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IMMUNOLOGICAL FEATURES OF WEGENER'S GRANULOMATOSIS
929
philic myelocytes, 4% neutrophilic metamyelocytes, 3% neutrophilic band forms, 0-5% orthochromatic normoblasts. Mitotic elements 4-5%. Fetal haemoglobin 1%., serum-iron 140 !g. per 100 ml., serum-cholesterol 90 mg. per 100 ml., uric acid 6-8 mg. per 100 ml. Basal metabolic rate -9-91%. Radioactive iodine (1311) uptake: 1 hr. 7%, 24 hr. 6%, 48 hr. 6%.
Acute myeloblastic leukxmia was diagnosed and combined therapy with corticosteroid, mercaptopurine, and vincristine was started. The patient was transfused several times. Despite this, her condition deteriorated and she died from bleeding. Propylthiouracil may depress granulocytopoiesis and occasionally depresses the bone-marrow. We are inclined to think that, in our patient with acute myeloblastic leukxmia, this antithyroid agent was possibly one of the factors leading to the blood disorder. Section of Hæmatology, Internal Clinic of Istanbul Medical School,
Capa, Istanbul, Turkey.
MUZAFFER AKSOY SAKIR ERDEM HIKMET TEZEL TUNA TEZEL.
Methods for Wegener’s granulomatosis is unclear. detecting circulating immune complexes remain imperfect, but they were not found in 8 of our 10 patients tested by the anti-complementary method.9 We agree that this does not exclude the possibility that immune complexes might be localised in the kidneys, although in the case-histories quoted by Dr Fauci and Dr Wolff this was not considered an important finding. Indeed, in one of them there was a preponderance of fibrin and very little globulin,to and fibrin was also found in this type of lesion, in the absence of either immunoglobulin or complement.ll In Wegener’s granulomatosis it is of course possible that, as in leprosy 12 and the well-known animal model of lymphocytic choriomeningitis,13 there is a spectrum of different clinicopathological patterns, in some of which a depression of cell-mediated immunity might be associated with or followed by immune complex deposition.
Guy’s Hospital, London SE1 9RT.
IMMUNOLOGICAL FEATURES OF WEGENER’S GRANULOMATOSIS
SIR,-We read the letter by Dr Fauci and Dr Wolff and await with interest their papers in the press. Although corticosteroids have been shown to deplete lymphocytes and to inhibit cell-mediated immune reactions in animal models, 1,2 the evidence that therapeutic doses of corticosteroids in man suppress delayed hypersensitivity reactions is at best inconclusive. 3-66 The brief review citedby Fauci and Wolff clearly indicates that, although early reports suggest suppression in some patients, later reports usually failed to confirm this finding. A point that seemed to have been overlooked is that delayed hypersensitivity responses were absent in 4 of our 5 patients who had not received steroids. A possible reason for the difference between our results and those of Fauci and Wolff 11 may lie in the clinical status of the patients. Many of their patients were in partial or complete remission at the time skin tests were carried out, whereas all our patients had active disease. We think that patients with active disease are more likely to reveal a basic abnormality than patients who are in a therapeutically induced remission. We wish to emphasise that skin tests alone do not provide In an adequate assessment of cell-mediated immunity. the only published paper on the subject at the time we completed our manuscript,8the only tests of delayed hypersensitivity which seem to have been performed were skin tests with S.K.S.D. and mumps antigen. In addition to skin tests we carried out lymphocyte transformation and macrophage migration inhibition studies with 4 antigens and P.H.A. and found a significant impairment of lymphocyte transformation, both in the presence of antigens and with the mitogen. This was associated with an apparently intact macrophage migration inhibition. The defect was seen in both treated and untreated patients, and the response to P.H.A. in our untreated cases ranged from 9-6% to 72% of normal. The role of immune complexes in the xtiology of
(April 13, p. 688)
1. 2. 3.
4. 5. 6. 7. 8.
