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ENDOMYOCARDIAL FIBROSIS AND RHEUMATIC HEART-DISEASE
639 TABLE II-SERUM T.S.H. LEVELS IN HYPOTHYROID PATIENTS WITH CIRCULATING A.T.A., IN EUTHYROID PATIENTS WITH CIRCULATING A.T.A. AND IN EUTHYROID PATIENTS WITHOUT A.T.A.
with " atrophic thyroiditis ", especially when patients the age of 50 are considered (P <0.01).
over
CONCLUSION
In patients with probable asymptomatic detectable serum-levels of T.S.H. are higher thyroiditis, in matched controls in the subgroup over 70 years than when non-detectable levels are taken of age (P < 005); into account, all patients with " atrophic thyroiditis " have increased serum-T.s.H. when compared with adequate controls (P < 0-01). 9 of 15 hypothyroid patients have T.s.H. levels which may be found in healthy subjects. However, the myxoedematous patients as a group form a population which is different from the healthy subjects and from the patients
(p < 001).
ENDOMYOCARDIAL fibrosis is a progressive heart-disease characterised in the established condition by fibrosis in the inflow tract and the apex of one or both ventricles. It has been most frequently reported from East and West Africa, and at present the aetiology is completely unknown. No apology is made for putting forward a hypothesis which may sound far-fetched to many interested in this field, for in a disorder such as this a firm working hypothesis capable of being proved or disproved is better than no hypothesis at all. Analysis of the tribal origins of cases of endomyocardial fibrosis (E.M.F.) coming to necropsy in Mulago Hospital in the period 1950-61 showed a clear preponderance of this condition among those groups immigrant to Buganda,* in particular, those originating from Ruanda-Urundi (now Rwanda and Burundi).1 The condition was far less common than expected among the indigenous Baganda people. The increased susceptibility of this immigrant group was considered to be associated with their inferior socioeconomic conditions, which might include not only nutritional factors but also an increased exposure and susceptibility to bacterial and other infections. It was noted that the local Baganda group, with a socio-economic background which would still be regarded as suboptimal by Western standards, appeared to be protected somewhat
against E.M.F. A similar analysis of tribal origin has been carried out for rheumatic heart-disease (R.H.D.) seen at necropsy in Mulago Hospital in 1950-61, with results which contrast strikingly with the findings in E.M.F. Rheumatic heartdisease occurs predominantly among the indigenous Baganda subjects, and it is significantly less common than would be expected in subjects originating from Rwanda/ Burundi.
*
to
completely independent
calculate the
M. BONNYNS M.D.
Department of Medicine, St. Pierre Hospital, Brussels, and University of Brussels
Brussels
P. A. BASTENIE M.D.
Brussels
Kabir, D. J., Doniach, D., Turner-Warwick, R. J. clin. Endocr. 1963, 23, 10.
16. El
E.M.F. and R.H.D. should occur in the the total necropsy population and the subject, given incidence of E.M.F. and R.H.D. in this population. In a necropsy population of 5815 subjects with 124 cases of E.M.F. and 111 cases of R.H.D., there should be 2·4 cases in which both conditions are present. In the Mulago Hospital series of E.M.F. and R.H.D. cases, there were in fact 11 in which it was considered that both conditions were definitely present on macroscopic examination and a furthere 6 in which it was considered very likely that both conditions were present. While I am aware of the problems inherent in retrospective studies of necropsy material, in most cases under discussion in this review the hearts were very fully described and in many instances photographs were available. Even if the incidence of mixed cases—i.e., R.H.D. and E.M.F.—is taken as 11, the level of probability is <0·01 for the difference between the on
which both
same
ENDOMYOCARDIAL FIBROSIS AND RHEUMATIC HEART-DISEASE
are two
hish levels 12 remains obscure.
sions
Hypothesis
If E.M.F. and R.H.D. conditions it is possible
Morphological studies have shown that the pituitary of fatal cases of asymptomatic, focal, or diffuse " atrophic thyroiditis " may contain thyroidectomy cells, comparable to those seen in myxaedema.5 Therefore our finding of increased levels of serum-T.S.H. in patients with circulating antithyroglobulin antibodies is not surprising: most probably these patients are affected with latent " atrophic thyroiditis " and subclinical hypothyroidism.The reason why similar observations have not been made in patients with struma lymphomatosa (Hashimoto’s disease) 16 and why all hypothyroid patients do not present with very
number of
occa-
Buganda is the province of Uganda in which Kampala is situated. 1. Shaper, A. G., Coles, R. M. Br. Heart J. 1965, 27, 121.
