- Email: [email protected]
GRANULOCYTE TRANSFUSIONS—A NEW CAVEAT
1405 situ (CIS) is
not
known, but increased familiarity with CIS is
the view that only some CIS will Patients with CIS within to carcinoma. invasive progress and having bladder irritation patchy erythematous areas, no tumour (clinical type 1), seem more likely to but symptoms get a highly invasive carcinoma than do patients with superficial papillary tumours in whom CIS is discovered by random biopsies from normal mucosa (clinical type 2). Are there two different types of CIS or is the behaviour determined by the clinical setting? Does CIS of clinical type 2 evolve into type I? What action should be taken when the diagnosis of CIS is based on urine cytology only? Much more information on the natural history, morphology, and pathology must be collected before these urgent questions can be answered. Another exciting area in bladder cancer research is Feyrter’s concept of the urothelium as a local endocrine (paracrine) organ-a concept which now has considerable backing. Admixture of endocrine cells in bladder tumours is probably commoner than has been supposed. Whether hormonal peptides produced by these cells modify the initiation or progression of cancer and whether they can be used as tumour markers remains to be determined. Despite the efforts of biochemists and immunologists, a reliable, specific, and sensitive indicator of bladder cancer has yet to be found. In the experimental sphere the achievements have included transplantation of human tumour cell lines into athymic nude mice and culture of human tumour cell lines as an in-vitro clonogenic assay for testing sensitivity to
leading many urologists
to
chemotherapeutic agents. Aetiological factors in bladder cancer are likely to multiple, involving complex multistage interactions
be of
initiators, promoters, and propagators. Bladder cancer was of the first occupational cancers recognised, in 1895 by Rehnl in workers in the aniline-dye industry. In addition to one
chemicals which are known bladder firm link has been established between bladder a carcinogens, cancer and cigarette smoking. Since the induction time of bladder cancer may be 20 or 30 years, new carcinogens may remain undetected for some years to come and so it is important that industries keep accurate records of morbidity and mortality. Industrial exposure and smoking are, however, unlikely to account for most bladder cancers, and other possible factors, such as diet, drugs, genetic predisposition, and immune status should continue to be the
industrial
explored.
be of great benefit to some patients.3-5 Thus the problem is not whether granulocyte transfusions can be effective, but rather to select the patient who will benefit, to decide when to initiate treatment, how best to collect donor cells, how many cells to transfuse, and at what intervals, and to define donorrecipient compatibility. Moreover, if granulocyte transfusions help to control infection can they be valuable in preventing infection in granulocytopenic patients? On their possible "prophylactic" role in the granulocytopenic patient without clinical infection, opinions differ. 6-8 Some of these questions would be less important if donor granulocytes were as readily available as, say, donor red cells in the blood bank. Unfortunately they are not and the effort and cost of collecting granulocytes by leucapheresis9 and the inconvenience to the donor are considerable. Furthermore, unlike donor red cells, donor granulocytes can be stored for only a day or twol °and do not function after cryopreservation. Perhaps most important of all, donor granulocytes should not be administered without good indication because of possible side-effects. They can, for example, be responsible for transmission of infectious disease, Ithey can induce graftversus-host disease in the recipient 12,13(though this can be prevented by irradiation of the donor cells in vitro), and they can engender allergic reactions 14 and various adverse pulmonary effects. 15 The pulmonary troubles may be due to fluid overload, sequestration of granulocytes in an extensive pulmonary lesion, interaction of transfused granulocytes with circulating endotoxin (possibly leading to the shocklung syndrome), 16 or the effects of circulating leucoagglutinins with embolisation of leucocyte aggregates to the lungs. 17 A further pulmonary problem has now been encountered by Wright and his colleagues at the National Cancer Institute. 18 They observed two patients with acute myeloid
leukaemia who were receiving daily granulocytes for treatment of gram-negative septicaemia; when amphotericin
Controlled prospective studies of granulocyte transfusion therapy. Exp Hemat 1977; 5: suppl 1, 57-64. 4. Schiffer CA Some aspects of recent advances in the use of blood cell components. Br J Haematol 1978; 39: 289-94. 5. Benbunan M, Borberg H, Fortuny I, et al. Granulocyte transfusions-an established or still an experimental procedure? International Forum. Vox Sang 1980; 38: 40-56. 6. Clift RA, Sanders JE, Thomas ED, Williams B, Buckner CD. Granulocyte transfusions for the prevention of infection in patients receiving bone marrow 3.
