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Successful treatment of autoimmune hemolytic anemia in common variable immunodeficiency with high-dose intravenous gamma globulin
Successful Treatment of Autoimmune Hemolytic Anemia in Common Variable lmmunodeficiency with High-Dose Intravenous Gamma Globulin
FREDERICK E. LEICKLY, M.D.* REBECCA H. BUCKLEY, M.D. Durham, North Carolina
A patient with common variable immunodeficiency and autoimmune hemolytic anemia was given high-dose (450 mg/kg) intravenous gamma globulin (Sandoglobulin) for five days, followed by single doses of 100 to 200 mg/kg at four-week intervals or whenever the hemoglobin level and hematocrit fell or the reticulocyte count increased. This treatment was accompanied by a stabilization of hematopoietic parameters and reversal of Coombs’ positivity, which have been sustained for 34 months. The use of high-dose gamma globulin for autoimmune hemolytic anemia can eliminate the need for other therapeutic modalities that may be detrimental to an immunocompromised host. Therapeutic approaches to the treatment of autoimmune hemolytic anemia have included the use of steroids, splenectomy, and various cytotoxic agents. When autoimmune hemolytic anemia occurs in association with a primary immunodeficiency, however, such treatment modalities could further increase the patient’s susceptibility to infection. Recent reports of the successful use of high-dose intravenous gamma globulin in the treatment of idiopathic thrombocytopenic purpura and the fact that
this agent is standard therapy for common variable immunodeficiency prompted us to use it in a patient with this defect and autoimmune hemolytic anemia. In contrast to mixed results in the limited number of cases treated in this manner reported to date [l-3], our patient’s autoimmune hemolytic anemia was successfully reversed.
CASEREPORT
From the Departments of Pediatrics and Microbi’ ology and Immunology, Duke University School of Medicine, Durham, North Carolina. This work was supported by General Clinical Research Centers Grant RR-30 and by a grant from the National Institute of Allergy and Infectious Diseases (5ROl-A118613). Dr. Leickly’s postdoctoral fellowship training was supported by an Institutional National Research Service Award in Allergy and Immunology (5T32-A107062). Requests for reprints should be addressed to Dr. Rebecca H. Buckley, Box 2898, Duke University Medical Center, Durham, North Carolina 27710. Manuscript submitted August 15, 1985, and accepted September 12, 1985. *Current address: Division of Allergy, Department of Pediatrics, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.
A Zl-year-old white man presented for re-evaluation of his candidacy for splenectomy in treatment of autoimmune hemolytic anemia. He had been initially referred to Duke University Medical Center for evaluation of massive splenomegaly at age 18 years. Shortly before that, his IgG level had been found to be 330 mg/dl, IgA level less than 4 mg/dl, and IgM level 24 mg/dl, leading to a diagnosis of common variable immunodeficiency. His past medical history was remarkable for chronic nasal congestion, rhinorrhea, sinusitis, otitis, bronchitis, recurrent pneumonia, and bronchiectasis. Laboratory evaluation at age 18 years revealed a hemoglobin level of 11.9 g/dl, a hematocrit of 37.4 percent, platelet count 1 13,000/mm3, and white blood cell count 5,700/mm3 with a normal differential. The reticulocyte count was 1.4 percent and serum haptoglobin level was normal at 159 mg/ dl (Table I). Results of direct and indirect Coombs’ tests were negative. Biopsy of a lymph node revealed lymphoid hyperplasia with large, prominent germinal centers. Splenectomy was deferred; at follow-up seven months later, his spleen size was unchanged and his hematologic parameters had improved (hemoglobin 13.7 g/dl and hematocrit 41.4 percent) with iron supplementation. Immunologic evaluation at Duke at age 18 l/2 years revealed normal percentages of IgM (9 percent)- and IgD (14 percent)-