observed and expected figures. The degree of concurrence of these two conditions in the necropsy population strongly suggests a relationship COUNTIES OF RESIDENCE OF TO
NECROPSY,
SUBJECTS
1950-1961 (MAIN
WITH E.M.F. OR R.H.D. COMING COUNTIES ONLY ARE
LISTED)
association of some kind between E.M.F. and R.H.D. It should perhaps be emphasised that the tribal differences described are not in two peoples living in widely different parts of Buganda, for the Rwanda and Baganda subjects referred to in these studies live in the same areas. Indeed, the tribal differences in E.M.F. and R.H.D. distribution are seen even at a county level (see accompanying table). There are other ways in which E.M.F. and R.H.D. may be compared and contrasted. When the age and sex distribution of the subjects coming to necropsy with proved E.M.F. and R.H.D. are compared, there is a remarkable
or
M4
640 in the general pattern, but there are some differences which may be of importance. 30% of both E.M.F. and R.H.D. necropsies are in subjects under 24 years of age, but a far greater proportion of R.H.D. subjects (23%) fall into the over-45-year age-group than do E.M.F. subjects (11%). This may indicate that subjects with R.H.D. survive somewhat longer than those with E.M.F. Intracardiac thrombi are found in 46% of E.M.F. cases at necropsy, mainly in the right atrium and left ventricle.2 In R.H.D. only 11 % of hearts show antemortem thrombi, almost entirely in the atria. However, embolic phenomena in the absence of bacterial endocarditis occur in 15% of E.M.F. cases and 14% of R.H.D. cases. This similarity in incidence of embolisation, despite the distinct difference in incidence of intracardiac thrombi, suggests that while thrombi are forming in both conditions they are more adherent in the E.M.F. subjects. Moreover embolisation to the aorta or one of its main peripheral arteries occurred in 4 of the E.M.F. cases,2 but in none of the R.H.D. series, possibly indicating that the thrombi formed in E.M.F. are larger, which would not be unexpected in a disorder with large areas of abnormal endocardium. There is little doubt that E.M.F. is a progressive heartdisease and that there must be some early stage of this disorder which at present is poorly defined. The natural history of this disorder has not been adequately studied.3 In an attempt to define the early stage, workers in Ibadan have reviewed the findings in about 100 patients diagnosed as having E.M.F., including some in whom the initial form of cardiac disease was obscure but who subsequently developed typical E.M.F.4 Much of the argument in their paper depends on the clinical histories; their description of an acute initial illness is based on the history and/or observations in 14 cases. They describe an ill-defined episode usually lasting a few weeks, with fever and listlessness, merging into symptoms of pulmonary or systemic The early clinical picture is summarised as congestion. " a carditis with some unusual features ", and they note that the pericardium has been found to be histologically abnormal in patients with active disease following the initial illness. Clearly the authors are describing a pancarditis ; and, while they agree that " in many ways its effect upon the heart is analogous to rheumatic infection, particularly in its natural history ", they consider that the association between R.H.D. and E.M.F. seen by Abrahams5 in the same hospital was due to chance in those early cases. In the 10 case-histories given in this latest paper from Nigeria, no mention is made of antistreptolysin-0 titres or throat-swab findings, even though 8 of the subjects were under 21 years of age. Earlier, Abrahams5 suggested that E.M.F. was an expression of the rheumatic process, since antistreptolysin-0 titres were raised during active carditis in some cases and perivascular collections of cells resembling Aschoff nodes were found. Subsequently6 this opinion was revised: " It seems probable that E.M.F. is the final common path resulting from many different forms of myocardial damage. In Southern Nigeria we suggest that rheumatic carditis may be concerned with this process in some cases." At Mulago Hospital, Kampala, in a recent series of clinically diagnosed subjects under 30 years of age we
similarity
2. 3.
Shaper, A. G., Wright, D. H. ibid. 1963, 25, 502. Hutt, M. S. R., Ikeme, A. C., Lucas, A. O., Prata, A., Puigbo, J. J., Shaper, A. G., Somers, K., Fejfar, Z. Bull. Wld Hlth Org. 1965, 33,
4. 5. 6.
Parry, E. H. O., Abrahams, D. G. Q. Jl Med. 1965, 34, 383. Abrahams, D. G. Lancet, 1959, ii, 111. Abrahams, D. G., Brigden, W. Br. med. J. 1961, ii, 134.
