CHAPTER 32 PURE RED CELL APLASIA
CHAPTER 32 PURE RED CELL APLASIA
ALLAN J. ERSLEV
Acute Transient Pure Red Cell Aplasia
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Chronic Pure Red Cell Aplasia—Constitutional
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Chronic Pure Red Cell Aplasia—Acquired
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Pure red cell aplasia is caused by a selective destruction or inhibition of erythroid progenitor or precursor cells. It is characterized by an anemia and reticulocytopenia and occurs as an acute or chronic condition. The acute pure red cell aplasia is a transient disorder and is seen primarily in childhood but can occur at all ages. When a cause is found, it usually involves a viral invasion of the erythroid progenitor cells, mostly by the parvovirus B19, but a number of drugs and chemicals have also been shown to cause a toxic or immunologic rejection of these cells. The chronic pure red cell anemias are either constitutional or acquired. The constitutional form is diagnosed in early childhood and can be inborn or inherited. It is caused by the emergence of abnormal progenitor cells, poorly responsive to the action of erythropoietin. The patients may respond to glucocorticoids, but they are rarely, if ever, cured. The acquired form of chronic pure red cell aplasia is an autoimmune disorder, occasionally associated with thymic tumors. It is either caused by T cell-mediated destruction of erythroid progenitor or precursor cells or by B cell production of antibodies to these cells. As in the case of all autoimmune disorders, the results of treatment with glucocorticoids and cytotoxic drugs or immunosuppressive agents are unpredictable, and treatment often leads to serious complications.
Acronyms and abbreviations that appear in this chapter include: ADA, adenosine deaminase; BFU-E, burst forming units–erythroid; CFU-E, colony-forming units–erythroid; CFU-GM, colony forming unit–granulocyte-monocyte.
Pure red cell aplasia is a widely used name for an anemia caused and characterized by an isolated depletion of erythroblasts. Many terms have been applied to this marrow disorder, and names such as erythroblast hypoplasia, erythroblastopenia, erythroid hypoplasia, and red cell agenesis are all as good as pure red cell aplasia. Certain other names, however, such as hypoplastic anemia and aregenerative anemia, may lead to confusion, since they also are used to characterize the pancytopenia of aplastic anemia and the refractory anemia of chronic disorders, respectively. In this chapter, the term pure red cell aplasia has been chosen because it is vivid and descriptive. Pure red cell aplasia was first clearly separated from aplastic anemia in 1922 by Kaznelson.1 Since then because of its intriguing relationship to autoimmunity and to thymic tumors, it has received steadily increasing attention as attested to by numerous case reports and several recent reviews.2,3 At the present, it can be classified into three types: an acute transient type and a chronic type, either constitutional or acquired. The term transient erythroblastopenia of childhood has been introduced to describe a pure red cell aplasia of unknown cause that is seen in previously healthy children.4 However, it is uncertain whether this is a distinct entity. As such, the term will not be used in this chapter.
ACUTE TRANSIENT PURE RED CELL APLASIA
DEFINITION AND HISTORY
In 1942, Lyngar5 recognized that the anemic crisis in children with hereditary spherocytosis was frequently caused by decreased production of red cells rather than by increased hemolysis. In a paper in 1948, Owren6 employed the term aplastic crisis for this temporary production defect and outlined its natural history from the onset of a mild infection, through total erythroid aplasia, to recovery with rebound erythroid hyperplasia (Fig. 32-1). The following year, Gasser7 described a similar type of self-limited erythroid aplasia in patients without hemolytic anemia. Since then, numerous instances of transient erythroid aplasia have been reported in children and adults.
FIGURE 32-1 Erythroid parameters measured 50 years ago but still very typical of a young man with hereditary spherocytosis who developed an aplastic crisis following a brief febrile illness of unknown cause. (Case 4 in Owren.6)
ETIOLOGY AND PATHOGENESIS
Most cases of self-limited aplastic crisis have been reported in patients with chronic hemolytic disorders such as hereditary spherocytosis,8,9 and 10 acquired hemolytic anemia,11,12 and 13 paroxysmal nocturnal hemoglobinuria,14 sickle cell anemia,15,16 and others.17,18,19 and 20 A brief period of erythroid aplasia in a patient with a short red cell life span will have a more rapid and noticeable effect on the hemoglobin concentration than the same period of aplasia will have in an individual with a normal red cell life span. Consequently, it can be assumed that the cases of aplastic crisis reported without underlying hemolytic disorders21 represent merely a fraction of the actual occurrence of temporary erythroid aplasia.