January
1987
The American
Journal
of Medicine
Volume
82
159
GAMMA
GLOBULIN
TABLE I
FOR AUTOIMMUNE
Hematologic
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
Data
Time Relative to Onsef of
Autoimmune HemolyticAnemia*
Haptoglobint
im$dl)
Coombs’TestResult
3 years before
159
At onset
<5
Direct IgG positive
50
Direct
Day 56
Negative IgG positive
Direct IgG positive 8 months 147 Negative IQ months 73 Negative * Intravenous gamma globulin begun on day 71. t Normal 40 to 180 mg/dl. Day 76
104
bearing B cells but decreased serum immunoglobulin concentrations (IgG 240 mg/dl, IgA 0 mg/dl, IgM IO mg/dl). In vitro synthesis of IgG and IgM by pokeweed mitogen-stimulated blood lymphocytes was very low. Co-culture of the patient’s lymphocytes with those of a normal control subject resulted in 61 percent and 30 percent suppression of the expected amount of IgG and IgM synthesis, respectively. He had no isohemagglutinins and no anti-tetanus or antidiphtheria antibodies. His absolute lymphocyte count was 1 ,650/mm3. The percentage of total T cells and lymphocyte proliferative responses to antigens and mitogens were normal. However, he had a decreased percentage (25.7 percent) of cells of the T4 (helper) phenotype and an increased percentage (41.2 percent) of cells of the T8 (suppressor) phenotype, resulting in an inverted T4/T8 ratio of 0.61. Gamma globulin therapy was recommended for the treatment of his primary immunodeficiency. Intravenous immunoglobulin (Gamimune) infusions were given at doses of 50 mglkg every four weeks. The subsequent two and a half years were remarkable only for onset of a seizure disorder, which was treated with carbamazepine. Hematologic parameters were normal during that period.
lPrednisone\[
At 21 years of age, he experienced the insidious onset of weakness, malaise and lethargy. A hematologic evaluation revealed a hemoglobin level of 5.3 g/dl, a hematocrit of 16.2 percent, and a reticulocyte count of 1.2 percent. Serum haptoglobin level was less than 5 mg/dl, and results of a direct Coombs’ test were positive (Table I). A bone marrow aspirate showed increased red cell precursors and normal iron stores. Treatment with oral prednisone was begun at 60 mg per day, resulting in marked clinical and laboratory improvement. Two and one half months after diagnosis of autoimmune hemolytic anemia, splenectomy was again considered so as to avoid long-term steroid therapy and because of his persistent massive splenomegaly. At that time, he was asymptomatic while receiving carbamazepine, ferrous sulfate, prednisone, and trimethoprim/sulfamethoxasole. Laboratory evaluation revealed a hemoglobin level of 12.8 g/dl, a hematocrit of 39 percent and a reticulocyte count of 9.7 percent, but a strongly positive result of a direct IgG Coombs’ test. Serum haptoglobin level was low-normal at 50 mg/dl. A red blood cell survival study revealed a slightly low red cell mass and shortened survival but no evidence of splenic sequestration. Prednisone dose was tapered rapidly and then discontinued. High-dose (450 mg/kg) intravenous gamma globulin (Sandoglobulin) was then given daily for five consecutive days. After the fifth infusion, his hemoglobin level was 12.3 g/dl, hematocrit 38.6 percent, reticulocyte count 4.4 percent, and haptoglobin level 104 mg/dl (Table I). Results of a direct IgG Coombs’ test were still strongly positive. For the next 16 months, he received 100 to 200 mg/kg intravenous gamma globulin every four weeks, during which time his hemoglobin level, hematocrit, and reticulocyte count remained stable (Figure 1). At both eight and 19 months after the onset of the autoimmune hemolytic anemia, results of a direct Coombs’ test were negative and haptoglobin concentrations were 147 and 73 mg/dl, respectively (Table I).
Introvenous Gommo Globulin
Figure 1. Hemoglobin and hematocrit values and reticulocyte counts during 19 months following onset of autoimmune hemolytic anemia.