observed that antistreptolysin-0 titres were positive to a titre of over 1/200 in 9 out of 20 R.H.D. patients and in 5 out of 10 E.M.F. subjects. The numbers are small but suggest that in both groups the incidence of recent streptococcal infection is high. The relation of infection with group-A haemolytic streptococci to the subsequent development of rheumatic fever is clearly established. The actual manner in which the streptococci provoke R.H.D. is not known, although certain clinical and laboratory features provide strong support for an immunological mechanism.’ The demonstration in the sera of patients with recent streptococcal infections of antibodies which cross-react with streptococcal antigens and heart tissue8 suggests an immunological reaction involving streptococcal antibody with a tissue antigen that shares antigenic determinants with the streptococcus.7 Immunopathological studies of rheumatic hearts have shown widely distributed deposits of bound y-globulin localised to sarcolemma and subsarcolemmal sarcoplasm of cardiac myofibres and, to a lesser extent, to interstitial connective tissue and smooth muscle of endocardium.9 10 These observations of circulating antibodies to constituents of cardiac myofibres in rheumatic sera and bound y-globulin in cardiac myofibres have suggested that circulating antibodies to heart may become fixed in vivo." From a study at Mulago Hospital of patients with E.M.F. van der Geld et al.l2 report a high incidence of circulating heart antibodies and the common occurrence of IgM-IgG cryoglobulinasmia—a phenomenon also postulated to be of an autoimmune nature. Bound y-globulin was demonstrated in these hearts, localised mainly in sarcolemmal and subsarcolemmal sites in myofibres and to a much lesser extent in the endocardium. These abnormalities were not found in tissues from patients with myocardial infarction and hypertensive heartdisease, and the authors apparently did not contrast the E.M.F. material with R.H.D. material. The similarity of their findings to the observations on R.H.D. material by Kaplan and his colleagues 11 is striking and seems to strengthen the suggestion that the pathogenesis of E.M.F. is similar to that of R.H.D. All this information suggests that E.M.F. may be a disorder similar to R.H.D. in being a hypersensitivity response to some infection, or even that E.M.F. may be another type of response to streptococcal infection; it might be wiser not to state that E.M.F. may be another form of R.H.D. since the rheumatic element is not in evidence in any of the published reports-though in many tropical countries acute rheumatic fever is only occasionally seen even where chronic R.H.D. is common.13 As a working hypothesis I suggest that endomyocardial fibrosis does in fact represent another form of hypersensitivity response to infection with streptococci. The main reason for the appearance in certain susceptible individuals of E.M.F. rather than R.H.D. is probably immunological. While non-specific nutritional factors may determine the degree or nature of the immune response to the streptococcal infection, there is almost certainly in these susceptible individuals some prior 7. 8. 9. 10. 11.
257. 12. 13.
Vosti, K. L. Med. Clins N. Am. 1965, 49, 1717. Kaplan, M. H., Svec, K. H. J. exp. Med. 1964, 119, 651. Kaplan, M. H., Dallenbach, F. D. ibid. 1961, 113, 1. Kaplan, M. H., Meveserian, M. Lancet, 1962, i, 706. Kaplan, M. H. in The Streptococcus, Rheumatic Fever and glomerulonephritis (edited by J. W. Uhr); p. 169. Baltimore 1964. van de Geld, H., Somers, K., Pelton, F. Lancet, Jan. 1, 1966, p. 48. Shaper, A. G., Williams, A. W. Trans. R. Soc. trop. Med. Hyg. 1960, 54, 12.
641 state which determines the pathogenesis of this condition. If one postulates that E.M.F. is a disorder, like R.H.D., resulting from exposure to streptococcal infection, why then are the Rwandan subjects in Buganda particularly susceptible ? The Rwandan patients seen at this hospital are subject to another condition which almost certainly involves an immunological process-i.e., idiopathic splenomegaly,14 The spleen plays a major role in the development of immunity,15 and in a study of spleenweights in all subjects coming to necropsy at Mulago Hospital in 1950-61 a striking difference has emerged between the Baganda subjects and those originating from Rwanda and the neighbouring areas of Ugandai.e., Kigezi and Ankole.11 When spleen-weights are plotted against age for the Baganda and Rwanda subjects there are no differences in mean spleen-weights up to the age of 4 years. In the 5-10-year age-group the mean spleen-weight in the Rwanda children (258 g.) is almost twice that of the Baganda children (146 g.), and this difference persists into adult life. Rwanda subjects aged 15-44 years have a mean spleen-weight of 512 g. compared with a mean spleen-weight of 357 g. in the Baganda. All the areas inhabited by the Baganda are at least moderately malarial-i.e., malaria occurs at all seasons with increased transmission after periods of heavy rainfall. The Ruanda, Kigezi, and Ankole areas are either normally malaria-free or only malarious near water, and the malaria risk is seasonal. While the older Rwanda subjects may have larger spleen-weights because they have come from an area of low malarial endemicity and are then exposed to a highly malarial situation, it is probable that a large proportion of the Rwandan children under 10 years of age have been born in Buganda. Their increased spleen-weights compared with those of the Baganda children is difficult to explain except perhaps in terms of increased exposure or increased response to