Aplastic crises are frequently preceded by a mild febrile illness, an upper respiratory infection, or gastroenteritis and may afflict several members of a family within a short period of time. When identified, the etiologic agent is usually a virus22 including those responsible for infectious mononucleosis23 or hepatitis.24,25
However, the great majority of patients experiencing an acute aplastic crisis are infected by the B19 parvovirus.26 This DNA virus has been known to cause erythema infantosum, or fifth disease, in children. It has the capacity to invade and destroy rapidly proliferating erythroid progenitor and precursor cells. This may cause a temporary and often unnoticed erythroid aplasia12,13,27 that is terminated by the emergence of neutralizing IgM and IgG antibodies.
Previously uninfected adults contracting a B19 parvovirus infection may develop an aplastic crisis.28 In infected pregnant women29,30 the virus may pass the placenta and invade the rapidly proliferating erythroid tissue of the fetus. This will in some cases result in a spontaneous abortion, and in others in hydrops fetalis similar to the condition seen in a-thalassemia.31
In the absence of a demonstrable parvovirus infection, humoral inhibitors of erythroid progenitor cells have been demonstrated in some and suspected in many others as the cause of acute transient pure red cell aplasia.11,23 In one study of 12 such patients IgG inhibitors of progenitor cells, both burst forming units–erythroid (BFU-E) and colony forming units–erythroid (CFU-E), could be identified in 8 patients.32 These inhibitors had no effect on erythroid precursor cells, erythropoietin, or myeloid progenitors. The brief and self-limited course has precluded more extensive observations on these inhibitors.
Aplastic crises have also been related to drug toxicity,33 and possible offenders are listed in Table 32-1.34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70 and 71 In a carefully studied case of diphenylhydantoin-induced pure red cell aplasia it was found that the patient’s serum IgG suppressed the growth of both allogeneic and autologous erythroid progenitor cells in the presence of diphenylhydantoin but had no effect on the growth of granulocyte-monocyte colony forming units (CFU-GM) in vitro.52 The same kind of study carried out in a patient with rifampicin-induced red cell aplasia also suggested that the drug might act like a hapten.68 In other cases the drug may act as a toxin and merely be the first manifestation of a general marrow suppression that is prevented by the immediate discontinuation of the drug.
TABLE 32-1 DRUGS ASSOCIATED WITH THE DEVELOPMENT OF APLASTIC CRISIS
Folic acid deficiency has been suspected to be a cause of aplastic crisis.72 There is undoubtedly an increased requirement for folic acid in chronic hemolytic anemia,73 and folic acid deficiency or resistance can produce reticulocytopenia and erythroid hypoplasia.74,75 In the few patients treated with folic acid, however, physiologic doses were ineffective.
Deficiencies of vitamin C and riboflavin and protein malnutrition also have been implicated in the etiology of aplastic crises. Although kwashiorkor may be associated with reticulocytopenia, erythroid hypoplasia, and giant proerythroblast,76,77 the association between nutritional deficiencies and aplastic crises is still very tenuous.
The rapid onset of listlessness and increasing pallor in a patient with a chronic, well-adjusted hemolytic process should always raise the suspicion of an aplastic crisis. Characteristically, there is a history of a recent suspected or confirmed viral illness or the use of drugs for intercurrent bacterial or inflammatory diseases. However, an aplastic crisis may occur without any preceding illness. Apart from pallor, the physical examination does not contribute any specific clues unless a careful examiner detects decreased jaundice in a patient with chronic hemolytic anemia.
The laboratory examination reveals anemia with red cell morphologic features characteristic of the underlying hematologic disorder, virtual absence of reticulocytes, and normal or low serum bilirubin. Moderate granulocytopenia and thrombocytopenia may be present, but granulocytes and platelets are usually normal or even increased in number. Because of the advanced mean age of surviving erythrocytes, the pyrimidine 5′-nucleotidase activity is uniformly diminished, but most other red cell enzyme activities are normal because of the slow decline of enzyme activity after the reticulocyte stage (see Chap. 23).78,79 Erythrocyte adenosine deaminase (ADA) activity is also normal.