Days
160
January
1967
The American
Journal
of Medicine
Volume
62
GAMMA
GLOBULIN
COMMENTS Autoimmune hemolytic anemia is a clinical syndrome in which an aberrant immune response is initiated and antibody against normal host red cell antigens is produced [4]. Autoimmune hemolytic anemia can be associated with a number of disease states, such as infection, neoplasia, other autoimmune phenomena, drugs, or various immunodeficiencies. The latter include, particularly, common variable immunodeficiency and selective IgA deficiency, both of which are commonly accompanied by autoantibody formation [5-81. No specific infectious cause could be identified in our patient, who had underlying common variable immunodeficiency. It is speculated that in the latter condition, there may also be failure of normal immunoregulation, which leads to recognition of “self” antigens [9]. Treatments used for autoimmune hemolytic anemia in the past have included steroids, cytotoxic agents, transfusions, splenectomy, and plasmapheresis. Steroid therapy has resulted in clinical improvement in 68 to 90 percent of patients [ IO,1 I]. The mechanism of the steroid effect is not entirely known, but is thought to be due to either decreased monocyte binding of IgGcoated red blood cells, decreased target cell-bound IgG, and/or decreased antibody production [IO]. Prednisone provided a prompt reduction in red cell destruction in our patient; however, he still had a reticulocyte count of 9.7 percent and a strongly positive direct IgG Coombs’ test result just prior to high-dose intravenous gamma globulin therapy. Splenectomy has been shown to be effective in 81 percent of patients with autoimmune hemolytic anemia not responsive to steroids [ 1 I]. Other modes of therapy include cyclophosphamide, 6-mercaptopurine, methotrexate, cytosine arabinoside, procarbazine, vincristineloaded platelets, and azathioprine [ 12- 141. All of these forms of therapy carry risks in normal hosts and particularly in immunodeficient patients, in whom they may increase the incidence of severe or opportunistic infections. Splenectomy may also increase the risk of infectious sequelae, as the spleen represents a major component of the immune system. In normal hosts, splenectomy has been followed by a decrease in serum IgM levels, altered antibody responses, and an increased incidence of septicemia [ 151. For patients with immunodeficiency, a mode of autoimmune hemolytic anemia therapy different from any of these and one that does not increase the risk of infection would be highly desirable. While treating children with idiopathic thrombocytopenit purpura with high-dose intravenous gamma globulin, lmbach et al [ 161 noted striking increases in their platelet counts. Some of the patients had a sustained response after one dose, whereas others needed further doses to maintain the therapeutic effect. The mechanism of action may be through saturation of Fc receptors on cells of the
January
FOR AUTOIMMUNE
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
reticuloendothelial system and consequent decreased phagocytosis of immunoglobulin-coated red blood cells. The blockade of the reticuloendothelial system may occur through competition for Fc receptors by the increased serum concentration of IgG or by circulating immune complexes [ 171. Altered Fc receptor affinity or suppression of autoantibody production has been proposed as another mechanism. The latter could have been an effect in our patient, as he eventually had reversal of his Coombs’ positivity. The few other previous attempts to treat autoimmune hemolytic anemia with high-dose intravenous gamma globulin gave mixed results. Salama et al [ 181 demonstrated no effect in two of three nonimmunodeficient adult patients and increased hemolysis in the third. These results suggests that the IgG infused did not inhibit clearance and may have actually increased red cell sequestration. In another report [ 191, a patient with autoimmune hemolytic anemia also experienced clinical deterioration after the use of intravenous gamma globulin, but he was also receiving steroids, cyclophosphamide, and azathioprine; he had a favorable response to plasmapheresis. In 1983, Bussell et al [I] reported on two adult patients with autoimmune hemolytic anemia in whom high-dose intravenous gamma globulin led to a transient reversal of hemolysis in one and complete remission in the second [I]. Success with this therapy was also reported in two children with autoimmune hemolytic anemia; however, both required extremely high doses (5 g/kg), followed by maintenance doses of 2 g/kg per week [2]. This report documents the successful treatment of autoimmune hemolytic anemia in a patient with common variable immunodeficiency. The infusion of 450 mg/kg per day for five days, followed by infusions of single doses of 100 to 200 mg/kg whenever the hemoglobin level or hematocrit fell or the reticulocyte count rose, led to resolution of the aberrant hematologic parameters. Because of his immunodeficiency, he would have been given such infusions every four weeks in any case, since the half-life of gamma globulin is 19 to 21 days. Thus, this safe and preferred treatment of severe humoral immunodeficiency was also effective in reversing autoimmune hemolytic anemia in this patient and avoided the need for splenectomy. ACKNOWLEDGMENT We are indebted to Mrs. Ruby Johnson and Mrs. Sherrie Schiff for their skilled technical assistance, and to Mrs. Lora Whitfield for her excellent secretarial assistance. We thank Dr. Michael Zambie of Monroe, Louisiana, and Dr. Herbert 0. Sieker of Duke Medical Center for referring this patient, and Dr. Wayne Brinkman for the red cell survival studies. The intravenous gamma globulin was provided by Sandoz, Inc.