Higby DJ.
transplants. N Engl J Med 1978; 298: 1052-57 JM, Cullen MH. Prophylactic granulocyte transfusions. Exp Hematol 1977; 5: suppl 1, 65-72. Mannoni P, Brun B, Rodet M, Vernant JP, Rochant H, Dreyfus B. Granulocyte transfusions for prevention of infection. N EnglJ Med 1978; 299: 489.
7. Ford 8.
9. Rosenhein
MS, Farewell VT, Price TH, Larson EB, Dale DC. The cost effectiveness and prophylactic leukocyte transfusion. N EnglJ Med 1980; 302:
of therapeutic 1058-62.
GRANULOCYTE TRANSFUSIONS—A NEW CAVEAT WHEN
patients with severe granulocytopenia due to acute leukaemia, aplastic anaemia, or the effects of cytotoxic drugs acquire bacterial infections, immediate treatment with combinations of antibiotics at high dosage often rapidly controls the infection. For patients who respond slowly or not at all, the next logical step is transfusion of granulocytes collected from normal donors or from patients with chronic granulocytic leukaemia. Though the value of such transfusions was at one time regarded as dubious,2 they can 1 Rehn VL
Blasengeschwulste bei Fuchsin-Arbeitern. Arch Klin Chir 1895, 50: 588-600. 2. Boggs DR. Transfusion of neutrophils as prevention or treatment of infection in patients with neutropenia. N Engl J Med 1974; 290: 1055.
10. McCullough J, Weiblen BJ, Peterson PK, Quie PG. Effects of temperature on granulocyte preservation. Blood 1978; 52: 301-10. 11. Siegel S, Lunde MN, Geldermann AH, Halterman RH, Brown JA, Levine AS, Graw RG. Transmission of toxoplasmosis by leukocyte transfusion. Blood 1971; 37: 388-94. 12. Ford JM, Lucey JJ, Cullen MH, Tobias JS, Lister TA. Fatal graft-versus-host disease following transfusion of granulocytes from normal donors. Lancet 1976; 11 1167-69 13. Weiden PL, Zuckerman N, Hansen JA, Sale GE, Remlinger K, Back TM, Buckner CD. Fatal graft-versus-host disease in a patient with lymphoblastic leukemia following normal granulocyte transfusions. Blood 1981; 57: 328-32. 14. Goldstein IM, Eyre HJ, Terasaki PI, Henderson ES, Graw RG. Leukocyte transfusions: role of leukocyte alloantibodies in determining transfusion response
Transfusion 1971; 11: 19-24. 15. Higby DJ, Burnett D. Granulocyte transfusions: current status Blood 1980; 55: 2-8. 16. Jacob HS. Granulocyte-complement interaction. Arch Intern Med 1978, 138: 461-63 461-63 17. Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions Ann Intern Med 1970; 73: 689-94. 18. Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981, 304: 1185-89.
1406
B
was
added, both patients become acutely dyspnoeic with
haemoptysis, hypoxaemia, and interstitial infiltrates on the chest X-rays. Both required intubation and assisted ventilation. This led Wright and colleagues to review the case records of 57 patients with bacterial infections who had received daily granulocyte transfusions for four more days between 1973 and 1980. 22 of these patients had also received amphotericin B at some time during the granulocyte transfusions and 14 (64%) had shown signs of deterioration in respiratory function; of the 35 patients not receiving amphotericin B, only 2 (6%) had respiratory problems. Concluding that the pulmonary syndrome was due to the combined effects of granulocyte transfusions and amphotericin B, Wright and co-workers speculated that amphotericin B might act by lysing donor leucocytes trapped in the lung, thereby permitting release of leucocyte proteases and damaging lung tissues. These conclusions were challenged, however, by Dana and his colleagues in Arizona: spurred by the preliminary N.C.I. report they examined the records of 144 patients in Tucson.19 32 patients had received granulocyte transfusions and amphotericin B simultaneously and there had been respiratory deterioration on eleven occasions; in most instances, however, the respiratory troubles were traceable to other causes-and the respiratory problems were much the same in those who received amphotericin B and those who did not. Thus, to the Arizona workers the combination of granulocyte transfusions with amphotericin B seemed not to be especially harmful. The N.C.I. group responded 18 by pointing out that the average number of granulocyte transfusions in each course administered to the Arizona patients may have been less than four and that only a minority of the Arizona patients had gram-negative septicaemia: the observed pulmonary syndrome may in fact be due to the combined effects of granulocyte transfusions, amphotericin B, and endotoxaemia. The clinical relevance of these studies is clear enough. For patients receiving granulocyte transfusions amphotericin B must continue to be used when fungal infection is proven or strongly suspected. But the transfusion of the granulocytes should temporally be separated from that of the amphotericin as far as possible, the drug should be infused slowly, and the patient should be watched closely.