Early in the illness, the marrow is depleted of all erythroi elements. However, most patients are seen during the stage of spontaneous recovery, when the marrow may display cohorts of early erythroid cells. These cells are often erroneously interpreted as reflecting maturation arrest or megaloblastosis, but serial marrow examinations usually show a normal maturation sequence followed by a distinct reticulocytosis. Occasionally, there are large, intensely basophilic cells termed giant proerythroblasts.7 There is frequently some shift to the left in the myeloid series. The morphology of megakaryocytes is not measurably changed, and they are present in normal numbers.
The rapid recovery phase may be associated with severe bone pain, presumably because of marrow expansion, and by “rebound” reticulocytosis, granulocytosis, and thrombocytosis. In splenectomized patients, or in asplenic sickle cell anemia patients, the recovery phase may be characterized by the presence in blood films of nucleated red cells. This probably reflects the absence of splenic sequestration of immature erythroid cells.
During the aplastic phase, serum ferritin and serum iron are high, with almost complete saturation of iron-binding capacity. The erythropoietin level is also high initially and decreases moderately during the recovery phase.80
Studies aimed at establishing a viral etiology, especially B19 parvovirus infections, are usually of retrospective rather than diagnostic value.
A sudden isolated decrease in the concentration of hemoglobin associated with a low reticulocyte count, usually less than 1.0 percent and often zero, is probably the most important clue and deserves to be followed by a bone marrow examination.81
THERAPY, COURSE, AND PROGNOSIS
Therapy should include discontinuation, if possible, of all drugs, maintenance of an adequate hemoglobin concentration by transfusion of red cells if needed, treatment of any associated illness, and waiting for a spontaneous remission. Folic acid and multivitamins are usually given, but their effectiveness in acute aplastic crises is at best uncertain. Recovery occurs within days or weeks and is complete.
CHRONIC PURE RED CELL APLASIA—CONSTITUTIONAL
DEFINITION AND HISTORY
A chronic form of isolated erythroid hypoplasia occurring early in childhood and believed to be congenital or inherited was first reported by Joseph82 in 1936 and was again described 2 years later by Diamond and Blackfan.83 Since then, many hundreds of cases have been reported of this condition, now best known as the Diamond-Blackfan anemia.84,85
ETIOLOGY AND PATHOGENESIS
In a few infants, pallor and anemia are recognized at birth, but in most reported cases, a definite diagnosis of anemia is first made between the ages of 2 weeks and 1 year.85 There is no characteristic sex preponderance and no consistent abnormality of the pregnancy or delivery. In 10 percent of cases there is more than one affected family member, and the occasional reports of consanguinity suggest that in some cases there is an autosomal dominant or recessive inheritance85; however, most cases are sporadic. Also, chromosomal studies are usually normal or reveal only nonspecific breaks and inversions.86
Studies of erythroid colony formation have suggested that constitutional pure red cell aplasia is caused by the presence of a defective stem cell.87 Marrow CFU-E and marrow and blood BFU-E are markedly decreased in numbers88,89 and 90 and are also quite insensitive to the action of erythropoietin90 or IL-3.91 Although there is some improvement in their number and erythropoietin sensitivity after steroid-induced remissions, they remain abnormal.92 The progeny of the presumably defective stem cells are mature but abnormal red cells. They are macrocytic, contain increased amounts of fetal hemoglobin, have little-i surface antigens, and have a fetal distribution of intracellular enzymes.85 Although such changes could indicate a constitutional abnormality, they are also seen in normal individuals exposed to acute or chronic hematopoietic demands.93
The therapeutic effectiveness of steroids in constitutional pure red cell aplasia and its morphologic kinship to the acquired autoimmune cases have led to a search for an immunologic pathogenesis. Except for a few repeatedly transfused patients,94,95 no humoral or cellular inhibition of erythropoiesis has been found. Reports of excessive anthranilic acid excretion, suggesting a metabolic defect in the utilization of tryptophan96 for red cell production, and of high adenosine deaminase levels,97,98 although challenging, have not led to constructive working hypotheses.
The presenting symptoms and signs can vary in severity and may reflect the prognosis of this type of anemia. Pallor, listlessness, and poor appetite are early manifestations, progressing into borderline congestive failure with breathlessness, hepatomegaly, and splenomegaly. These initial symptoms and signs respond readily to transfusions. Subsequently, however, transfusion may lead to hemosiderosis with all its problems (see Chap. 42).
variety of minor congenital abnormalities have been reported,85 but in contradistinction to Fanconi anemia, major abnormalities have only rarely been observed.99 Thymic hyperplasia and thymic tumors are not manifestations of constitutional pure red cell aplasia.