Harris, S., Harris, T. N. Proc. Soc. exp. Biol. Med. 1950, 74, 186. Osgood, C. K., Favour, C. B. J. exp. Med. 1951, 94, 415. Harvier, P., Camus, J. L., Deuil, R., Di Matteo, J. J. franç. Med. Chir. Thor. 1951, 5, 164. Marie, J., Cruciani, C. Presse méd. 1952, 60, 829. Truelove, L. H. Br. med. J. 1957, ii, 1131. Toh, B. H., Roberts-Thompson, I. C., Mathers, J. D., Whittingham, S., Mackay, I. R. Clin. exp. Immun. 1973, 13, 55. Gabrielsen, A. E., Good, R. A. Adv. Immun. 1967, 6, 92. Fauci, A. S., Wolff, S. M., Johnson, J. S. Now Engl. J. Med. 1971, 285, 1493.
E. J. SHILLITOE T. LEHNER M. H. LESSOF D. F. N. HARRISON.
CO-TRIMOXAZOLE AND THE BLOOD
SIR,-Although the adverse effects of co-trimoxazole have attracted comment, 14,1.5 they seem to be more frequent and serious than is realised. Of 112 patients with megaloblastic anaemia investigated in this department during 1972 and 1973, 108 had deficiencies of folate, vitamin B12, or both. Co-trimoxazole appeared to be a precipitating factor in the remaining 4 (3-6%). Case 1.-A pregnant woman aged 31 presented with iron-deficiency anaemia (Hb 8.0 g. per 100 ml., mean corpuscular volume 63 fl., mean corpuscular haemoglobin 20-4 pg.). After treatment with parenteral iron, her hxmoglobin rose to 9-8 g. (M.C.V. 9-1fl., M.C.H. 28-7 pg.). She was then given two courses of co-trimoxazole (9’60 g. each) for urinary-tract infection. Hxmoglobin fell to 8-3 g. per 100 ml. and M.C.V. rose to 103 fl. Erythropoiesis was megaloblastic. Folic acid was given for 10 days without improvement.
It
was
(9-60 g.) had When it
was
discovered that a third course of the antibacterial been prescribed concurrently with the folic acid. stopped the reticulocyte count rose and anaemia
improved. Case 2.-Pharyngo-laryngo-oesophagectomy was performed upon a woman aged 70 years. Three weeks after operation her haemoglobin was 11-1 g. per 100 ml. (M.C.V. 89 fl., M.C.H. 29-9 pg.). A chest infection developed and she was given cotrimoxazole (total dose 13-44 g.) for one week. Eight days later the hxmoglobin level had fallen to 7-3 g. per 100 ml. (M.C.V. 89 fl., M.C.H. 30 pg.) with neutropenia (2100 per c.mm.) and thrombocytopenia (5000 per c.mm.). A blood-film showed neutrophil hypersegmentation and a few macrocytes. Although hypocellular, the marrow showed megaloblastic changes. She was given parenteral folic acid and the blood picture soon returned to normal. Case 3.-A woman of 83 was given two courses of co-trimoxazole (total dose 19-20 g.) for urinary-tract infection. The haemoglobin
level fell from 12-9 g. to 11-4 g. per 100 ml. and the M.C.V. rose from 97 fl. to 110 fl. during six weeks in hospital. Erythropoiesis was megaloblastic. She died of bronchopneumonia before the blood condition could be treated effectively. Case 4.-A
man
of 81 with chronic
congestive heart-failure and
Mowbray, J. F., Hoffbrand, A. V., Holborow, E. J., Seah, P. P., Fry, L. Lancet, 1973, i, 400. 10. Roback, S. A., Herdmann, R. C., Horger, J., Good, R. A. Am. J. Dis. Child. 1969, 118, 608. 11. Paronetto, F. in Textbook of Immunopathology (edited by P. A. Miescher, H. J. Muller-Eberhard); p. 722. New York and London, 9.
1969.