the malarial infection. I suggest that an immunological factor related to malarial infection may condition the response of this group to other infections-e.g., streptococcal. Of the cases of endomyocardial fibrosis reported in Caucasians after residence in the tropics, most had had malaria 17-19 or been exposed to possible infection.20-23 In a sense these expatriate Caucasians in the tropics resemble the Rwandans in Uganda in coming from an area of low malarial endemicity to one of high malarial endemicity. In the 20 patients with R.H.D. and 10 subjects with E.M.F. referred to earlier in this paper in regard to anti-streptolysin-0 titres, the malarial antibody titres were over 1/100 in 10% of the R.H.D. cases and 80% of the E.M.F. cases. We have already indicated that most of the R.H.D. subjects are Baganda and the E.M.F. subjects are mainly Rwandan; hence these observations may be a further indication of increased exposure or increased response by the Rwandans to malarial infection. The burden of this polemic is that in any study concerning endomyocardial fibrosis constant comparison should be made with rheumatic heart-disease, whether
immunological
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
Hamilton, P. J. S., Hutt, M. S. R., Wilks, N. E., Olweny, C. Ndawula, R. L., Mwanje, L. E. Afr. med. J. 1965, 42, 191. Taliafero, W. H. Am. J. trop. Med. Hyg. 1956, 5, 391. Shaper, A. G. Unpublished. Grav, I. R. Br. Heart J. 1951, 13, 387. Clark, E. M. New Engl. J. Med. 1956, 254, 349. Coelho, E., Pimentel, J. C. Am. J. Med. 1963, 35, 569. Edge, J. R. Lancet, 1946, ii, 675. Fienberg, R., Holzmann, D. Bull. int. Ass. med. Mus. 1951, 32, 34. Lynch, J. B., Watt, J. Br. Heart J. 1957, 19, 173. Fisher, E. R., Davis, E. R. Am. Heart J. 1958, 56, 537.
the study be epidemiological or concerned with pathogensis and/or immunology. In addition, an attempt should be made to define susceptible subjects or groups, and to determine whether these have been exposed to malaria or other parasitic infections which might condition their immunological response to later bacterial or
virus infections. This work is supported by the World Health Organisation. I am grateful to Prof. M. S. R. Hutt for his cooperation, to Prof W. D. Foster and Dr. N. Wilks for their assistance, and to all these colleagues and Dr. David Bradley for the benefit of discussing this hypothesis with them. Requests for reprints should be addressed to A. G. S. at the Department of Medicine, Makerere University College Medical School, P.O. Box 2072, Kampala, Uganda, East Africa. A. G. SHAPER Department of Medicine, Makerere University College M.B. Cape Town, Medical School, M.R.C.P., D.T.M. &
Kampala, Uganda
H.
Reviews of Books The
Fungous Diseases of Man
.
J. WALTER WILSON, M.D., clinical professor of medicine (dermatology), University of California, Los Angeles; ORDA A. PLUNKETT, PH.D., professor emeritus of botany (mycology) and research professor, department of dermatology, University of California. Berkeley and Los Angeles: University of California Press. London: Cambridge University Press. 1965. Pp. 428. 120s.
" Three times is a lot," said Winston Churchill-and this is the third comprehensive textbook of medical mycology to have appeared in this country in two years. This is evidence of the increasing interest in the subject; but it poses a problem of selection, at least to the general reader. This latest work gives due emphasis to both clinical and laboratory aspects. The text is authoritative and is based, not only on the wide personal experience of the authors, but also on that of other medical mycologists. The crowning glory of this volume, however, is its illustrations. The British reader may never have come across a case of disseminated coccidioidomycosis, of cutaneous sporotrichosis, or of histoplasmosis of the tongue; but he may well be able to recognise these and other diseases after studying the colour plates in this book. These are unparalleled.
The Thalassaemia
Syndromes
D.
J. WEATHERALL, M.D., M.R.C.P., department of medicine, Johns Hopkins University School of Medicine, Baltimore, U.S.A.
Pp.
272.
Oxford: Blackwell Scientific Publications. 45s.
1965.
Dr. Weatherall’s book is timely in collecting the great amount information on thalassaemias into a single volume, and in explaining this information to the non-specialist. He has moreover gathered together many differences and modifications in thalasseemia which in due course will be linked with abnormalities in haemoglobin synthesis. He discusses the abnormal haemoglobins and some genetic variants of special interest. An example is haemoglobin Lepore in which the non-fx-chains are composed of both -chains of hxmoglobin A and 8-chains of haemoglobin A2, thereby indicating the closeness on one chromosome of the two genes responsible. There are sections on the laboratory diagnosis of thalassaemia and on treatment and a very extensive list of references. This is bound to become a standard work of reference in the libraries of laboratories interested in haematological disorders, and it will also interest
of
geneticists. What Freud Really Said
STAFFORD-CLARK, M.D., F.R.C.P., D.P.M., physician in charge, department of psychological medicine, Guy’s hospital, London. London: Macdonald. 1965. Pp. 264. 18s. DAVID
THIS first volume of a new series sets a very high standard, both in selection of Freud’s essential work and in its mode of presentation. Apart from his scientific genius, Freud has long been acknowledged as a master of clarity in his writings, and
with " atrophic thyroiditis ", especially when patients the age of 50 are considered (P <0.01).