1987
The American
Journal
of Medicine
Volume
82
161
GAMMA
GLOBULIN
FOR AUTOIMMUNE
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
REFERENCES 1.
2.
3.
4. 5.
6. 7. a. 9. 10. 11.
162
Bussel A, Jaisson F, Janvier M, Traulle C, Schenmetzler C: Utilisation des gammaglobulines intraveineuses a fortes doses dans le traitement des anemies hemolytiques autoimmunes. Presse Med 1963; 41: 2626. Bussel JB, Cunningham-Rundles C, Hilgattner MW: Intravenous treatment of autoimmune hemolytic anemia with gamma globulin. Pediatr Res 1964; 16: 237A. Kutti J, Wadenvik H, Safai-Kutti S, et al: Successful treatment of refractory autoimmune haemolytic anemia by plasmapheresis. Stand J Haematol 1964; 32: 149-152. Pirofsky B: Clinical aspects of autoimmune hemolytic anemia. Semin Hematol 1976; 13: 251-265. Robbins JB, Skinner RC, Pearson HA: Autoimmune hemolytic anemia in a child with congenital x-linked hypogammaglobulinema. N Engl J Med 1969; 260: 75-79. Hobbs JR, Russell A, Worlledge SM: Dysgammaglobulinemia tvpe IVC. Clin Exo lmmunol 1967: 2: 569-599. Dacie J:‘Autoimmune hemolytic anemia. Arch Intern Med 1975; 135: 1293-1300. Weens JH, Schartz RS: Etiologic factors in autoimmune hemolytic anemia. Ser Haematol 1974; 7: 303-327. Schaller JG: lmmunodeficiency and autoimmunity. Birth Defects 1975; 11: 175-183. Cohen JR: Pathogenesis of hemolysis in immune hemolytic anemia. West J Med 1977; 127: 363-365. Zupanska B, Sylwestrowicz T, Pawelski S: The results of prolonged treatment of autoimmune hemolytic anemia.
January
1967
The American
Journal
of Medicine
Volume
12. 13.
14.
15.
16.
17.
ia.
19.
62
Haematologia 1961; 14: 425-433. Murphy S, LoBuglio AF: Drug therapy of autoimmune hemolytic anemia. Semin Hematol 1976; 13: 323-334. Stoelinga GBA, Van Munster PJJ, Slooff JP: Antibody deficiency syndrome and autoimmune hemolytic anemia in a boy with isolated IgM deficiency dysimmunoglobulinemia type 5. Acta Paediatr Stand 1969; 56: 352-362. Ahn YS, Harrington WJ, Byrnes JJ, et al: Treatment of autoimmune hemolytic anemia with vinca-loaded platelets. JAMA 1963; 249: 2169-2194. Graffner H, Gullstrand P, Hallberg T: lmmunocompetence after incidental splenectomy. Stand J Haematol 1962; 28: 369-375. lmbach P, d’Apuzzo V, Hirt A, et al: High dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1961; I: 1226-1231. Bussel JB, Hilgartner MW: The use and mechanism of action of intravenous immunoglobulin in the treatment of immune haematologic disease. Br J Haematol 1964; 56: l7. Salama A, Mueller-Eckhard C, Kiefel V: The effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983; II: 193-195. Andersen 0, Taaning E, Rosenkvist J, et al: Autoimmune hemolytic anemia treated with multiple transfusions, immunosuppressive therapy, plasma exchange and desferrioxamine. Acta Paediatr Stand 1964; 73: 145-146.
