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Acquired angioedema, autoimmune hemolytic anemia, and lymphoma: Resolution after therapy
ANGIOEDEMA,
AIHA,
AND
LYMPHOMA
643
900-1X@), IgA 76 mg% (normal 170-410), IgM 98 mg% (normal SO-llO), and cryoglobulin and cryofibrinogen were not detectable. ANA was positive at 1:40 with homogenous fluorescence, C3 71 mg% (normal 54- 105), C4 4.3 mg% (normal 20-40), CH,, 9.7 units/ml (normal 28-48), and Cl inhibitor 18.0 units/ml (normal 21-58). Direct and indirect Coombs’ tests were positive. IgG and C3 were both detected on the red blood cell membranes. A chromium-51 red blood cell survival study showed the apparent red cell half-life to be approximately 14 days and the spleen to liver ratio consistent with a splenic trapping mechanism. In December 1975 the patient experienced an episode of swelling of the neck, left arm, and left breast. In January 1976 a splenectomy was performed (her hemoglobin at that time was 5.1% and reticulocyte count 19.4%). At surgery she was found to have an enlarged spleen (1150 g after removal) with prominent lymph nodes at the hilum. Spleen histology showed lymphoblastic lymphoma. A liver biopsy was normal. She was treated with Cytoxan, Oncovin, prednisone, and procarbazine (with dosage modification as necessary for occasional leukopenia). Her hemoglobin and reticulocyte count returned to normal. Following surgery she has had no more angioedema episodes and her complement values have returned to normal (see Fig. 1). Aside from the general improvement in her condition, she developed herpes zoster of the left hemithorax in May 1976 and had difficulties with pain in that area for several months. Chemotherapy was discontinued in
la75 lem lsn FIG. 1. Depicts the clinical course of the patient relative to time and changing laboratory studies. The hemolytic abnormalities rapidly improved after splenectomy, while the complement values slowly increased. Angioedema did not occur after the surgery and the Cl inhibitor increased to within the normal range.
644
FIECHTNER
ET AL.
January 1978. A mastectomy was subsequently lomatosis with infiltrating duct carcinoma. MATERIALS
required for an intraductal
papil-
AND METHODS
Serum samples were obtained and tested immediately or after storage at - 70°C. Total serum complement (CH,,, units/ml) was measured by the hemolytic method of Garvey et al. (9) using sheep red blood cells (standardized to 0.700 OD and veranol-buffered saline (pH 7.35 and 2.20 x lo4 pmho conductivity) in a total volume of 5 ml. Radial immunodiffusion (RID) techniques were used to determine Cl inhibitor (units/ml), C3 (mgidl), C4 (mg/dl), and Factor B (units/ml). Goat anti-human Cl inhibitor and Factor B (Cordis Laboratories, Miami, Fla.) in 1% Seakem agarose (MCI Biomedical, Rockland, Maine) was used to prepare agar plates for the RID determinations according to the method of Fahey and McKelvey (10). C3 and C4 were determined using commercially available kits from Behring Laboratories (Somerville, N.J.). Normal ranges were established using normal serum pool from 10 healthy volunteers as standards and a large number of healthy volunteers as controls. The calculated range for normal is the mean ? 2 standard deviations. Our normal values closely coincide with those commonly given by other investigators. Lymphocyte enumeration and function were determined by methods as previously described (II). T cells were determined by sheep red cell rosettes and B cells by surface immunoglobulins and complement receptors. Lymphocyte function was assessed as response to a panel of mitogens (phytohemagglutinin. pokeweed mitogen. and concanavalin A) and antigen (streptokinase streptodornase. mumps, candidin, histoplasmin, and tuberculin PPD). and by migration inhibition studies with the same antigens. Results are compared to a normal control subject assessed at the same time. DISCUSSION
Androgens have been used to reverse the clinical and laboratory abnormalities of HAE (8) but reversible nonhereditary angioedema and Cl INH deficiency has not previously been described in the literature. The lack of family history. the absence of clinical symptoms at an earlier age. and the increase of Cl INH after therapy should exclude hereditary angioedema even though family members could not be tested. Five patients with angioedema and lymphoproliferative disorders have previously been reported (2-6). All have had Cl inhibitor deficiency and early component depletion (Cl, C2, C4) while retaining normal C3 levels. Four additional patients with acquired Cl INH deficiency but without clinical angioedema have been described (5). Of the nine cases, three were diagnosed as lymphosarcoma, three as chronic lymphocytic leukemia, two as lymphocytic lymphoma, and one as “immunoproliferative disorder.” Low molecular weight IgM was identified in six of the nine cases (7 S IgM in 4/6) and circulating immune complexes were found in four patients. In one case a cold reactive IgM antilymphocyte antibody in the serum was thought to be the cause of Cl activation. In another, peripheral and tumor monocytes were found to be Cl depleting.
ANGIOEDEMA,
AIHA,
AND LYMPHOMA
645
Hauptmann et al. (6) described a patient very similar to ours with AIHA, angioedema, and CLL whose symptoms improved with chemotherapy but Cl INH continued to be diminished. A 7 S IgM was discovered and thought to be responsible for the disease process. Our studies do not elucidate the mechanism for the unusual series of immunological events that we saw, but may well include production of abnormal immunoglobulins by tumor cells and/or the interaction of tumor cells with C 1 INH (2-6), causing the clinical syndrome. These findings seem to be in direct contrast to other workers (12- 14) who are attempting to use elevations of Cl INH as an indicator of the presence of certain forms of malignant disease. Their findings are, however, not universal, and our patient may represent a small subset of patients in which other unidentified perturbations serve to lower the Cl INH leading to the clinical syndrome. This study points out the value of evaluation of the complement system in circumstances where abnormal antibodies are produced. ACKNOWLEDGMENTS The authors thank Cynthia Motszko Miyashita for secretarial assistance.
for technical assistance and Juddie Krumrei
and Yikiko
REFERENCES 1. Donaldson, V. H., and Evans, R. R., Amer. J. Med. 35, 37, 1963. 2. Caldwell, J. R., Ruddy, S., Schur, P. H., and Austin, K. F., C/in. Immunol. Immunopathol. 1,39, 1972. 3. Day, N. K., Wintield, J. B., Winchester, R. J., Gee, T. S., and Kunkel, H. G., C/in. Res. 23, 410A, 1975 (abstract). 4. Rosenfeld, S. I., Staples, P. J., and Leddy, J. P., J. Allergy C/in. Immunol. 55, 104, 1975 (abstract). 5. Schreiber, A. D., Zweiman, B., Atkins, P., Goldwein, F., Pietra, G., Atkinson, B., and Abdou, N. I., Blood 48, 567, 1976. 6. Hauptmann, G., Lang, J., North, M., Oberling, F., Mayer, G., and Lachmann, P., Blur 32, 195, 1976. 7. Chaplin, H., and Avioli, L. V., Arch. Znr. Med. 137, 346, 1977. 8. Frank, M., Gelfand, J., and Atkinson, J., Ann. Int. Med. 84, 580, 1976. 9. Garvey, J. S., Cremer, N. E., and Sussdorf, 0. H., “Methods in Immunology,” pp. 379 and 387, Benjamin, New York, 1977. 10. Fahey, G. L., and McKelvey, E. M., .J. Immunol. 94, 84-90, 1%5. 11. Hansen, R. L., Marx, J. J., Ptacek, L. J., and Roberts, R. C., Amer. J. Dis. Child. 131, 518-521, 1977. 12. Bach-Mortensen, N., Osther, K., and Stroyer, I., Lancer 2,499, 1975. 13. Lachmann, P. J., and Wragge-Morley, J., Lancer 1, 703, 1976. 14. Astrup, J., Colstrup, H., and Frandsen, B., Acta. Radio/. Ther. Phys. Biol. 16, 394, 1977.
AIHA,
AND
LYMPHOMA
643
900-1X@), IgA 76 mg% (normal 170-410), IgM 98 mg% (normal SO-llO), and cryoglobulin and cryofibrinogen were not detectable. ANA was positive at 1:40 with homogenous fluorescence, C3 71 mg% (normal 54- 105), C4 4.3 mg% (normal 20-40), CH,, 9.7 units/ml (normal 28-48), and Cl inhibitor 18.0 units/ml (normal 21-58). Direct and indirect Coombs’ tests were positive. IgG and C3 were both detected on the red blood cell membranes. A chromium-51 red blood cell survival study showed the apparent red cell half-life to be approximately 14 days and the spleen to liver ratio consistent with a splenic trapping mechanism. In December 1975 the patient experienced an episode of swelling of the neck, left arm, and left breast. In January 1976 a splenectomy was performed (her hemoglobin at that time was 5.1% and reticulocyte count 19.4%). At surgery she was found to have an enlarged spleen (1150 g after removal) with prominent lymph nodes at the hilum. Spleen histology showed lymphoblastic lymphoma. A liver biopsy was normal. She was treated with Cytoxan, Oncovin, prednisone, and procarbazine (with dosage modification as necessary for occasional leukopenia). Her hemoglobin and reticulocyte count returned to normal. Following surgery she has had no more angioedema episodes and her complement values have returned to normal (see Fig. 1). Aside from the general improvement in her condition, she developed herpes zoster of the left hemithorax in May 1976 and had difficulties with pain in that area for several months. Chemotherapy was discontinued in
la75 lem lsn FIG. 1. Depicts the clinical course of the patient relative to time and changing laboratory studies. The hemolytic abnormalities rapidly improved after splenectomy, while the complement values slowly increased. Angioedema did not occur after the surgery and the Cl inhibitor increased to within the normal range.
644
FIECHTNER
ET AL.
January 1978. A mastectomy was subsequently lomatosis with infiltrating duct carcinoma. MATERIALS
required for an intraductal
papil-
AND METHODS
Serum samples were obtained and tested immediately or after storage at - 70°C. Total serum complement (CH,,, units/ml) was measured by the hemolytic method of Garvey et al. (9) using sheep red blood cells (standardized to 0.700 OD and veranol-buffered saline (pH 7.35 and 2.20 x lo4 pmho conductivity) in a total volume of 5 ml. Radial immunodiffusion (RID) techniques were used to determine Cl inhibitor (units/ml), C3 (mgidl), C4 (mg/dl), and Factor B (units/ml). Goat anti-human Cl inhibitor and Factor B (Cordis Laboratories, Miami, Fla.) in 1% Seakem agarose (MCI Biomedical, Rockland, Maine) was used to prepare agar plates for the RID determinations according to the method of Fahey and McKelvey (10). C3 and C4 were determined using commercially available kits from Behring Laboratories (Somerville, N.J.). Normal ranges were established using normal serum pool from 10 healthy volunteers as standards and a large number of healthy volunteers as controls. The calculated range for normal is the mean ? 2 standard deviations. Our normal values closely coincide with those commonly given by other investigators. Lymphocyte enumeration and function were determined by methods as previously described (II). T cells were determined by sheep red cell rosettes and B cells by surface immunoglobulins and complement receptors. Lymphocyte function was assessed as response to a panel of mitogens (phytohemagglutinin. pokeweed mitogen. and concanavalin A) and antigen (streptokinase streptodornase. mumps, candidin, histoplasmin, and tuberculin PPD). and by migration inhibition studies with the same antigens. Results are compared to a normal control subject assessed at the same time. DISCUSSION
Androgens have been used to reverse the clinical and laboratory abnormalities of HAE (8) but reversible nonhereditary angioedema and Cl INH deficiency has not previously been described in the literature. The lack of family history. the absence of clinical symptoms at an earlier age. and the increase of Cl INH after therapy should exclude hereditary angioedema even though family members could not be tested. Five patients with angioedema and lymphoproliferative disorders have previously been reported (2-6). All have had Cl inhibitor deficiency and early component depletion (Cl, C2, C4) while retaining normal C3 levels. Four additional patients with acquired Cl INH deficiency but without clinical angioedema have been described (5). Of the nine cases, three were diagnosed as lymphosarcoma, three as chronic lymphocytic leukemia, two as lymphocytic lymphoma, and one as “immunoproliferative disorder.” Low molecular weight IgM was identified in six of the nine cases (7 S IgM in 4/6) and circulating immune complexes were found in four patients. In one case a cold reactive IgM antilymphocyte antibody in the serum was thought to be the cause of Cl activation. In another, peripheral and tumor monocytes were found to be Cl depleting.
ANGIOEDEMA,
AIHA,
AND LYMPHOMA
645
Hauptmann et al. (6) described a patient very similar to ours with AIHA, angioedema, and CLL whose symptoms improved with chemotherapy but Cl INH continued to be diminished. A 7 S IgM was discovered and thought to be responsible for the disease process. Our studies do not elucidate the mechanism for the unusual series of immunological events that we saw, but may well include production of abnormal immunoglobulins by tumor cells and/or the interaction of tumor cells with C 1 INH (2-6), causing the clinical syndrome. These findings seem to be in direct contrast to other workers (12- 14) who are attempting to use elevations of Cl INH as an indicator of the presence of certain forms of malignant disease. Their findings are, however, not universal, and our patient may represent a small subset of patients in which other unidentified perturbations serve to lower the Cl INH leading to the clinical syndrome. This study points out the value of evaluation of the complement system in circumstances where abnormal antibodies are produced. ACKNOWLEDGMENTS The authors thank Cynthia Motszko Miyashita for secretarial assistance.
for technical assistance and Juddie Krumrei
and Yikiko
REFERENCES 1. Donaldson, V. H., and Evans, R. R., Amer. J. Med. 35, 37, 1963. 2. Caldwell, J. R., Ruddy, S., Schur, P. H., and Austin, K. F., C/in. Immunol. Immunopathol. 1,39, 1972. 3. Day, N. K., Wintield, J. B., Winchester, R. J., Gee, T. S., and Kunkel, H. G., C/in. Res. 23, 410A, 1975 (abstract). 4. Rosenfeld, S. I., Staples, P. J., and Leddy, J. P., J. Allergy C/in. Immunol. 55, 104, 1975 (abstract). 5. Schreiber, A. D., Zweiman, B., Atkins, P., Goldwein, F., Pietra, G., Atkinson, B., and Abdou, N. I., Blood 48, 567, 1976. 6. Hauptmann, G., Lang, J., North, M., Oberling, F., Mayer, G., and Lachmann, P., Blur 32, 195, 1976. 7. Chaplin, H., and Avioli, L. V., Arch. Znr. Med. 137, 346, 1977. 8. Frank, M., Gelfand, J., and Atkinson, J., Ann. Int. Med. 84, 580, 1976. 9. Garvey, J. S., Cremer, N. E., and Sussdorf, 0. H., “Methods in Immunology,” pp. 379 and 387, Benjamin, New York, 1977. 10. Fahey, G. L., and McKelvey, E. M., .J. Immunol. 94, 84-90, 1%5. 11. Hansen, R. L., Marx, J. J., Ptacek, L. J., and Roberts, R. C., Amer. J. Dis. Child. 131, 518-521, 1977. 12. Bach-Mortensen, N., Osther, K., and Stroyer, I., Lancer 2,499, 1975. 13. Lachmann, P. J., and Wragge-Morley, J., Lancer 1, 703, 1976. 14. Astrup, J., Colstrup, H., and Frandsen, B., Acta. Radio/. Ther. Phys. Biol. 16, 394, 1977.