Normochromic, macrocytic anemia with absolute severe reticulocytopenia is found in all cases. The white blood cell count is normal or only slightly decreased, but the platelet count is often mildly elevated. Characteristically, the marrow is cellular with a profound erythroid hypoplasia and a high myeloid/erythroid ratio. The few remaining erythroid cells are usually young and may display some nuclear changes suggestive of megaloblastosis. The morphology and maturation sequences of the myeloid cells and megakaryocytes are normal, and the plasma cells and mononuclear lymphoid cells also appear normal. Erythropoietin levels in the serum are appropriately elevated.81
Serum iron and serum ferritin levels are at a high normal level with increased saturation of iron-binding protein. Folic acid and vitamin B12 serum levels are normal. Fetal hemoglobin, distributed unevenly among the red cells, is elevated in most cases, as is the concentration of i antigen on the red cell surface.85 Erythrocyte ADA is elevated in many, if not most, patients.98
The virtual absence of reticulocytes from the blood and erythroblasts from the marrow, accompanied by a near-normal concentration of neutrophils and platelets in the blood and neutrophil and megakaryocyte precursors in the marrow, are characteristics of red cell aplasia. Marrow examination is useful for a definitive diagnosis, but the absence of reticulocytes from the blood is invariably associated with marrow erythroid aplasia and separates this condition from other anemias in infancy. The absence of a sudden onset and spontaneous resolution separates it from acute pure red cell aplasia. An elevated adenosine deaminase activity98 is useful in confirming the diagnosis.
THERAPY, COURSE, AND PROGNOSIS
Transfusions and glucocorticoids are standard therapeutic agents and can maintain many patients in nearly normal health for years. Hemosiderosis is an unavoidable complication of transfusions (see Chap. 42). Failure of growth and sexual maturity may mar an otherwise successful therapeutic regimen, and myocardial failure is frequently responsible for death.99 Intensive iron chelation by continuous infusions of desferrioxamine may ameliorate and postpone the effect of iron overload. Splenectomy may be needed to abolish hypersplenism secondary to hepatic fibrosis. Otherwise, splenectomy would not be expected to influence erythropoietic function of the marrow. Neither would the use of recombinant human erythropoietin, but recombinant IL-3 has been reported to cause remissions.100
Glucocorticoids have been used extensively and have been held responsible for temporary improvements, complete remissions, and even cures.84,85 Nevertheless, glucocorticoids do not cure but act by rendering abnormal erythroid progenitor cells more responsive to marrow growth factors, permitting them to differentiate to abnormal but functioning precursor cells. Glucocorticoids must be given in large doses, initially at 1 to 2 mg/kg of prednisone or prednisone equivalents, and the therapeutic trial should not be abandoned until the end of 4 to 6 weeks of unsuccessful therapy. At that point a trial of high doses of methylprednisolone may be justified.101 If a reticulocyte response occurs, the dosage should be reduced appropriately. In such cases, it is frequently possible to maintain adequate red cell production with small doses of glucocorticoids. The most distressing complication has been growth retardation, muscle weakness, and osteopenia. Treatment with cyclosporine has been followed in the best of cases by only short and incomplete remissions.102 Androgens have been used in refractory cases,85 but their use should be undertaken with reluctance in a prepubertal child. Marrow transplantation has been used103,104 and should be considered in patients who are refractory to therapy and have HLA-compatible siblings.
The survival data on 500 cases from the literature has been carefully analyzed85 and shows a gratifying increase in longevity of recent cases carefully managed with glucocorticoids and cytokine factors and most recently with tranplantations.85 Still the toll of therapy has been considerable, since most deaths are related to therapeutic complications. A few patients have developed various malignancies,105 rarely if ever, aplastic anemia.85
CHRONIC PURE RED CELL APLASIA—ACQUIRED
DEFINITION AND HISTORY
Acquired chronic pure red cell aplasia is an unusual disorder characterized by an absence of or marked decrease in red cell production and occurring mostly in adults but with many links to the erythroid aplasia of childhood. In the 1930s, clinicians became aware of the association between red cell aplasia and thymomas.106 This association led subsequently to our present concept that it mainly is a T-cell- or B-cell-derived autoimmune disorder. However, sometimes drugs or viruses may initiate and perpetuate this disorder. In some cases, it involves defective or absent progenitor cells resembling the constitutional form of pure red cell aplasia.107,108
ETIOLOGY AND PATHOGENESIS
In the early reports of patients with chronic pure red cell aplasia, there were almost as many with as without thymoma.109,110,111,112,113 and 114 This, however, does not reflect the true prevalence of thymomas in this disease, since there undoubtedly is more of a tendency to publish cases with a challenging concurrence of two rare diseases than there is to publish cases of either disease alone. Although there still are many reports of thymomas with pure red cell aplasia,114,115 it is comforting for hematologists who in vain have tried to find a thymoma in their patients with pure red cell aplasia to know that in a series of 37 carefully studied cases, only 2 were associated with a thymoma.116 In patients with thymoma, the prevalence of pure red cell aplasia has been estimated to be 7 percent, probably also an unrealistically high incidence.