FREDERICK E. LEICKLY, M.D.* REBECCA H. BUCKLEY, M.D. Durham, North Carolina
A patient with common variable immunodeficiency and autoimmune hemolytic anemia was given high-dose (450 mg/kg) intravenous gamma globulin (Sandoglobulin) for five days, followed by single doses of 100 to 200 mg/kg at four-week intervals or whenever the hemoglobin level and hematocrit fell or the reticulocyte count increased. This treatment was accompanied by a stabilization of hematopoietic parameters and reversal of Coombs’ positivity, which have been sustained for 34 months. The use of high-dose gamma globulin for autoimmune hemolytic anemia can eliminate the need for other therapeutic modalities that may be detrimental to an immunocompromised host. Therapeutic approaches to the treatment of autoimmune hemolytic anemia have included the use of steroids, splenectomy, and various cytotoxic agents. When autoimmune hemolytic anemia occurs in association with a primary immunodeficiency, however, such treatment modalities could further increase the patient’s susceptibility to infection. Recent reports of the successful use of high-dose intravenous gamma globulin in the treatment of idiopathic thrombocytopenic purpura and the fact that
this agent is standard therapy for common variable immunodeficiency prompted us to use it in a patient with this defect and autoimmune hemolytic anemia. In contrast to mixed results in the limited number of cases treated in this manner reported to date [l-3], our patient’s autoimmune hemolytic anemia was successfully reversed.
CASEREPORT
From the Departments of Pediatrics and Microbi’ ology and Immunology, Duke University School of Medicine, Durham, North Carolina. This work was supported by General Clinical Research Centers Grant RR-30 and by a grant from the National Institute of Allergy and Infectious Diseases (5ROl-A118613). Dr. Leickly’s postdoctoral fellowship training was supported by an Institutional National Research Service Award in Allergy and Immunology (5T32-A107062). Requests for reprints should be addressed to Dr. Rebecca H. Buckley, Box 2898, Duke University Medical Center, Durham, North Carolina 27710. Manuscript submitted August 15, 1985, and accepted September 12, 1985. *Current address: Division of Allergy, Department of Pediatrics, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.
A Zl-year-old white man presented for re-evaluation of his candidacy for splenectomy in treatment of autoimmune hemolytic anemia. He had been initially referred to Duke University Medical Center for evaluation of massive splenomegaly at age 18 years. Shortly before that, his IgG level had been found to be 330 mg/dl, IgA level less than 4 mg/dl, and IgM level 24 mg/dl, leading to a diagnosis of common variable immunodeficiency. His past medical history was remarkable for chronic nasal congestion, rhinorrhea, sinusitis, otitis, bronchitis, recurrent pneumonia, and bronchiectasis. Laboratory evaluation at age 18 years revealed a hemoglobin level of 11.9 g/dl, a hematocrit of 37.4 percent, platelet count 1 13,000/mm3, and white blood cell count 5,700/mm3 with a normal differential. The reticulocyte count was 1.4 percent and serum haptoglobin level was normal at 159 mg/ dl (Table I). Results of direct and indirect Coombs’ tests were negative. Biopsy of a lymph node revealed lymphoid hyperplasia with large, prominent germinal centers. Splenectomy was deferred; at follow-up seven months later, his spleen size was unchanged and his hematologic parameters had improved (hemoglobin 13.7 g/dl and hematocrit 41.4 percent) with iron supplementation. Immunologic evaluation at Duke at age 18 l/2 years revealed normal percentages of IgM (9 percent)- and IgD (14 percent)-
January
1987
The American
Journal
of Medicine
Volume
82
159
GAMMA
GLOBULIN
TABLE I
FOR AUTOIMMUNE
Hematologic