Turk, J. L. in Immune Complex Diseases (edited by L. Bonomo and J. L. Turk); p. 165. Milan, 1970. 13. Hirsch, M. S., Murphy, F. A., Hicklin, M. D. J. exp. Med. 1968, 127, 757. 14. Lancet, 1973, ii, 950. 15. Hamblin, T. J. ibid. p. 1153. 12.
philic myelocytes, 4% neutrophilic metamyelocytes, 3% neutrophilic band forms, 0-5% orthochromatic normoblasts. Mitotic elements 4-5%. Fetal haemoglobin 1%., serum-iron 140 !g. per 100 ml., serum-cholesterol 90 mg. per 100 ml., uric acid 6-8 mg. per 100 ml. Basal metabolic rate -9-91%. Radioactive iodine (1311) uptake: 1 hr. 7%, 24 hr. 6%, 48 hr. 6%.
Acute myeloblastic leukxmia was diagnosed and combined therapy with corticosteroid, mercaptopurine, and vincristine was started. The patient was transfused several times. Despite this, her condition deteriorated and she died from bleeding. Propylthiouracil may depress granulocytopoiesis and occasionally depresses the bone-marrow. We are inclined to think that, in our patient with acute myeloblastic leukxmia, this antithyroid agent was possibly one of the factors leading to the blood disorder. Section of Hæmatology, Internal Clinic of Istanbul Medical School,
Capa, Istanbul, Turkey.
MUZAFFER AKSOY SAKIR ERDEM HIKMET TEZEL TUNA TEZEL.
Methods for Wegener’s granulomatosis is unclear. detecting circulating immune complexes remain imperfect, but they were not found in 8 of our 10 patients tested by the anti-complementary method.9 We agree that this does not exclude the possibility that immune complexes might be localised in the kidneys, although in the case-histories quoted by Dr Fauci and Dr Wolff this was not considered an important finding. Indeed, in one of them there was a preponderance of fibrin and very little globulin,to and fibrin was also found in this type of lesion, in the absence of either immunoglobulin or complement.ll In Wegener’s granulomatosis it is of course possible that, as in leprosy 12 and the well-known animal model of lymphocytic choriomeningitis,13 there is a spectrum of different clinicopathological patterns, in some of which a depression of cell-mediated immunity might be associated with or followed by immune complex deposition.
Guy’s Hospital, London SE1 9RT.
IMMUNOLOGICAL FEATURES OF WEGENER’S GRANULOMATOSIS
SIR,-We read the letter by Dr Fauci and Dr Wolff and await with interest their papers in the press. Although corticosteroids have been shown to deplete lymphocytes and to inhibit cell-mediated immune reactions in animal models, 1,2 the evidence that therapeutic doses of corticosteroids in man suppress delayed hypersensitivity reactions is at best inconclusive. 3-66 The brief review citedby Fauci and Wolff clearly indicates that, although early reports suggest suppression in some patients, later reports usually failed to confirm this finding. A point that seemed to have been overlooked is that delayed hypersensitivity responses were absent in 4 of our 5 patients who had not received steroids. A possible reason for the difference between our results and those of Fauci and Wolff 11 may lie in the clinical status of the patients. Many of their patients were in partial or complete remission at the time skin tests were carried out, whereas all our patients had active disease. We think that patients with active disease are more likely to reveal a basic abnormality than patients who are in a therapeutically induced remission. We wish to emphasise that skin tests alone do not provide In an adequate assessment of cell-mediated immunity. the only published paper on the subject at the time we completed our manuscript,8the only tests of delayed hypersensitivity which seem to have been performed were skin tests with S.K.S.D. and mumps antigen. In addition to skin tests we carried out lymphocyte transformation and macrophage migration inhibition studies with 4 antigens and P.H.A. and found a significant impairment of lymphocyte transformation, both in the presence of antigens and with the mitogen. This was associated with an apparently intact macrophage migration inhibition. The defect was seen in both treated and untreated patients, and the response to P.H.A. in our untreated cases ranged from 9-6% to 72% of normal. The role of immune complexes in the xtiology of
(April 13, p. 688)
1. 2. 3.
4. 5. 6. 7. 8.