Nevertheless, T-cell-mediated erythroid rejection has been argued to play a major pathogenic role in eradicating erythroid progenitor cells, particularly in B-cell chronic lymphocytic leukemia.117,118,119,120,121,122,123,124 and 125 Chronic red cell aplasia also has been found in association with numerous systemic autoimmune diseases, such as rheumatoid arthritis,126 systemic lupus erythematosus,127 autoimmune hemolytic anemia,128 myasthenia gravis,129 or Sjögren’s syndrome.130 Although in some cases autoantibodies were suspected to play a pathogenic role, it was not until 1967 that direct evidence was provided for such a mechanism.131 Subsequently it has been found that nearly half of all patients have serum IgG autoantibodies that can suppress the in vitro growth of both allogeneic and autologous erythroid progenitor cells.132,133,134 and 135 Some antibodies are complement-fixing and cytolytic, while others apparently can inhibit cell growth in the absence of complement.135 In some cases the antibodies are directed against erythropoietin,136,137 but in general erythropoietin levels are high and apparently unaffected. Although it has been speculated that autoantibodies directed against erythropoietin receptors could play a pathogenic role,138 such autoantibodies have not yet been observed in patients with this disease.
Deficient antibody production in immune compromised individuals also may cause pure red cell aplasia. In AIDS patients, for example, an infection with the B19 parvovirus will persist in the absence of neutralizing antibodies and if unchecked will continue to destroy erythroid progenitor cells.139,140 and 141 This may also occur in pregnancy142 and especially in patients receiving chemotherapy before organ transplantation.143,144,145 and 146
Pallor is usually the only physical finding of note on the initial examination. Some patients will have a thymoma, although such tumors are only rarely large enough to be detected on physical examination. Later on, after prolonged transfusion and glucocorticoid therapy, there may be additional findings caused by secondary hemochromatosis and steroid-induced side effects.
The anemia accompanying this disease is normochromic and normo- or macrocytic and is associated with absolute reticulocytopenia. The leukocyte and platelet counts are normal or reflect the underlying disease. The marrow is cellular but with profound erythroid hypoplasia. The remaining erythroid cells are immature but morphologically normal. In the marrow, there may be an increase in eosinophils and small mononuclear cells.
The serum iron level is elevated with almost complete saturation of the iron-binding capacity, the half-life of radioactive iron is prolonged, and the iron utilization is low, conforming to the morphologic observation of erythroid hypoplasia. The red cell life span is normal initially but may become shortened owing to transfusion-induced hemosiderosis with congestive splenomegaly or to the presence of red cell antibodies. Serum protein electrophoresis and antibody analyses reflect the underlying disorders. The metabolism of folic acid or vitamin B12 is usually unimpaired, although in a few cases megaloblastosis and the response to folic acid have suggested an abnormal handling or availability of this coenzyme.
Thymic enlargement, when present, is usually detected on routine chest X-ray examinations as a mass in the anterior mediastinum. However, a CT scan or MRI may be needed to demonstrate a small thymoma. In one series of 56 cases of pure red cell anemia with thymoma,109 the thymomas in 46 cases were encapsulated and composed primarily of spindle cells. The germinal centers were absent, but there was diffuse scant infiltration with small lymphocytes. In 10 cases the thymomas were infiltrating and were considered malignant. In these cases the tissues were composed of lymphocytes and reticulum cells in a disorganized pattern. In the seven patients in this series with associated myasthenia gravis, the gross or microscopic pattern did not differ significantly from the other cases.