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
Data
Time Relative to Onsef of
Autoimmune HemolyticAnemia*
Haptoglobint
im$dl)
Coombs’TestResult
3 years before
159
At onset
<5
Direct IgG positive
50
Direct
Day 56
Negative IgG positive
Direct IgG positive 8 months 147 Negative IQ months 73 Negative * Intravenous gamma globulin begun on day 71. t Normal 40 to 180 mg/dl. Day 76
104
bearing B cells but decreased serum immunoglobulin concentrations (IgG 240 mg/dl, IgA 0 mg/dl, IgM IO mg/dl). In vitro synthesis of IgG and IgM by pokeweed mitogen-stimulated blood lymphocytes was very low. Co-culture of the patient’s lymphocytes with those of a normal control subject resulted in 61 percent and 30 percent suppression of the expected amount of IgG and IgM synthesis, respectively. He had no isohemagglutinins and no anti-tetanus or antidiphtheria antibodies. His absolute lymphocyte count was 1 ,650/mm3. The percentage of total T cells and lymphocyte proliferative responses to antigens and mitogens were normal. However, he had a decreased percentage (25.7 percent) of cells of the T4 (helper) phenotype and an increased percentage (41.2 percent) of cells of the T8 (suppressor) phenotype, resulting in an inverted T4/T8 ratio of 0.61. Gamma globulin therapy was recommended for the treatment of his primary immunodeficiency. Intravenous immunoglobulin (Gamimune) infusions were given at doses of 50 mglkg every four weeks. The subsequent two and a half years were remarkable only for onset of a seizure disorder, which was treated with carbamazepine. Hematologic parameters were normal during that period.
lPrednisone\[
At 21 years of age, he experienced the insidious onset of weakness, malaise and lethargy. A hematologic evaluation revealed a hemoglobin level of 5.3 g/dl, a hematocrit of 16.2 percent, and a reticulocyte count of 1.2 percent. Serum haptoglobin level was less than 5 mg/dl, and results of a direct Coombs’ test were positive (Table I). A bone marrow aspirate showed increased red cell precursors and normal iron stores. Treatment with oral prednisone was begun at 60 mg per day, resulting in marked clinical and laboratory improvement. Two and one half months after diagnosis of autoimmune hemolytic anemia, splenectomy was again considered so as to avoid long-term steroid therapy and because of his persistent massive splenomegaly. At that time, he was asymptomatic while receiving carbamazepine, ferrous sulfate, prednisone, and trimethoprim/sulfamethoxasole. Laboratory evaluation revealed a hemoglobin level of 12.8 g/dl, a hematocrit of 39 percent and a reticulocyte count of 9.7 percent, but a strongly positive result of a direct IgG Coombs’ test. Serum haptoglobin level was low-normal at 50 mg/dl. A red blood cell survival study revealed a slightly low red cell mass and shortened survival but no evidence of splenic sequestration. Prednisone dose was tapered rapidly and then discontinued. High-dose (450 mg/kg) intravenous gamma globulin (Sandoglobulin) was then given daily for five consecutive days. After the fifth infusion, his hemoglobin level was 12.3 g/dl, hematocrit 38.6 percent, reticulocyte count 4.4 percent, and haptoglobin level 104 mg/dl (Table I). Results of a direct IgG Coombs’ test were still strongly positive. For the next 16 months, he received 100 to 200 mg/kg intravenous gamma globulin every four weeks, during which time his hemoglobin level, hematocrit, and reticulocyte count remained stable (Figure 1). At both eight and 19 months after the onset of the autoimmune hemolytic anemia, results of a direct Coombs’ test were negative and haptoglobin concentrations were 147 and 73 mg/dl, respectively (Table I).
Introvenous Gommo Globulin
Figure 1. Hemoglobin and hematocrit values and reticulocyte counts during 19 months following onset of autoimmune hemolytic anemia.
