clinical Aspects of Immunology; chap 43 (edited by P. H. Gell, R. R. A. Coombs, and P. J. Lachmann), Oxford Clinics
in
1975. 14. Gell, P. H., Coombs, R. R. A., Lachmann, P. J. (editors) ibid. 15. Macleod, J. (editor) Davidson’s Textbook of Medicine. Edinburgh, 1974 16. Passmore, R., Robson, J. S. (editors). Companion to Medical Studies; vols, I-III. Oxford, 1974-76. 17. Peters, D. K. (editor). Advanced Medicine: 12th symposium in Advanced Medicine. Royal College of Physicians, London, 1976.
451
.
nology, supplements the report of the clinical immunology committee of the International Union of Immunological Societies which discussed the organisation of clinical immunology, the training
opportunities in clinical immunology, and the recognition of it as a specialty. Towards these same ends the future of clinical immunology was the basis of a joint report by the Royal Colleges of Physicians, the Royal College of Pathologists, and the British Society for Immunology,19 and of a previous report by the Society’s working party on clinical immunology. 20 Essentially, all these reports point the same way: to the need for clinical immunology to emerge as a specialty in its own right in the N.H.S. and the universities. Much has already been achieved in the recognition of training for physicians,21 scientists, and technicians. What is needed now is a careers structure with posts and training courses leading to M.sc., M.R.C.PATH. (IMMUNOL.), and .I.M.L.S. (IMMUNOL.). The subject has become too large and its impact too significant for it to continue to depend so heavily on ad-hoc support from research grants. Another important move must be the standardisation of reagents and tests used in diagnosis. Dr REEVES emphasises that the service provisions for clinical immunology that are available in England and Wales are patchy, with many area health authorities providing the minimum cover. Clearly, the way in which clinical-immunology services should be provided will vary greatly from area to area. Thus, if clinical immunology is already well represented in a medical school, the situation differs from that where there is little or no accumulated experience. As emphasised by the International Union and by the American Association of Immunologists,22 where there are already a number of departments involved in different aspects of the subject, integration of resources (both clinical and scientific) between these departments should be encouraged. In this way, the combination of service and research and the strong links with the conventional specialties which have proved so productive in the advancement of clinical immunology in the United Kingdom may be maintained. On the other hand, where there are little or no facilities, then, as the B.S.I. working party has pointed out in Dr REEVE s’s article, the initial establishment might well be the appointment of an immunopathologist working in conjunction with a physician who has had training and experience in immunology and who also continues to be involved
relation
.
to
18 See Lancet, 1976, i, 796. 19 Report of the Joint Committee on Clinical Immunology. The three Royal Colleges of Physicians, the Royal College of Pathologists and the British Society for Immunology, 1972. 20 Second report of the British Society for Immunology Working Party on Clinical Immunology. Clin. exp. Immun. 1975, 22, 550. 21 Second report of the Joint Committee on Higher Medical Training. Royal College of Physicians, London, 1975. 22 Report of the Committee on Hospital-based Laboratory and Clinical Immunology of the Amencan Association of Immunologists. J. Immun. 1975, 115, 609.