over
CONCLUSION
In patients with probable asymptomatic detectable serum-levels of T.S.H. are higher thyroiditis, in matched controls in the subgroup over 70 years than when non-detectable levels are taken of age (P < 005); into account, all patients with " atrophic thyroiditis " have increased serum-T.s.H. when compared with adequate controls (P < 0-01). 9 of 15 hypothyroid patients have T.s.H. levels which may be found in healthy subjects. However, the myxoedematous patients as a group form a population which is different from the healthy subjects and from the patients
(p < 001).
ENDOMYOCARDIAL fibrosis is a progressive heart-disease characterised in the established condition by fibrosis in the inflow tract and the apex of one or both ventricles. It has been most frequently reported from East and West Africa, and at present the aetiology is completely unknown. No apology is made for putting forward a hypothesis which may sound far-fetched to many interested in this field, for in a disorder such as this a firm working hypothesis capable of being proved or disproved is better than no hypothesis at all. Analysis of the tribal origins of cases of endomyocardial fibrosis (E.M.F.) coming to necropsy in Mulago Hospital in the period 1950-61 showed a clear preponderance of this condition among those groups immigrant to Buganda,* in particular, those originating from Ruanda-Urundi (now Rwanda and Burundi).1 The condition was far less common than expected among the indigenous Baganda people. The increased susceptibility of this immigrant group was considered to be associated with their inferior socioeconomic conditions, which might include not only nutritional factors but also an increased exposure and susceptibility to bacterial and other infections. It was noted that the local Baganda group, with a socio-economic background which would still be regarded as suboptimal by Western standards, appeared to be protected somewhat
against E.M.F. A similar analysis of tribal origin has been carried out for rheumatic heart-disease (R.H.D.) seen at necropsy in Mulago Hospital in 1950-61, with results which contrast strikingly with the findings in E.M.F. Rheumatic heartdisease occurs predominantly among the indigenous Baganda subjects, and it is significantly less common than would be expected in subjects originating from Rwanda/ Burundi.
*
to
completely independent
calculate the
M. BONNYNS M.D.
Department of Medicine, St. Pierre Hospital, Brussels, and University of Brussels
Brussels
P. A. BASTENIE M.D.
Brussels
Kabir, D. J., Doniach, D., Turner-Warwick, R. J. clin. Endocr. 1963, 23, 10.
16. El
E.M.F. and R.H.D. should occur in the the total necropsy population and the subject, given incidence of E.M.F. and R.H.D. in this population. In a necropsy population of 5815 subjects with 124 cases of E.M.F. and 111 cases of R.H.D., there should be 2·4 cases in which both conditions are present. In the Mulago Hospital series of E.M.F. and R.H.D. cases, there were in fact 11 in which it was considered that both conditions were definitely present on macroscopic examination and a furthere 6 in which it was considered very likely that both conditions were present. While I am aware of the problems inherent in retrospective studies of necropsy material, in most cases under discussion in this review the hearts were very fully described and in many instances photographs were available. Even if the incidence of mixed cases—i.e., R.H.D. and E.M.F.—is taken as 11, the level of probability is <0·01 for the difference between the on
which both
same
ENDOMYOCARDIAL FIBROSIS AND RHEUMATIC HEART-DISEASE
are two
hish levels 12 remains obscure.
sions
Hypothesis
If E.M.F. and R.H.D. conditions it is possible
Morphological studies have shown that the pituitary of fatal cases of asymptomatic, focal, or diffuse " atrophic thyroiditis " may contain thyroidectomy cells, comparable to those seen in myxaedema.5 Therefore our finding of increased levels of serum-T.S.H. in patients with circulating antithyroglobulin antibodies is not surprising: most probably these patients are affected with latent " atrophic thyroiditis " and subclinical hypothyroidism.The reason why similar observations have not been made in patients with struma lymphomatosa (Hashimoto’s disease) 16 and why all hypothyroid patients do not present with very
number of
occa-
Buganda is the province of Uganda in which Kampala is situated. 1. Shaper, A. G., Coles, R. M. Br. Heart J. 1965, 27, 121.