WHAT IS CLINICAL IMMUNOLOGY? THE Royal College of Physicians plans to lay down a programme in clinical immunology as part of training in general medicine,and clinical immunologists are already to be found in a few centres. The specialty is here to stay, but whether the orientation will be laboratory or bedside is not yet clear. No doubt many clinical immunologists, like many haematologists, would opt for a foot in each camp, but it seems that their colleagues in other specialties take a different view: they would confine the clinical immunologist largely to his laboratory, and would keep their hold on the day-to-day management of immunological problems. This was the conclusion reached by Dr A. M. Denman, who approached BW, Dune BGM, White RF, Huestis DW Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: absence of significant pulmonary toxicity. Blood 1981; 57: 90-94. Royal College of Physicians. Third report on Higher Medical Training. London: RCP,
question "What is clinical immunology?" by a novel method;2he presented ten genuine case histories, each with the
different immunological emphasis, to five physicians in different types of hospital practice. They were asked specific questions about their approach to diagnosis and treatment. The questions related particularly to immunological tests and their relevance, and to the role of clinical immunologists. The answers may not be representative of physicians in general, because those selected were known to have special immunological interests, but they will be of little cheer to immunologists bent on clinical involvement. The physicians indicated that they would consult an immunologist for advice about less well established tests, such as the definition of lymphocyte subpopulations in cases of lymphoma, but none would delegate responsibility to a clinical immunologist for day-to-day care of even a case of systemic lupus erythematosus, let alone disease where, in the eyes of ordinary physicians, immunology plays a supporting role rather than the principal part. Perhaps attitudes amongst general physicians will change as the management of immunological disorders becomes more complex-rather as haematologists and oncologists have found an increasingly important clinical commitment. Despite a cool response to the question of clinical involvement by immunologists, Denman found that everyone recognised the need for regional immunological laboratory services, where tests beyond the resources of district pathology laboratories can be done; such regional laboratories should have several additional important functions-for example, in training, research and development, and in quality control. Decisions about the types of immunological tests to be performed in district pathology laboratories as opposed to regional centres depend to some extent on local interests, but it seems reasonable to expect most of the commonly requested tests to be done locally. These include serum immunoglobulin levels,
immunoelectrophoresis, complement assays (C3, C4, CH50), autoantibody screening, rheumatoid factor, antinuclear antibodies, and HBsAg. Tests more suitable for a regional laboratory include specialised characterisation of abnormal immunoglobulins, rarer complement assays, lymphocyte assays, and transplantation immunology. One thorny related problem is the question of allergy. Should it be a separate specialty to which clinical immunologists/allergists may reasonably lay claim, or should the existing system continue wherein patients with allergic problems may find themselves referred to a general physician, a chest physician, a dermatologist, an ENT specialist, an allergist, or even a psychiatrist? The obvious answer must be for allergic matters to be dealt with by a trained specialist in allergy, but at present no suitable training programme exists. Curiously enough, the fault may lie with those most interested in allergy, amongst whom there are very considerable differences of opinion on the management of common allergic diseases. Clinical interpretation of skin prick tests, the need for total IgE and RAST tests, the extent and importance of food allergy, and the place of desensitisation (if any) are all areas of controversy. Until clinicians with an interest in allergy can present a more united front, there may be difficulty in persuading outsiders that allergy qualifies as a specialty.