aspect of laboratory work. Clinical immunology should not be regarded solely as a laboratory subject, for it involves not only consultation about the management of patients but also in-vivo diagnostic tests which require a medical attendant. The integration between physician and scientist in
some
be assiduously preserved, since both are essential. The several reports agree that there is a need for the universities to recognise clinical immunology as an academic discipline, appreciating that it may be best to do so on an interdepartmental basis: a chairman would represent departments or committees of immunology and clinical immunology ; combined symposia would be promoted; a joint responsibility would be created for the training of undergraduates, postgraduates, and technicians ; and personal chairs would be established where indicated. In times of great financial stress, obviously not all of the recommendations can be accomplished; but some of them require only effective organisation. The service aspects, however, inescapably mean money. must
Dialysis Osteodystrophy HAEMODIALYSis relieves many features of the uraemic syndrome; but others are unaffected or may worsen. Foremost amongst those that may progress, or even arise, are bone pain and metabolic bone disease. The progressive metabolic bone disease in these patients should be called dialysis osteodystrophy, a term which distinguishes it from renal osteodystrophy in undialysed patients: despite the histological similarities (a picture ranging from osteitis fibrosa to osteomalacia, with or without osteosclerosis) the two disorders have different mechanisms. Variations in the incidence and rate of progression of dialysis osteodystrophy between different dialysis centres and between different countries 1have given rise to much speculation on the aetiology. Dialysis osteodystrophy progresses or arises despite maintenance of plasma calcium and magnesium, and their fractions, at concentrations which in a healthy person would neither hamper bone mineralisation nor stimulate the parathyroid glands.3 These patients do have high circulating plasma immunoreactive parathyroid-hormone concentrations, 45 and the increased values are partly due to diminished hormonal skeletal or calcaemic response;6 another factor in this rise may be the Tatler, G. L. V., Baillod, R. A., Varghese, Z., Young, W. B., Farrow, S., Wills, M. R., Moorhead, J. F. Br. med. J. 1973, iv, 315. 2. Simpson, W., Kerr, D. N. S., Hill, A. V. L., Siddiqui, J. Y. Radiology, 1973, 107, 313. 3. Varghese, Z., Moorhead, J. F., Wills, M. R. Lancet, 1973, ii, 985. 4. Wills, M. R., Fairney, A., Varghese, Z., Tatler, G. L. V., Baillod, R. A., Moorhead, J. F. Clinica chim. Acta, 1974, 57, 83. 5. Shen, F. H., Baylink, D. J., Sherrard, D. J., Shen, L., Maloney, N. A., Wergedal, J. E. J. clin. Endocr. 1975, 40, 1009. 6. Massry, S. G., Coburn, J. W., Lee, D. B. N., Jowsey, J., Kleeman, C. R. Ann. intern. Med. 1973, 78, 357. 1.
.
of unrecognised infarcts during the next 5 years. The computer thus turned out to be the best predictor of subsequent unrecognised infarcts. Multivariate analysis of the 5-year incidence of unrecognised infarctions revealed that the most significantly related variables were age, left-axis deviation and left-ventricular hypertrophy on E.C.G., cigarette smoking, blood-pressure, and peripheral vascular disease. Some of the known risk factors for clinical infarct or angina, such as serumcholesterol, diabetes, anxiety, and psychosocial pro-
blems,
were
not
important
in
unrecognised
in-
farcts. Over the
7-year follow-up for mortality, the general study population had an average annual mortality-rate of 4-6/1000, whereas those with unrecognised infarcts had almost 4 times this rate In those with overt clinical infarcts 75/1000, 4y times the rate of the unrecognised infarcts and 16 times the rate of the infarct-free section of the population. This observation is at variance with those at Framingham,7 where subjects with unrecognised infarcts had the same mortality as those with clinical infarcts, but the Israeli workers regard the Framingham results
(17-3/1000).
the rate
was
as possibly misleading, since fatal cases were excluded from analysis. The American and Israeli studies suggest that for every clinical infarct detected there is probably as least one unrecognised one in the same population. Apparently the unrecognised infarct is a less severe episode of myocardial ischaemia than the clinically overt infarction, with a lower 7-year mortality-rate. These findings raise a number of issues-notably, concerning screening of populations at risk. Should one take frequent E.c.G.s for vague or suspicious symptoms, particularly in those with known risk factors such as hypertension or diabetes mellitus? In societies high in the world league-table for C.H.D., the social and financial consequences of regular E.c.G. surveillance of all middle-aged subjects with one or more risk factors and/or minor symptoms are frightening to contemplate. Despite the lack of conclusive evidence that removal of risk factors reduces the incidence of c.H.D., an attempt at prevention9 seems the only way out of the present epidemic.