observed and expected figures. The degree of concurrence of these two conditions in the necropsy population strongly suggests a relationship COUNTIES OF RESIDENCE OF TO
NECROPSY,
SUBJECTS
1950-1961 (MAIN
WITH E.M.F. OR R.H.D. COMING COUNTIES ONLY ARE
LISTED)
association of some kind between E.M.F. and R.H.D. It should perhaps be emphasised that the tribal differences described are not in two peoples living in widely different parts of Buganda, for the Rwanda and Baganda subjects referred to in these studies live in the same areas. Indeed, the tribal differences in E.M.F. and R.H.D. distribution are seen even at a county level (see accompanying table). There are other ways in which E.M.F. and R.H.D. may be compared and contrasted. When the age and sex distribution of the subjects coming to necropsy with proved E.M.F. and R.H.D. are compared, there is a remarkable
or
M4
640 in the general pattern, but there are some differences which may be of importance. 30% of both E.M.F. and R.H.D. necropsies are in subjects under 24 years of age, but a far greater proportion of R.H.D. subjects (23%) fall into the over-45-year age-group than do E.M.F. subjects (11%). This may indicate that subjects with R.H.D. survive somewhat longer than those with E.M.F. Intracardiac thrombi are found in 46% of E.M.F. cases at necropsy, mainly in the right atrium and left ventricle.2 In R.H.D. only 11 % of hearts show antemortem thrombi, almost entirely in the atria. However, embolic phenomena in the absence of bacterial endocarditis occur in 15% of E.M.F. cases and 14% of R.H.D. cases. This similarity in incidence of embolisation, despite the distinct difference in incidence of intracardiac thrombi, suggests that while thrombi are forming in both conditions they are more adherent in the E.M.F. subjects. Moreover embolisation to the aorta or one of its main peripheral arteries occurred in 4 of the E.M.F. cases,2 but in none of the R.H.D. series, possibly indicating that the thrombi formed in E.M.F. are larger, which would not be unexpected in a disorder with large areas of abnormal endocardium. There is little doubt that E.M.F. is a progressive heartdisease and that there must be some early stage of this disorder which at present is poorly defined. The natural history of this disorder has not been adequately studied.3 In an attempt to define the early stage, workers in Ibadan have reviewed the findings in about 100 patients diagnosed as having E.M.F., including some in whom the initial form of cardiac disease was obscure but who subsequently developed typical E.M.F.4 Much of the argument in their paper depends on the clinical histories; their description of an acute initial illness is based on the history and/or observations in 14 cases. They describe an ill-defined episode usually lasting a few weeks, with fever and listlessness, merging into symptoms of pulmonary or systemic The early clinical picture is summarised as congestion. " a carditis with some unusual features ", and they note that the pericardium has been found to be histologically abnormal in patients with active disease following the initial illness. Clearly the authors are describing a pancarditis ; and, while they agree that " in many ways its effect upon the heart is analogous to rheumatic infection, particularly in its natural history ", they consider that the association between R.H.D. and E.M.F. seen by Abrahams5 in the same hospital was due to chance in those early cases. In the 10 case-histories given in this latest paper from Nigeria, no mention is made of antistreptolysin-0 titres or throat-swab findings, even though 8 of the subjects were under 21 years of age. Earlier, Abrahams5 suggested that E.M.F. was an expression of the rheumatic process, since antistreptolysin-0 titres were raised during active carditis in some cases and perivascular collections of cells resembling Aschoff nodes were found. Subsequently6 this opinion was revised: " It seems probable that E.M.F. is the final common path resulting from many different forms of myocardial damage. In Southern Nigeria we suggest that rheumatic carditis may be concerned with this process in some cases." At Mulago Hospital, Kampala, in a recent series of clinically diagnosed subjects under 30 years of age we
similarity
2. 3.
Shaper, A. G., Wright, D. H. ibid. 1963, 25, 502. Hutt, M. S. R., Ikeme, A. C., Lucas, A. O., Prata, A., Puigbo, J. J., Shaper, A. G., Somers, K., Fejfar, Z. Bull. Wld Hlth Org. 1965, 33,
4. 5. 6.
Parry, E. H. O., Abrahams, D. G. Q. Jl Med. 1965, 34, 383. Abrahams, D. G. Lancet, 1959, ii, 111. Abrahams, D. G., Brigden, W. Br. med. J. 1961, ii, 134.