The diagnosis is suspected when a patient or a previously normal individual develops a sustained anemia in the presence of a severe reticulocytopenia, normal white cell total and differential count, and normal platelet count. The marrow confirms the blood findings having an absence of erythroid precursors but a normal pattern of granulocyte and megakaryocytic cells. Cytogenetic studies of marrow cells are normal. These findings distinguish erythroid aplasia from other refractory anemias, such as those that characterize the preleukemic or myelodysplastic disorders (see Chap. 92). The presence of a thymoma is helpful in establishing the diagnosis, but its absence is of little diagnostic significance. Serologic and marrow culture studies may be of importance in difficult cases.
THERAPY, COURSE, AND PROGNOSIS
Transfusion Transfusion with packed red cells is the mainstay of symptomatic therapy. A hemoglobin concentration maintained at 8 to 10 g/dl is an attainable goal in complete erythroid aplasia but demands transfusion of about 2 units of packed red cells every 2 weeks. A gradual shortening of the effective life span of transfused red cells because of hypersplenism or red cell antibodies can make this therapy increasingly frustrating and ineffective.
Erythropoietin Recombinant human erythropoietin when given alone has occasionally been of benefit.146,147 However, it is most often given in addition to other medications in order to enhance their effect.148 It should initially be given in large doses such as 10,000 units, three times a week subcutaneously, with subsequent modulation of the dose according to its effect.
Thymectomy Whenever thymic enlargement is found, it is advisable to perform a thymectomy in order to provide a diagnosis, prevent possible malignant extension, and promote reactivation of the marrow. In one series of 56 patients, 25 were treated by thymectomy, and 16 appeared to benefit from the operation.109 The benefit derived from thymectomy could not always be related directly to surgery, and it is still difficult to assess the therapeutic effect of thymectomy alone. However, in one case a serum inhibitor of the erythroid tissue apparently disappeared after thymectomy.149 Irradiation of the thymus was completely unsuccessful in the five patients so treated.109 The current consensus appears to be that removing a normal-sized thymus gland without a thymoma is of no help to a patient with pure red cell aplasia.
Steroid Hormones Glucocorticoids are frequently effective in reactivating red cell production either by blocking antibody production or action or by sensitizing abnormal erythroid progenitor cells to normal growth factors.116 Unfortunately, rather substantial doses may be needed, and side effects often preclude the continuous employment of these drugs. When small maintenance doses are effective, however, glucocorticoid treatment can eliminate transfusion dependence and be the treatment of choice. The immunosuppressive androgen danazol150 has also been used and may be a useful adjunct to glucocorticoid therapy.
Immunosuppressive Drugs On the assumption that acquired red cell aplasia is an autoimmune disorder, therapy with cyclophosphamide or 6-mercaptopurine has been tried and has been successful in a number of cases.116,148 However, the use of potentially leukemogenic drugs should always be instituted with some reluctance and after less toxic drugs have been found to be ineffective. Intravenous gamma-globulin treatment has been remarkably effective and in some cases has eradicated persistent viremia with the B19 parvovirus.151,152 Antithymic or antilymphocyte serum has also been used with considerable success. When effective, it may cause a remission within days rather than the months needed for a remission induced in aplastic anemia.148,153 Cyclosporine A with the addition of erythropoietin has also been used successfully.154,155 and 156 Single reports list the potential efficacy of interferon a157 and T3.3
Plasmapheresis A good response to plasmapheresis has been reported in several patients.158 This response may actually be longlasting, far longer than can be explained on the basis of the temporary removal of antibodies.
Splenectomy Splenectomy has been performed in many patients, but unless there is evidence for abnormal splenic sequestration of red cells, the therapeutic benefit derived has been minimal. Obviously, pathologic splenic red cell destruction and excessive splenic antibody formation will be eliminated by splenectomy, but the underlying disease is not dependent on splenic function and will not be helped by splenectomy.
COURSE AND PROGNOSIS
Remissions have been induced in about 25 percent of patients either with or without thymomas, but only half of these have been sustained without further therapy. In most cases, maintenance therapy with transfusions, erythropoietin, and adrenal steroids has been responsible for both symptomatic control of the disease and high mortality. In one series of 56 patients with thymomas, 17 died within 6 months of the date of diagnosis, and a total of 50 were dead at the time of the compilation of the report.109 Of 16 cases without thymomas observed at the Mayo Clinic, 8 died 1 to 3 years after the onset of the disease.111 The causes of death were hemosiderosis, steroid-induced hemorrhages, or infections. With the current use of immunosuppressive drugs and improved supportive care, the prognosis is no longer so grim. About 50 percent of patients enter remissions, and median survival with idiopathic disease is greater than 10 years.116
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn