Acquired pure red cell aplasia is an uncommon cause of anemia that occurs principally in older adults. The blood counts and marrow appearance are indistinguishable from the picture of Diamond-Blackfan anemia, that is, anemia, severe reticulocytopenia, and absent marrow erythroid precursor cells. The nosologic origins of acquired pure red cell aplasia are obscure. Early descriptions are intermixed with those of aplastic anemia (in retrospect, a poor term for generalized marrow failure). Kaznelson104 is credited with the first case report in 1922. Early distinction of the two syndromes was stimulated by the relationship of red cell aplasia to thymoma. Although red cell aplasia shares with aplastic anemia an immune pathophysiology and responsiveness to immunosuppressive therapies, the absence of involvement of neutrophils, monocytes, and platelets makes the diagnostic distinction evident. Many of the diverse clinical associations (Table 36–1) are consistent with an immune-mediated pathophysiology. The mechanism of red cell failure is best understood for T cell–mediated autoimmune destruction and persistent B19 parvovirus infection.
Table 36–1.Classification of Pure Red Cell Aplasia ||Download (.pdf) Table 36–1. Classification of Pure Red Cell Aplasia
|Fetal red cell aplasia (nonimmune hydrops fetalis) |
|Parvovirus B19 in utero |
|Inherited (Diamond-Blackfan anemia) |
| RPS19 and other RPS mutations |
| Transient pure red cell aplasia |
| Acute B19 parvovirus infection in hemolytic disease (transient aplastic crisis; ~100% of cases) |
| Transient erythroblastopenia of childhood |
| Chronic pure red cell aplasia |
| Large granular lymphocytic leukemia |
| Chronic lymphocytic leukemia |
| Clonal myeloid diseases (especially 5q-syndrome) |
| Persistent B19 parvovirus infection in immunodeficient host (~15% of cases) |
| Thymoma |
| Collagen vascular diseases |
| Post–stem cell transplantation |
| Anti-ABO antibodies |
| Drug induced |
| Antierythropoietin antibodies |
| Pregnancy |
ETIOLOGY AND PATHOGENESIS
Immune-Mediated Erythropoietic Failure
Clinical and laboratory evidence supports both antibody and cellular mechanisms of inhibition of erythropoiesis. Red cell aplasia is associated with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, autoimmune hemolytic anemia, acquired hypoimmunoglobulinemia, autoimmune polyglandular syndrome, and especially thymoma, and with lymphoproliferative processes, such as chronic lymphocytic leukemia (CLL) and Hodgkin disease, in which immune dysregulation is common. Serum inhibitors can be detected in the laboratory. Krantz and colleagues showed that immunoglobulin fractions from the patient’s blood inhibited heme synthesis and red cell progenitor assays in vitro.87 Antibodies that inhibit BFU-E and CFU-E colony formation are present frequently in patients with red cell aplasia. A pathophysiologic role can be inferred, first from the response of patients to specific treatments directed at antibodies, such as plasmapheresis and a monoclonal antibody to a cluster of differentiation molecule expressed on the surface of all mature B cells, CD20, and second from decreased or absent plasma antibody in recovered patients. Antibodies may be involved in the red cell aplasia of pregnancy.105
Autoantibodies to erythropoietin rarely have caused this disease.106,107 More frequently, red cell aplasia secondary to antibodies is elicited by administration of recombinant erythropoietin to patients undergoing renal dialysis.108,109,110,111,112,113 Anemia can be profound, and some patients remain transfusion dependent despite discontinuation of hormone therapy. Glycosylation of recombinant erythropoietin is different from the native molecule, but antibodies are directed against conformational epitopes of the protein and not to the sugar moieties. Erythropoietin immunogenicity associates with human leukocyte antigen (HLA) specificities.114 The second example of antibodies of known specificity causing red cell aplasia occurs after hematopoietic stem cell transplantation using donors mismatched at a major ABO locus, which can lead to delayed donor erythroid engraftment or late erythropoietic failure.115,116,117,118 In most instances, however, the target antigen(s) responsible for this outcome is (are) not known.
Suppression of erythropoiesis by T cells may be more common than antibody inhibition as a mechanism of erythropoietic failure.119 Suggestive clinical observations include the frequent association of red cell aplasia with CLL (Chap. 92) in approximately 6 percent of cases120; CLL is also associated with autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura121 and with large granular lymphocytic leukemia (LGL; Chap. 94) in approximately 7 percent of cases.122 In a series of 47 red cell aplasia patients, four had CLL and nine had LGL.123 More sensitive flow cytometric and molecular methods may detect clonal T-cell expansion in patients with normal numbers of circulating lymphocytes.124,125 An attractive molecular mechanism underlying CD8 cell expansion is signal transducer and activator of transcription 3 gene mutations (STAT3), leading to constitutive activation of a clone of cytotoxic T cells, which is relatively frequent in patients with large granular lymphocytosis126 and has been described in patients with pure red cell aplasia.127,128,129 Functionally, lymphocytes from patients with idiopathic pure red cell aplasia130,131,132 or red cell aplasia associated with CLL,133,134 LGL,135,136,137 thymoma,138 other lymphoid malignancies,139,140 Epstein-Barr virus infection,141 and human T-cell leukemia virus 1 infection142 suppressed erythropoiesis in colony assays. Several mechanisms of cell killing have been suggested.122,143 When effector cells show histocompatibility locus A class I–restricted killing, recognition of a specific antigen peptide is implied by a T cell with an αβ T-cell receptor.144 In one man with red cell aplasia and LGL, erythropoiesis was inhibited by non–MHC (major histocompatibility) antigen-restricted γδ T cells that lysed CFU-E. T cells downregulated class I histocompatibility antigens and thus were unable to engage the natural killer cell’s inhibitory receptors.137
Persistent B19 Parvovirus Infection
B19 parvovirus specifically infects and is toxic to erythroid progenitor cells. Parvovirus infection normally is terminated within 1 to 2 weeks of infection by the humoral immune response. Linear neutralizing epitopes are localized to a relatively small region of the capsid protein.145 In the absence of an effective antibody response, infection persists and causes pure red cell aplasia.65,145 Erythropoietic failure may be the only evidence of parvoviral infection. Persistence of B19 parvovirus infection may occur in the setting of immunodeficiency (Chap. 80), most commonly caused by chemotherapeutic and immunosuppressive drugs,146 human immunodeficiency virus 1 infection,147 and occasionally with Nezelof syndrome’s subtle immunologic abnormalities.148 Parvovirus at one time may have accounted for approximately 15 percent of severe anemia in patients with AIDS,149 but highly effective antiretroviral drug regimens have reduced its role.150,151 Persistent B19 parvovirus infection can occur in the fetus exposed during the midtrimester of pregnancy (Chap. 55). The infection can cause hydrops fetalis as a result of viral cytotoxicity for erythroid progenitors in the fetal liver and death of the newborn as a result of severe anemia and congestive heart failure.65 In rare instances, parvovirus-infected or hydropic infants rescued by red cell transfusion show congenital red cell aplasia or dyserythropoietic anemia.33
Intrinsic Cellular Defects Leading to Failed Red Blood Cell Production
Red cell aplasia can be the first or the major manifestation of myelodysplasia.152 Discrete genetic defects can lead to failure of erythropoiesis. Activating point mutations in N-RAS, an oncogene in the RAS family occur in some cases of myelodysplastic syndrome.153,154 Mutant N-RAS in vitro can induce a proliferative defect in erythroid progenitor cells.155 Loss of the RPS14 gene in 5q− deletions leads to red cell aplasia in this myelodysplastic syndrome.22,156 In vitro colony formation may distinguish such intrinsic cellular defects from immune mediated marrow failure, with higher BFU-E numbers predicting response to immunosuppressive therapies.157
Idiosyncratic drug reactions account for a far smaller proportion of red cell aplasia than of agranulocytosis (Chap. 65). Case reports have implicated various agents, such as diphenylhydantoin, sulfa and sulfonamide drugs, azathioprine, allopurinol, isoniazid, procainamide, ticlopidine, ribavirin, and penicillamine. Causality is impossible to assign from case reports; with nonsteroidal antiinflammatory drugs, gold, and colchicine, the underlying rheumatic syndrome may be the etiologic link.
Symptomatic anemia in the older patient may manifest as pallor, fatigue, lassitude, pulsatile tinnitus, and anginal chest pain (Chap. 34). Iatrogenic Cushing syndrome and the physical stigmata of secondary hemochromatosis are seen in patients after prolonged glucocorticoid administration and long-term red cell transfusion therapy. Concomitant diseases include CLL and lymphomas, collagen vascular disorders, myasthenia gravis, especially in the setting of thymoma, and some cancers. Red cell aplasia also occurs with pregnancy. Persistent B19 parvovirus infection should be suspected in the anemic cancer patient after stem cell transplantation, in patients treated with immunosuppressive drugs, in patients with AIDS, and in patients with a family or personal history suggestive of inherited immune disorder. Other viral infections have been implicated in pure red cell aplasia, including infectious mononucleosis and an unknown agent in seronegative hepatitis.
Anemia is either normocytic or macrocytic, reticulocytopenia is profound, and white cell and platelet counts are generally normal. The marrow shows absent or very few erythroid precursor cells, but normal granulopoiesis and megakaryocytopoiesis. Iron saturation and ferritin level frequently are elevated and rise further after repeated red cell transfusions. Erythroid colony assays may predict responsiveness to immunosuppressive treatment. The presence of marrow or blood BFU-E and CFU-E correlates with hematologic improvement,130,158,159 but these tests may not be generally available.
Thymomas are frequently associated with autoimmune disease, myasthenia gravis most prominently and occasionally with marrow failure syndromes.160 In pure red cell aplasia, a thymoma should be sought by chest imaging, including computed tomographic scan. The association of thymoma and pure red cell aplasia has been emphasized but is uncommon: thymoma in only two of 37 red cell aplasia patients,161 and only two instances of red cell aplasia in a series of 29 thymoma patients.162 The thymomas usually are encapsulated and have a spindle cell histology. In one series, 10 of 56 cases were considered malignant because of their locally infiltrating character163; therefore, the tumors should be surgically excised, if feasible.
CLL should be evident based on elevated lymphocyte count and immunophenotyping for monoclonality. LGL (Chap. 94), which frequently underlies red cell aplasia, may be more subtle. It’s diagnosis requires careful examination of the blood film for typical lymphocytic forms, flow cytometry for cell surface markers characteristic of natural killer and cytotoxic lymphocytes, and demonstration of monoclonal T-cell proliferation by molecular studies.
Persistent parvovirus infection can be difficult to diagnose. Giant pronormoblasts scattered on the marrow film are the most characteristic of the condition (see Fig. 36–1), but such typical cells may not be observed. Marrow morphologies that are dysplastic or suggestive of leukemia also have been described. Serum antibodies specific to the virus are absent or only IgM is positive. Parvovirus DNA should be present in high concentrations in the blood and readily detected by molecular techniques.
Distinction between inherited and acquired red cell aplasia may be impossible in the younger patient. Rarely, pure red cell aplasia is difficult to distinguish from more generalized marrow failure if other blood counts are borderline. A dysmorphic marrow smear and abnormal chromosomes point to myelodysplasia as responsible for isolated anemia and reticulocytopenia. B19 parvovirus infection should always be suspected and searched for in any immunosuppressed individual who is anemic because the infection can be treated.
THERAPY, COURSE, AND PROGNOSIS
As with inherited red cell aplasia, transfusions and iron chelation are basic to management.164 In an adult, 1 unit of packed erythrocytes per week can replace marrow erythropoiesis, which for convenience usually is transfused as 2 units every 2 weeks. The goal of preventing symptoms of anemia is achievable in most patients if the nadir hemoglobin is greater than 7 g/dL (70 g/L). A goal greater than 9 g/dL (90 g/L) may be preferable in patients with cardiac or pulmonary disease and in older patients. Even refractory pure red cell aplasia is consistent with a prolonged and perhaps even normal life expectancy, and iron-chelation therapy can be initiated based on the ferritin level (Chap. 43).
Immunosuppressive agents are used to treat disease of suspected immune origin. Response is likely in the majority of patients, but sequential treatment with a variety of agents often is required. Some patients, however, remain refractory to treatment.119,164,165,166 Typically, oral prednisone 1 to 2 mg/kg/day is given first, and about half of patients improve. A 1- to 2-month trial can be associated with significant toxicity and evidence of Cushing syndrome. Higher response rates have been cited for cyclosporine, and some investigators advocate using this drug first.53,167,168,169,170,171 Cytotoxic agents, especially azathioprine and cyclophosphamide,172 can be beneficial but are not first-choice because of their mutagenic and leukemogenic properties. These drugs may be preferred for red cell aplasia associated with LGL, in which cytoreduction is required.124,173,174 Acquired pure red cell aplasia often responds to antithymocyte globulin.130,159,175 More specific monoclonal antibodies have less toxicity than does antilymphocyte globulin, and can be administered without hospitalization.176 Daclizumab, a monoclonal antibody directed against the IL-2 receptor, is effective in approximately 40 percent of patients.177 Success has been reported also using rituximab (anti-CD20 monoclonal antibody)178,179,180 and alemtuzumab (anti-CD52).181,182,183 Some patients with resistant disease respond to fludarabine and cladribine.184,185 Plasmapheresis186,187 has produced long-lasting improvement in a few patients, presumably by removing pathogenic antibodies.186 The absence of randomized trials and even case series of adequate sample size makes the extrapolation of case reports to quantitative estimates of response problematic for many of these therapies.164
A thymoma should be excised to prevent local spread of a malignant tumor, but thymectomy does not necessarily improve marrow function.163 Red cell aplasia can follow thymectomy. Cyclosporine appears the most effective drug to treat pure red cell aplasia associated with thymoma.188 Red cell aplasia is rarely an indication for stem cell transplantation because the anemia usually can be managed with less drastic approaches. Unresponsive patients have been cured by infusion of allogeneic stem cells after cyclophosphamide conditioning.189,190
Despite early favorable case reports, androgens, erythropoietin, and splenectomy are not routinely used to treat pure red cell aplasia.
Immunoglobulin for Persistent B19 Parvovirus Infection
Persistent parvovirus infection results from the inability of the host to mount an effective humoral immune response. It can be effectively treated in almost all cases by administration of commercial immunoglobulin,191,192 an excellent source of neutralizing antibodies present in a large proportion of the normal population. Infusion of immunoglobulin at 0.4 g/kg/day for 5 to 10 days should produce brisk reticulocytosis and restore a hemoglobin level appropriate for the patient. A single course may be adequate to cure longstanding red cell aplasia resulting from an underlying inherited immunodeficiency syndrome,193 but patients with AIDS may not show complete clearance of parvovirus from the circulation and may relapse, requiring retreatment147 or maintenance immunoglobulin injections (Fig. 36–2).147,194 Patients suffering from persistent B19 parvovirus infection do not have typical manifestations of a viral infection, such as fever. In these patients, immunoglobulin infusions can induce fifth disease symptoms of variable severity, including cutaneous eruptions and arthritis. Older case reports of red cell aplasia responsive to immunoglobulin infusions likely represent treatment of patients with previously unrecognized parvovirus infection.
Diagram of the clinical course of a HIV-1–infected patient with red cell aplasia caused by B19 persistent parvovirus.123 Note the increase of the reticulocyte count (open circles) to the first infusion of immunoglobulin (Ig) G (hatched bar) and the subsequent decline in parvovirus titers. Thereafter, the reticulocyte count and the hemoglobin (Hgb) concentration (closed circles) decrease, reflecting the return of the anemia. A second IgG treatment increases the reticulocyte count and Hgb concentration and decreases the parvovirus titers. PRBC, packed red blood cells.