Clinical
Immunology
CLINICAL immunology has developed at a brisk pace, both academically and in relation to the practice of medicine, since the late 1950s; and those associated with it enjoy the intellectual stimulus of a subject where the basic physiology is unravelling, often with prompt application to the elucidation of 9. Joint Working Party of the Royal College of Physicians of London and the British Cardiac Society. Jl.R. Coll. Physns. 1976, 10, 213. 10. Roitt, I. M. Essential Immunology. Oxford, 1974.
disorders hitherto obstinately obscure. Thus, ideas on the pathogenesis of pernicious anaemia have moved from the contemplation of the drinking of too much hot tea to the picture of an organ-specific autoimmune process against the specialised cells of the mucosa of the body of the stomach and to the recognition that the condition is one of the family of organ-specific autoimmune diseases, whose members are mainly endocrine disorders including juvenile-onset diabetes." Immune complexes and antibody to glomerular basement members are important in the causation and diagnosis of different types of glomerulonephritis; 12 and allergic reactions are the underlying mechanism in certain hitherto unexplained lung diseases.13 Other examples abound of the application of immunology to
medicine. 14 The fuller understanding of the immunodeficiency disorders that has emerged from the better appreciation of the physiology of the immune system has led to remarkable therapeutic achievements. The role of plasma exchange in Goodpasture’s syndrome and other conditions is becoming established. Prevention of haemolytic disease of the newborn is now routine by means of immunological techniques; and there is hope that immuno-suppression may achieve greater specificity than has so far been possible. The association between certain HLA phenotypes and immune-response genes is yielding exciting evidence about the linkage between genetics and the behaviour of the immune system and susceptibility to disorders linked with immunopathology. Again the immune mechanisms which may cause tissue damage are being more closely defined. The rapid establishment of Clinical and Experimental Immunology as a major publication within the past ten years, the much stronger representation of basic and applied immunology in undergraduate and postgraduate texts,ls-1’ and the popularity of the clinical immunology course for physicians and scientists held in Edinburgh each year all testify to the growth of the subject, especially within the United Kingdom. All the references we have cited so far are to British work. Although it is perhaps un-British to talk of this country’s achievements in thisarea, it is the needs of the subject in Britain which are the theme of the article by Dr REEVES on p. 459 this week. His paper, which emanates from the British Society for Immunology’s working party on clinical immu11. Irvine, W.
J. (editor) Autoimmunity in Endocrine Disease; vol. 4, no 2, of Endocrinology. London, 1975. 12. Peters, D. K., Williams, D. C. in Recent Advances in Renal Disease, edited by N. F. Jones), Edinburgh, 1975. 13. Pepys, J., Turner-Warrick, M. in Clinical Aspects of Immunology; chap 43 (edited by P. H. Gell, R. R. A. Coombs, and P. J. Lachmann), Oxford Clinics
in
1975. 14. Gell, P. H., Coombs, R. R. A., Lachmann, P. J. (editors) ibid. 15. Macleod, J. (editor) Davidson’s Textbook of Medicine. Edinburgh, 1974 16. Passmore, R., Robson, J. S. (editors). Companion to Medical Studies; vols, I-III. Oxford, 1974-76. 17. Peters, D. K. (editor). Advanced Medicine: 12th symposium in Advanced Medicine. Royal College of Physicians, London, 1976.
451
.
nology, supplements the report of the clinical immunology committee of the International Union of Immunological Societies which discussed the organisation of clinical immunology, the training
opportunities in clinical immunology, and the recognition of it as a specialty. Towards these same ends the future of clinical immunology was the basis of a joint report by the Royal Colleges of Physicians, the Royal College of Pathologists, and the British Society for Immunology,19 and of a previous report by the Society’s working party on clinical immunology. 20 Essentially, all these reports point the same way: to the need for clinical immunology to emerge as a specialty in its own right in the N.H.S. and the universities. Much has already been achieved in the recognition of training for physicians,21 scientists, and technicians. What is needed now is a careers structure with posts and training courses leading to M.sc., M.R.C.PATH. (IMMUNOL.), and .I.M.L.S. (IMMUNOL.). The subject has become too large and its impact too significant for it to continue to depend so heavily on ad-hoc support from research grants. Another important move must be the standardisation of reagents and tests used in diagnosis. Dr REEVES emphasises that the service provisions for clinical immunology that are available in England and Wales are patchy, with many area health authorities providing the minimum cover. Clearly, the way in which clinical-immunology services should be provided will vary greatly from area to area. Thus, if clinical immunology is already well represented in a medical school, the situation differs from that where there is little or no accumulated experience. As emphasised by the International Union and by the American Association of Immunologists,22 where there are already a number of departments involved in different aspects of the subject, integration of resources (both clinical and scientific) between these departments should be encouraged. In this way, the combination of service and research and the strong links with the conventional specialties which have proved so productive in the advancement of clinical immunology in the United Kingdom may be maintained. On the other hand, where there are little or no facilities, then, as the B.S.I. working party has pointed out in Dr REEVE s’s article, the initial establishment might well be the appointment of an immunopathologist working in conjunction with a physician who has had training and experience in immunology and who also continues to be involved
relation
.