Harris, S., Harris, T. N. Proc. Soc. exp. Biol. Med. 1950, 74, 186. Osgood, C. K., Favour, C. B. J. exp. Med. 1951, 94, 415. Harvier, P., Camus, J. L., Deuil, R., Di Matteo, J. J. franç. Med. Chir. Thor. 1951, 5, 164. Marie, J., Cruciani, C. Presse méd. 1952, 60, 829. Truelove, L. H. Br. med. J. 1957, ii, 1131. Toh, B. H., Roberts-Thompson, I. C., Mathers, J. D., Whittingham, S., Mackay, I. R. Clin. exp. Immun. 1973, 13, 55. Gabrielsen, A. E., Good, R. A. Adv. Immun. 1967, 6, 92. Fauci, A. S., Wolff, S. M., Johnson, J. S. Now Engl. J. Med. 1971, 285, 1493.
E. J. SHILLITOE T. LEHNER M. H. LESSOF D. F. N. HARRISON.
CO-TRIMOXAZOLE AND THE BLOOD
SIR,-Although the adverse effects of co-trimoxazole have attracted comment, 14,1.5 they seem to be more frequent and serious than is realised. Of 112 patients with megaloblastic anaemia investigated in this department during 1972 and 1973, 108 had deficiencies of folate, vitamin B12, or both. Co-trimoxazole appeared to be a precipitating factor in the remaining 4 (3-6%). Case 1.-A pregnant woman aged 31 presented with iron-deficiency anaemia (Hb 8.0 g. per 100 ml., mean corpuscular volume 63 fl., mean corpuscular haemoglobin 20-4 pg.). After treatment with parenteral iron, her hxmoglobin rose to 9-8 g. (M.C.V. 9-1fl., M.C.H. 28-7 pg.). She was then given two courses of co-trimoxazole (9’60 g. each) for urinary-tract infection. Hxmoglobin fell to 8-3 g. per 100 ml. and M.C.V. rose to 103 fl. Erythropoiesis was megaloblastic. Folic acid was given for 10 days without improvement.
It
was
(9-60 g.) had When it
was
discovered that a third course of the antibacterial been prescribed concurrently with the folic acid. stopped the reticulocyte count rose and anaemia
improved. Case 2.-Pharyngo-laryngo-oesophagectomy was performed upon a woman aged 70 years. Three weeks after operation her haemoglobin was 11-1 g. per 100 ml. (M.C.V. 89 fl., M.C.H. 29-9 pg.). A chest infection developed and she was given cotrimoxazole (total dose 13-44 g.) for one week. Eight days later the hxmoglobin level had fallen to 7-3 g. per 100 ml. (M.C.V. 89 fl., M.C.H. 30 pg.) with neutropenia (2100 per c.mm.) and thrombocytopenia (5000 per c.mm.). A blood-film showed neutrophil hypersegmentation and a few macrocytes. Although hypocellular, the marrow showed megaloblastic changes. She was given parenteral folic acid and the blood picture soon returned to normal. Case 3.-A woman of 83 was given two courses of co-trimoxazole (total dose 19-20 g.) for urinary-tract infection. The haemoglobin
level fell from 12-9 g. to 11-4 g. per 100 ml. and the M.C.V. rose from 97 fl. to 110 fl. during six weeks in hospital. Erythropoiesis was megaloblastic. She died of bronchopneumonia before the blood condition could be treated effectively. Case 4.-A
man
of 81 with chronic
congestive heart-failure and
Mowbray, J. F., Hoffbrand, A. V., Holborow, E. J., Seah, P. P., Fry, L. Lancet, 1973, i, 400. 10. Roback, S. A., Herdmann, R. C., Horger, J., Good, R. A. Am. J. Dis. Child. 1969, 118, 608. 11. Paronetto, F. in Textbook of Immunopathology (edited by P. A. Miescher, H. J. Muller-Eberhard); p. 722. New York and London, 9.
1969.
Turk, J. L. in Immune Complex Diseases (edited by L. Bonomo and J. L. Turk); p. 165. Milan, 1970. 13. Hirsch, M. S., Murphy, F. A., Hicklin, M. D. J. exp. Med. 1968, 127, 757. 14. Lancet, 1973, ii, 950. 15. Hamblin, T. J. ibid. p. 1153. 12.