19. Dana
1
1980
2. Denman AM. What
is
clinical
immunology? J Clin Pathol 1981; 34:
277-86
not
known, but increased familiarity with CIS is
the view that only some CIS will Patients with CIS within to carcinoma. invasive progress and having bladder irritation patchy erythematous areas, no tumour (clinical type 1), seem more likely to but symptoms get a highly invasive carcinoma than do patients with superficial papillary tumours in whom CIS is discovered by random biopsies from normal mucosa (clinical type 2). Are there two different types of CIS or is the behaviour determined by the clinical setting? Does CIS of clinical type 2 evolve into type I? What action should be taken when the diagnosis of CIS is based on urine cytology only? Much more information on the natural history, morphology, and pathology must be collected before these urgent questions can be answered. Another exciting area in bladder cancer research is Feyrter’s concept of the urothelium as a local endocrine (paracrine) organ-a concept which now has considerable backing. Admixture of endocrine cells in bladder tumours is probably commoner than has been supposed. Whether hormonal peptides produced by these cells modify the initiation or progression of cancer and whether they can be used as tumour markers remains to be determined. Despite the efforts of biochemists and immunologists, a reliable, specific, and sensitive indicator of bladder cancer has yet to be found. In the experimental sphere the achievements have included transplantation of human tumour cell lines into athymic nude mice and culture of human tumour cell lines as an in-vitro clonogenic assay for testing sensitivity to
leading many urologists
to
chemotherapeutic agents. Aetiological factors in bladder cancer are likely to multiple, involving complex multistage interactions
be of
initiators, promoters, and propagators. Bladder cancer was of the first occupational cancers recognised, in 1895 by Rehnl in workers in the aniline-dye industry. In addition to one
chemicals which are known bladder firm link has been established between bladder a carcinogens, cancer and cigarette smoking. Since the induction time of bladder cancer may be 20 or 30 years, new carcinogens may remain undetected for some years to come and so it is important that industries keep accurate records of morbidity and mortality. Industrial exposure and smoking are, however, unlikely to account for most bladder cancers, and other possible factors, such as diet, drugs, genetic predisposition, and immune status should continue to be the
industrial
explored.
be of great benefit to some patients.3-5 Thus the problem is not whether granulocyte transfusions can be effective, but rather to select the patient who will benefit, to decide when to initiate treatment, how best to collect donor cells, how many cells to transfuse, and at what intervals, and to define donorrecipient compatibility. Moreover, if granulocyte transfusions help to control infection can they be valuable in preventing infection in granulocytopenic patients? On their possible "prophylactic" role in the granulocytopenic patient without clinical infection, opinions differ. 6-8 Some of these questions would be less important if donor granulocytes were as readily available as, say, donor red cells in the blood bank. Unfortunately they are not and the effort and cost of collecting granulocytes by leucapheresis9 and the inconvenience to the donor are considerable. Furthermore, unlike donor red cells, donor granulocytes can be stored for only a day or twol °and do not function after cryopreservation. Perhaps most important of all, donor granulocytes should not be administered without good indication because of possible side-effects. They can, for example, be responsible for transmission of infectious disease, Ithey can induce graftversus-host disease in the recipient 12,13(though this can be prevented by irradiation of the donor cells in vitro), and they can engender allergic reactions 14 and various adverse pulmonary effects. 15 The pulmonary troubles may be due to fluid overload, sequestration of granulocytes in an extensive pulmonary lesion, interaction of transfused granulocytes with circulating endotoxin (possibly leading to the shocklung syndrome), 16 or the effects of circulating leucoagglutinins with embolisation of leucocyte aggregates to the lungs. 17 A further pulmonary problem has now been encountered by Wright and his colleagues at the National Cancer Institute. 18 They observed two patients with acute myeloid
leukaemia who were receiving daily granulocytes for treatment of gram-negative septicaemia; when amphotericin
Controlled prospective studies of granulocyte transfusion therapy. Exp Hemat 1977; 5: suppl 1, 57-64. 4. Schiffer CA Some aspects of recent advances in the use of blood cell components. Br J Haematol 1978; 39: 289-94. 5. Benbunan M, Borberg H, Fortuny I, et al. Granulocyte transfusions-an established or still an experimental procedure? International Forum. Vox Sang 1980; 38: 40-56. 6. Clift RA, Sanders JE, Thomas ED, Williams B, Buckner CD. Granulocyte transfusions for the prevention of infection in patients receiving bone marrow 3.