to
18 See Lancet, 1976, i, 796. 19 Report of the Joint Committee on Clinical Immunology. The three Royal Colleges of Physicians, the Royal College of Pathologists and the British Society for Immunology, 1972. 20 Second report of the British Society for Immunology Working Party on Clinical Immunology. Clin. exp. Immun. 1975, 22, 550. 21 Second report of the Joint Committee on Higher Medical Training. Royal College of Physicians, London, 1975. 22 Report of the Committee on Hospital-based Laboratory and Clinical Immunology of the Amencan Association of Immunologists. J. Immun. 1975, 115, 609.
aspect of laboratory work. Clinical immunology should not be regarded solely as a laboratory subject, for it involves not only consultation about the management of patients but also in-vivo diagnostic tests which require a medical attendant. The integration between physician and scientist in
some
be assiduously preserved, since both are essential. The several reports agree that there is a need for the universities to recognise clinical immunology as an academic discipline, appreciating that it may be best to do so on an interdepartmental basis: a chairman would represent departments or committees of immunology and clinical immunology ; combined symposia would be promoted; a joint responsibility would be created for the training of undergraduates, postgraduates, and technicians ; and personal chairs would be established where indicated. In times of great financial stress, obviously not all of the recommendations can be accomplished; but some of them require only effective organisation. The service aspects, however, inescapably mean money. must
Dialysis Osteodystrophy HAEMODIALYSis relieves many features of the uraemic syndrome; but others are unaffected or may worsen. Foremost amongst those that may progress, or even arise, are bone pain and metabolic bone disease. The progressive metabolic bone disease in these patients should be called dialysis osteodystrophy, a term which distinguishes it from renal osteodystrophy in undialysed patients: despite the histological similarities (a picture ranging from osteitis fibrosa to osteomalacia, with or without osteosclerosis) the two disorders have different mechanisms. Variations in the incidence and rate of progression of dialysis osteodystrophy between different dialysis centres and between different countries 1have given rise to much speculation on the aetiology. Dialysis osteodystrophy progresses or arises despite maintenance of plasma calcium and magnesium, and their fractions, at concentrations which in a healthy person would neither hamper bone mineralisation nor stimulate the parathyroid glands.3 These patients do have high circulating plasma immunoreactive parathyroid-hormone concentrations, 45 and the increased values are partly due to diminished hormonal skeletal or calcaemic response;6 another factor in this rise may be the Tatler, G. L. V., Baillod, R. A., Varghese, Z., Young, W. B., Farrow, S., Wills, M. R., Moorhead, J. F. Br. med. J. 1973, iv, 315. 2. Simpson, W., Kerr, D. N. S., Hill, A. V. L., Siddiqui, J. Y. Radiology, 1973, 107, 313. 3. Varghese, Z., Moorhead, J. F., Wills, M. R. Lancet, 1973, ii, 985. 4. Wills, M. R., Fairney, A., Varghese, Z., Tatler, G. L. V., Baillod, R. A., Moorhead, J. F. Clinica chim. Acta, 1974, 57, 83. 5. Shen, F. H., Baylink, D. J., Sherrard, D. J., Shen, L., Maloney, N. A., Wergedal, J. E. J. clin. Endocr. 1975, 40, 1009. 6. Massry, S. G., Coburn, J. W., Lee, D. B. N., Jowsey, J., Kleeman, C. R. Ann. intern. Med. 1973, 78, 357. 1.
.