observed that antistreptolysin-0 titres were positive to a titre of over 1/200 in 9 out of 20 R.H.D. patients and in 5 out of 10 E.M.F. subjects. The numbers are small but suggest that in both groups the incidence of recent streptococcal infection is high. The relation of infection with group-A haemolytic streptococci to the subsequent development of rheumatic fever is clearly established. The actual manner in which the streptococci provoke R.H.D. is not known, although certain clinical and laboratory features provide strong support for an immunological mechanism.’ The demonstration in the sera of patients with recent streptococcal infections of antibodies which cross-react with streptococcal antigens and heart tissue8 suggests an immunological reaction involving streptococcal antibody with a tissue antigen that shares antigenic determinants with the streptococcus.7 Immunopathological studies of rheumatic hearts have shown widely distributed deposits of bound y-globulin localised to sarcolemma and subsarcolemmal sarcoplasm of cardiac myofibres and, to a lesser extent, to interstitial connective tissue and smooth muscle of endocardium.9 10 These observations of circulating antibodies to constituents of cardiac myofibres in rheumatic sera and bound y-globulin in cardiac myofibres have suggested that circulating antibodies to heart may become fixed in vivo." From a study at Mulago Hospital of patients with E.M.F. van der Geld et al.l2 report a high incidence of circulating heart antibodies and the common occurrence of IgM-IgG cryoglobulinasmia—a phenomenon also postulated to be of an autoimmune nature. Bound y-globulin was demonstrated in these hearts, localised mainly in sarcolemmal and subsarcolemmal sites in myofibres and to a much lesser extent in the endocardium. These abnormalities were not found in tissues from patients with myocardial infarction and hypertensive heartdisease, and the authors apparently did not contrast the E.M.F. material with R.H.D. material. The similarity of their findings to the observations on R.H.D. material by Kaplan and his colleagues 11 is striking and seems to strengthen the suggestion that the pathogenesis of E.M.F. is similar to that of R.H.D. All this information suggests that E.M.F. may be a disorder similar to R.H.D. in being a hypersensitivity response to some infection, or even that E.M.F. may be another type of response to streptococcal infection; it might be wiser not to state that E.M.F. may be another form of R.H.D. since the rheumatic element is not in evidence in any of the published reports-though in many tropical countries acute rheumatic fever is only occasionally seen even where chronic R.H.D. is common.13 As a working hypothesis I suggest that endomyocardial fibrosis does in fact represent another form of hypersensitivity response to infection with streptococci. The main reason for the appearance in certain susceptible individuals of E.M.F. rather than R.H.D. is probably immunological. While non-specific nutritional factors may determine the degree or nature of the immune response to the streptococcal infection, there is almost certainly in these susceptible individuals some prior 7. 8. 9. 10. 11.
257. 12. 13.
Vosti, K. L. Med. Clins N. Am. 1965, 49, 1717. Kaplan, M. H., Svec, K. H. J. exp. Med. 1964, 119, 651. Kaplan, M. H., Dallenbach, F. D. ibid. 1961, 113, 1. Kaplan, M. H., Meveserian, M. Lancet, 1962, i, 706. Kaplan, M. H. in The Streptococcus, Rheumatic Fever and glomerulonephritis (edited by J. W. Uhr); p. 169. Baltimore 1964. van de Geld, H., Somers, K., Pelton, F. Lancet, Jan. 1, 1966, p. 48. Shaper, A. G., Williams, A. W. Trans. R. Soc. trop. Med. Hyg. 1960, 54, 12.
641 state which determines the pathogenesis of this condition. If one postulates that E.M.F. is a disorder, like R.H.D., resulting from exposure to streptococcal infection, why then are the Rwandan subjects in Buganda particularly susceptible ? The Rwandan patients seen at this hospital are subject to another condition which almost certainly involves an immunological process-i.e., idiopathic splenomegaly,14 The spleen plays a major role in the development of immunity,15 and in a study of spleenweights in all subjects coming to necropsy at Mulago Hospital in 1950-61 a striking difference has emerged between the Baganda subjects and those originating from Rwanda and the neighbouring areas of Ugandai.e., Kigezi and Ankole.11 When spleen-weights are plotted against age for the Baganda and Rwanda subjects there are no differences in mean spleen-weights up to the age of 4 years. In the 5-10-year age-group the mean spleen-weight in the Rwanda children (258 g.) is almost twice that of the Baganda children (146 g.), and this difference persists into adult life. Rwanda subjects aged 15-44 years have a mean spleen-weight of 512 g. compared with a mean spleen-weight of 357 g. in the Baganda. All the areas inhabited by the Baganda are at least moderately malarial-i.e., malaria occurs at all seasons with increased transmission after periods of heavy rainfall. The Ruanda, Kigezi, and Ankole areas are either normally malaria-free or only malarious near water, and the malaria risk is seasonal. While the older Rwanda subjects may have larger spleen-weights because they have come from an area of low malarial endemicity and are then exposed to a highly malarial situation, it is probable that a large proportion of the Rwandan children under 10 years of age have been born in Buganda. Their increased spleen-weights compared with those of the Baganda children is difficult to explain except perhaps in terms of increased exposure or increased response to the malarial infection. I suggest that an immunological factor related to malarial infection may condition the response of this group to other infections-e.g., streptococcal. Of the cases of endomyocardial fibrosis reported in Caucasians after residence in the tropics, most had had malaria 17-19 or been exposed to possible infection.20-23 In a sense these expatriate Caucasians in the tropics resemble the Rwandans in Uganda in coming from an area of low malarial endemicity to one of high malarial endemicity. In the 20 patients with R.H.D. and 10 subjects with E.M.F. referred to earlier in this paper in regard to anti-streptolysin-0 titres, the malarial antibody titres were over 1/100 in 10% of the R.H.D. cases and 80% of the E.M.F. cases. We have already indicated that most of the R.H.D. subjects are Baganda and the E.M.F. subjects are mainly Rwandan; hence these observations may be a further indication of increased exposure or increased response by the Rwandans to malarial infection. The burden of this polemic is that in any study concerning endomyocardial fibrosis constant comparison should be made with rheumatic heart-disease, whether
immunological
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
Hamilton, P. J. S., Hutt, M. S. R., Wilks, N. E., Olweny, C. Ndawula, R. L., Mwanje, L. E. Afr. med. J. 1965, 42, 191. Taliafero, W. H. Am. J. trop. Med. Hyg. 1956, 5, 391. Shaper, A. G. Unpublished. Grav, I. R. Br. Heart J. 1951, 13, 387. Clark, E. M. New Engl. J. Med. 1956, 254, 349. Coelho, E., Pimentel, J. C. Am. J. Med. 1963, 35, 569. Edge, J. R. Lancet, 1946, ii, 675. Fienberg, R., Holzmann, D. Bull. int. Ass. med. Mus. 1951, 32, 34. Lynch, J. B., Watt, J. Br. Heart J. 1957, 19, 173. Fisher, E. R., Davis, E. R. Am. Heart J. 1958, 56, 537.
the study be epidemiological or concerned with pathogensis and/or immunology. In addition, an attempt should be made to define susceptible subjects or groups, and to determine whether these have been exposed to malaria or other parasitic infections which might condition their immunological response to later bacterial or
virus infections. This work is supported by the World Health Organisation. I am grateful to Prof. M. S. R. Hutt for his cooperation, to Prof W. D. Foster and Dr. N. Wilks for their assistance, and to all these colleagues and Dr. David Bradley for the benefit of discussing this hypothesis with them. Requests for reprints should be addressed to A. G. S. at the Department of Medicine, Makerere University College Medical School, P.O. Box 2072, Kampala, Uganda, East Africa. A. G. SHAPER Department of Medicine, Makerere University College M.B. Cape Town, Medical School, M.R.C.P., D.T.M. &
Kampala, Uganda
H.
Reviews of Books The
Fungous Diseases of Man
.
J. WALTER WILSON, M.D., clinical professor of medicine (dermatology), University of California, Los Angeles; ORDA A. PLUNKETT, PH.D., professor emeritus of botany (mycology) and research professor, department of dermatology, University of California. Berkeley and Los Angeles: University of California Press. London: Cambridge University Press. 1965. Pp. 428. 120s.
" Three times is a lot," said Winston Churchill-and this is the third comprehensive textbook of medical mycology to have appeared in this country in two years. This is evidence of the increasing interest in the subject; but it poses a problem of selection, at least to the general reader. This latest work gives due emphasis to both clinical and laboratory aspects. The text is authoritative and is based, not only on the wide personal experience of the authors, but also on that of other medical mycologists. The crowning glory of this volume, however, is its illustrations. The British reader may never have come across a case of disseminated coccidioidomycosis, of cutaneous sporotrichosis, or of histoplasmosis of the tongue; but he may well be able to recognise these and other diseases after studying the colour plates in this book. These are unparalleled.
The Thalassaemia
Syndromes
D.
J. WEATHERALL, M.D., M.R.C.P., department of medicine, Johns Hopkins University School of Medicine, Baltimore, U.S.A.
Pp.
272.
Oxford: Blackwell Scientific Publications. 45s.
1965.
Dr. Weatherall’s book is timely in collecting the great amount information on thalassaemias into a single volume, and in explaining this information to the non-specialist. He has moreover gathered together many differences and modifications in thalasseemia which in due course will be linked with abnormalities in haemoglobin synthesis. He discusses the abnormal haemoglobins and some genetic variants of special interest. An example is haemoglobin Lepore in which the non-fx-chains are composed of both -chains of hxmoglobin A and 8-chains of haemoglobin A2, thereby indicating the closeness on one chromosome of the two genes responsible. There are sections on the laboratory diagnosis of thalassaemia and on treatment and a very extensive list of references. This is bound to become a standard work of reference in the libraries of laboratories interested in haematological disorders, and it will also interest
of
geneticists. What Freud Really Said
STAFFORD-CLARK, M.D., F.R.C.P., D.P.M., physician in charge, department of psychological medicine, Guy’s hospital, London. London: Macdonald. 1965. Pp. 264. 18s. DAVID
THIS first volume of a new series sets a very high standard, both in selection of Freud’s essential work and in its mode of presentation. Apart from his scientific genius, Freud has long been acknowledged as a master of clarity in his writings, and