Higby DJ.
transplants. N Engl J Med 1978; 298: 1052-57 JM, Cullen MH. Prophylactic granulocyte transfusions. Exp Hematol 1977; 5: suppl 1, 65-72. Mannoni P, Brun B, Rodet M, Vernant JP, Rochant H, Dreyfus B. Granulocyte transfusions for prevention of infection. N EnglJ Med 1978; 299: 489.
7. Ford 8.
9. Rosenhein
MS, Farewell VT, Price TH, Larson EB, Dale DC. The cost effectiveness and prophylactic leukocyte transfusion. N EnglJ Med 1980; 302:
of therapeutic 1058-62.
GRANULOCYTE TRANSFUSIONS—A NEW CAVEAT WHEN
patients with severe granulocytopenia due to acute leukaemia, aplastic anaemia, or the effects of cytotoxic drugs acquire bacterial infections, immediate treatment with combinations of antibiotics at high dosage often rapidly controls the infection. For patients who respond slowly or not at all, the next logical step is transfusion of granulocytes collected from normal donors or from patients with chronic granulocytic leukaemia. Though the value of such transfusions was at one time regarded as dubious,2 they can 1 Rehn VL
Blasengeschwulste bei Fuchsin-Arbeitern. Arch Klin Chir 1895, 50: 588-600. 2. Boggs DR. Transfusion of neutrophils as prevention or treatment of infection in patients with neutropenia. N Engl J Med 1974; 290: 1055.
10. McCullough J, Weiblen BJ, Peterson PK, Quie PG. Effects of temperature on granulocyte preservation. Blood 1978; 52: 301-10. 11. Siegel S, Lunde MN, Geldermann AH, Halterman RH, Brown JA, Levine AS, Graw RG. Transmission of toxoplasmosis by leukocyte transfusion. Blood 1971; 37: 388-94. 12. Ford JM, Lucey JJ, Cullen MH, Tobias JS, Lister TA. Fatal graft-versus-host disease following transfusion of granulocytes from normal donors. Lancet 1976; 11 1167-69 13. Weiden PL, Zuckerman N, Hansen JA, Sale GE, Remlinger K, Back TM, Buckner CD. Fatal graft-versus-host disease in a patient with lymphoblastic leukemia following normal granulocyte transfusions. Blood 1981; 57: 328-32. 14. Goldstein IM, Eyre HJ, Terasaki PI, Henderson ES, Graw RG. Leukocyte transfusions: role of leukocyte alloantibodies in determining transfusion response
Transfusion 1971; 11: 19-24. 15. Higby DJ, Burnett D. Granulocyte transfusions: current status Blood 1980; 55: 2-8. 16. Jacob HS. Granulocyte-complement interaction. Arch Intern Med 1978, 138: 461-63 461-63 17. Ward HN. Pulmonary infiltrates associated with leukoagglutinin transfusion reactions Ann Intern Med 1970; 73: 689-94. 18. Wright DG, Robichaud KJ, Pizzo PA, Deisseroth AB. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981, 304: 1185-89.
1406
B
was
added, both patients become acutely dyspnoeic with
haemoptysis, hypoxaemia, and interstitial infiltrates on the chest X-rays. Both required intubation and assisted ventilation. This led Wright and colleagues to review the case records of 57 patients with bacterial infections who had received daily granulocyte transfusions for four more days between 1973 and 1980. 22 of these patients had also received amphotericin B at some time during the granulocyte transfusions and 14 (64%) had shown signs of deterioration in respiratory function; of the 35 patients not receiving amphotericin B, only 2 (6%) had respiratory problems. Concluding that the pulmonary syndrome was due to the combined effects of granulocyte transfusions and amphotericin B, Wright and co-workers speculated that amphotericin B might act by lysing donor leucocytes trapped in the lung, thereby permitting release of leucocyte proteases and damaging lung tissues. These conclusions were challenged, however, by Dana and his colleagues in Arizona: spurred by the preliminary N.C.I. report they examined the records of 144 patients in Tucson.19 32 patients had received granulocyte transfusions and amphotericin B simultaneously and there had been respiratory deterioration on eleven occasions; in most instances, however, the respiratory troubles were traceable to other causes-and the respiratory problems were much the same in those who received amphotericin B and those who did not. Thus, to the Arizona workers the combination of granulocyte transfusions with amphotericin B seemed not to be especially harmful. The N.C.I. group responded 18 by pointing out that the average number of granulocyte transfusions in each course administered to the Arizona patients may have been less than four and that only a minority of the Arizona patients had gram-negative septicaemia: the observed pulmonary syndrome may in fact be due to the combined effects of granulocyte transfusions, amphotericin B, and endotoxaemia. The clinical relevance of these studies is clear enough. For patients receiving granulocyte transfusions amphotericin B must continue to be used when fungal infection is proven or strongly suspected. But the transfusion of the granulocytes should temporally be separated from that of the amphotericin as far as possible, the drug should be infused slowly, and the patient should be watched closely.