Days
160
January
1967
The American
Journal
of Medicine
Volume
62
GAMMA
GLOBULIN
COMMENTS Autoimmune hemolytic anemia is a clinical syndrome in which an aberrant immune response is initiated and antibody against normal host red cell antigens is produced [4]. Autoimmune hemolytic anemia can be associated with a number of disease states, such as infection, neoplasia, other autoimmune phenomena, drugs, or various immunodeficiencies. The latter include, particularly, common variable immunodeficiency and selective IgA deficiency, both of which are commonly accompanied by autoantibody formation [5-81. No specific infectious cause could be identified in our patient, who had underlying common variable immunodeficiency. It is speculated that in the latter condition, there may also be failure of normal immunoregulation, which leads to recognition of “self” antigens [9]. Treatments used for autoimmune hemolytic anemia in the past have included steroids, cytotoxic agents, transfusions, splenectomy, and plasmapheresis. Steroid therapy has resulted in clinical improvement in 68 to 90 percent of patients [ IO,1 I]. The mechanism of the steroid effect is not entirely known, but is thought to be due to either decreased monocyte binding of IgGcoated red blood cells, decreased target cell-bound IgG, and/or decreased antibody production [IO]. Prednisone provided a prompt reduction in red cell destruction in our patient; however, he still had a reticulocyte count of 9.7 percent and a strongly positive direct IgG Coombs’ test result just prior to high-dose intravenous gamma globulin therapy. Splenectomy has been shown to be effective in 81 percent of patients with autoimmune hemolytic anemia not responsive to steroids [ 1 I]. Other modes of therapy include cyclophosphamide, 6-mercaptopurine, methotrexate, cytosine arabinoside, procarbazine, vincristineloaded platelets, and azathioprine [ 12- 141. All of these forms of therapy carry risks in normal hosts and particularly in immunodeficient patients, in whom they may increase the incidence of severe or opportunistic infections. Splenectomy may also increase the risk of infectious sequelae, as the spleen represents a major component of the immune system. In normal hosts, splenectomy has been followed by a decrease in serum IgM levels, altered antibody responses, and an increased incidence of septicemia [ 151. For patients with immunodeficiency, a mode of autoimmune hemolytic anemia therapy different from any of these and one that does not increase the risk of infection would be highly desirable. While treating children with idiopathic thrombocytopenit purpura with high-dose intravenous gamma globulin, lmbach et al [ 161 noted striking increases in their platelet counts. Some of the patients had a sustained response after one dose, whereas others needed further doses to maintain the therapeutic effect. The mechanism of action may be through saturation of Fc receptors on cells of the
January
FOR AUTOIMMUNE
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
reticuloendothelial system and consequent decreased phagocytosis of immunoglobulin-coated red blood cells. The blockade of the reticuloendothelial system may occur through competition for Fc receptors by the increased serum concentration of IgG or by circulating immune complexes [ 171. Altered Fc receptor affinity or suppression of autoantibody production has been proposed as another mechanism. The latter could have been an effect in our patient, as he eventually had reversal of his Coombs’ positivity. The few other previous attempts to treat autoimmune hemolytic anemia with high-dose intravenous gamma globulin gave mixed results. Salama et al [ 181 demonstrated no effect in two of three nonimmunodeficient adult patients and increased hemolysis in the third. These results suggests that the IgG infused did not inhibit clearance and may have actually increased red cell sequestration. In another report [ 191, a patient with autoimmune hemolytic anemia also experienced clinical deterioration after the use of intravenous gamma globulin, but he was also receiving steroids, cyclophosphamide, and azathioprine; he had a favorable response to plasmapheresis. In 1983, Bussell et al [I] reported on two adult patients with autoimmune hemolytic anemia in whom high-dose intravenous gamma globulin led to a transient reversal of hemolysis in one and complete remission in the second [I]. Success with this therapy was also reported in two children with autoimmune hemolytic anemia; however, both required extremely high doses (5 g/kg), followed by maintenance doses of 2 g/kg per week [2]. This report documents the successful treatment of autoimmune hemolytic anemia in a patient with common variable immunodeficiency. The infusion of 450 mg/kg per day for five days, followed by infusions of single doses of 100 to 200 mg/kg whenever the hemoglobin level or hematocrit fell or the reticulocyte count rose, led to resolution of the aberrant hematologic parameters. Because of his immunodeficiency, he would have been given such infusions every four weeks in any case, since the half-life of gamma globulin is 19 to 21 days. Thus, this safe and preferred treatment of severe humoral immunodeficiency was also effective in reversing autoimmune hemolytic anemia in this patient and avoided the need for splenectomy. ACKNOWLEDGMENT We are indebted to Mrs. Ruby Johnson and Mrs. Sherrie Schiff for their skilled technical assistance, and to Mrs. Lora Whitfield for her excellent secretarial assistance. We thank Dr. Michael Zambie of Monroe, Louisiana, and Dr. Herbert 0. Sieker of Duke Medical Center for referring this patient, and Dr. Wayne Brinkman for the red cell survival studies. The intravenous gamma globulin was provided by Sandoz, Inc.