WHAT IS CLINICAL IMMUNOLOGY? THE Royal College of Physicians plans to lay down a programme in clinical immunology as part of training in general medicine,and clinical immunologists are already to be found in a few centres. The specialty is here to stay, but whether the orientation will be laboratory or bedside is not yet clear. No doubt many clinical immunologists, like many haematologists, would opt for a foot in each camp, but it seems that their colleagues in other specialties take a different view: they would confine the clinical immunologist largely to his laboratory, and would keep their hold on the day-to-day management of immunological problems. This was the conclusion reached by Dr A. M. Denman, who approached BW, Dune BGM, White RF, Huestis DW Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: absence of significant pulmonary toxicity. Blood 1981; 57: 90-94. Royal College of Physicians. Third report on Higher Medical Training. London: RCP,
question "What is clinical immunology?" by a novel method;2he presented ten genuine case histories, each with the
different immunological emphasis, to five physicians in different types of hospital practice. They were asked specific questions about their approach to diagnosis and treatment. The questions related particularly to immunological tests and their relevance, and to the role of clinical immunologists. The answers may not be representative of physicians in general, because those selected were known to have special immunological interests, but they will be of little cheer to immunologists bent on clinical involvement. The physicians indicated that they would consult an immunologist for advice about less well established tests, such as the definition of lymphocyte subpopulations in cases of lymphoma, but none would delegate responsibility to a clinical immunologist for day-to-day care of even a case of systemic lupus erythematosus, let alone disease where, in the eyes of ordinary physicians, immunology plays a supporting role rather than the principal part. Perhaps attitudes amongst general physicians will change as the management of immunological disorders becomes more complex-rather as haematologists and oncologists have found an increasingly important clinical commitment. Despite a cool response to the question of clinical involvement by immunologists, Denman found that everyone recognised the need for regional immunological laboratory services, where tests beyond the resources of district pathology laboratories can be done; such regional laboratories should have several additional important functions-for example, in training, research and development, and in quality control. Decisions about the types of immunological tests to be performed in district pathology laboratories as opposed to regional centres depend to some extent on local interests, but it seems reasonable to expect most of the commonly requested tests to be done locally. These include serum immunoglobulin levels,
immunoelectrophoresis, complement assays (C3, C4, CH50), autoantibody screening, rheumatoid factor, antinuclear antibodies, and HBsAg. Tests more suitable for a regional laboratory include specialised characterisation of abnormal immunoglobulins, rarer complement assays, lymphocyte assays, and transplantation immunology. One thorny related problem is the question of allergy. Should it be a separate specialty to which clinical immunologists/allergists may reasonably lay claim, or should the existing system continue wherein patients with allergic problems may find themselves referred to a general physician, a chest physician, a dermatologist, an ENT specialist, an allergist, or even a psychiatrist? The obvious answer must be for allergic matters to be dealt with by a trained specialist in allergy, but at present no suitable training programme exists. Curiously enough, the fault may lie with those most interested in allergy, amongst whom there are very considerable differences of opinion on the management of common allergic diseases. Clinical interpretation of skin prick tests, the need for total IgE and RAST tests, the extent and importance of food allergy, and the place of desensitisation (if any) are all areas of controversy. Until clinicians with an interest in allergy can present a more united front, there may be difficulty in persuading outsiders that allergy qualifies as a specialty.
19. Dana
1
1980
2. Denman AM. What
is
clinical
immunology? J Clin Pathol 1981; 34:
277-86