1987
The American
Journal
of Medicine
Volume
82
161
GAMMA
GLOBULIN
FOR AUTOIMMUNE
HEMOLYTIC
ANEMIA-LEICKLEY
and BUCKLEY
REFERENCES 1.
2.
3.
4. 5.
6. 7. a. 9. 10. 11.
162
Bussel A, Jaisson F, Janvier M, Traulle C, Schenmetzler C: Utilisation des gammaglobulines intraveineuses a fortes doses dans le traitement des anemies hemolytiques autoimmunes. Presse Med 1963; 41: 2626. Bussel JB, Cunningham-Rundles C, Hilgattner MW: Intravenous treatment of autoimmune hemolytic anemia with gamma globulin. Pediatr Res 1964; 16: 237A. Kutti J, Wadenvik H, Safai-Kutti S, et al: Successful treatment of refractory autoimmune haemolytic anemia by plasmapheresis. Stand J Haematol 1964; 32: 149-152. Pirofsky B: Clinical aspects of autoimmune hemolytic anemia. Semin Hematol 1976; 13: 251-265. Robbins JB, Skinner RC, Pearson HA: Autoimmune hemolytic anemia in a child with congenital x-linked hypogammaglobulinema. N Engl J Med 1969; 260: 75-79. Hobbs JR, Russell A, Worlledge SM: Dysgammaglobulinemia tvpe IVC. Clin Exo lmmunol 1967: 2: 569-599. Dacie J:‘Autoimmune hemolytic anemia. Arch Intern Med 1975; 135: 1293-1300. Weens JH, Schartz RS: Etiologic factors in autoimmune hemolytic anemia. Ser Haematol 1974; 7: 303-327. Schaller JG: lmmunodeficiency and autoimmunity. Birth Defects 1975; 11: 175-183. Cohen JR: Pathogenesis of hemolysis in immune hemolytic anemia. West J Med 1977; 127: 363-365. Zupanska B, Sylwestrowicz T, Pawelski S: The results of prolonged treatment of autoimmune hemolytic anemia.
January
1967
The American
Journal
of Medicine
Volume
12. 13.
14.
15.
16.
17.
ia.
19.
62
Haematologia 1961; 14: 425-433. Murphy S, LoBuglio AF: Drug therapy of autoimmune hemolytic anemia. Semin Hematol 1976; 13: 323-334. Stoelinga GBA, Van Munster PJJ, Slooff JP: Antibody deficiency syndrome and autoimmune hemolytic anemia in a boy with isolated IgM deficiency dysimmunoglobulinemia type 5. Acta Paediatr Stand 1969; 56: 352-362. Ahn YS, Harrington WJ, Byrnes JJ, et al: Treatment of autoimmune hemolytic anemia with vinca-loaded platelets. JAMA 1963; 249: 2169-2194. Graffner H, Gullstrand P, Hallberg T: lmmunocompetence after incidental splenectomy. Stand J Haematol 1962; 28: 369-375. lmbach P, d’Apuzzo V, Hirt A, et al: High dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1961; I: 1226-1231. Bussel JB, Hilgartner MW: The use and mechanism of action of intravenous immunoglobulin in the treatment of immune haematologic disease. Br J Haematol 1964; 56: l7. Salama A, Mueller-Eckhard C, Kiefel V: The effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983; II: 193-195. Andersen 0, Taaning E, Rosenkvist J, et al: Autoimmune hemolytic anemia treated with multiple transfusions, immunosuppressive therapy, plasma exchange and desferrioxamine. Acta Paediatr Stand 1964; 73: 145-146.