Chapter 36: Pure Red Cell Aplasia

Neal S. Young

INTRODUCTION

SUMMARY

Pure red cell aplasia is the diagnosis applied to isolated anemia secondary to failure of erythropoiesis. Cardinal findings are a low hemoglobin level combined with reticulocytopenia and absent or extremely infrequent marrow erythroid precursor. Historical names for pure red cell aplasia include erythroblast hypoplasia, erythroblastopenia, red cell agenesis, hypoplastic anemia, and aregenerative anemia. Aplastic anemia confers the same meaning, of course, but is applied to pancytopenia and an empty marrow (Chap. 35). Pure red cell aplasia was first separated from aplastic anemia by Kaznelson in 1922. The association of red cell aplasia and thymoma interested physicians in the 1930s and ultimately led to laboratory studies linking pure red cell aplasia to immune mechanisms, including the early identification of antierythroid precursor cell antibodies by Krantz and later characterization of T cells that inhibited erythropoiesis. Red cell aplasia as an acute and life-threatening complication of sickle cell disease and other hemolytic anemias was recognized in the 1940s, presaging the role of a specific virus in the etiology of both acute and chronic erythropoietic failure. Despite its infrequency, pure red cell aplasia has been a subject of much laboratory research because of its link to an immune mechanism of erythropoietic failure and as a manifestation of parvovirus B19 infection and viral destruction of red cell progenitors. However, because of its infrequency, pure red cell aplasia has not been the subject of large or controlled clinical trials; as a result, therapeutic recommendations are based on single cases or small series. Table 36–1 lists a practical classification of pure red cell aplasia.

Acronyms and Abbreviations:

B19, primate erythroparvovirus 1; BFU-E, burst-forming unit–erythroid; CD20, a cluster of differentiation molecule expressed on the surface of all mature B cells; CFU-E, colony-forming unit–erythroid; CLL, chronic lymphocytic leukemia; FA, Fanconi anemia; GATA1 gene, globin transcription factor 1; HLA, human leukocyte antigen; Ig, immunoglobulin; IL, interleukin; LGL, large granular lymphocytic leukemia; RPS14 and RPS19 genes, ribosomal protein S14 and S19 genes; STAT3 gene, signal transducer and activator of transcription 3 gene; T cell, thymus-derived lymphocyte.

INHERITED PURE RED CELL APLASIA (DIAMOND-BLACKFAN ANEMIA)

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DEFINITION AND HISTORY

Anemia in infancy and early childhood associated with absent reticulocytes in the blood and erythroid precursor cells in the marrow was described by Joseph¹ in 1936 as a “failure of erythropoiesis” and by Diamond and Blackfan² in 1938 as “congenital hypoplastic anemia.” Gasser³ first reported a response of a patient to glucocorticoids in 1951, and Diamond and associates⁴ presented a series of treated patients. Genetic linkage studies have identified etiologic mutations in ribosomal protein genes.^5,6,7,8,9 Hundreds of cases have been reported, and many excellent reviews have been published.¹⁰ Although Joseph was the first to describe the disorder, the anemia invariably is referred to as either Blackfan-Diamond or Diamond-Blackfan anemia.

ETIOLOGY AND PATHOGENESIS

An annual incidence of 5 cases per 1 million livebirths has been estimated from registry data.¹¹ Well-characterized pedigrees are consistent with an autosomal dominant or, less often, recessive inheritance pattern. Sporadic cases are seen most frequently. Retrospective studies may reveal subtle hematologic or biochemical lesions, or an abnormal gene, in an affected parent or another relative without clinical anemia.¹²

Recent genetic studies have led to the characterization of Diamond-Blackfan anemia as a disease of ribosomal biogenesis.^5,6,7,13,14 Linkage analyses of several dozen European families mapped to a site on chromosome 19q13¹⁵ and the finding of a translocation in one individual allowed cloning of the ribosomal protein S19 (RPS19) gene, which encodes a protein involved in ribosome assembly.^5,6,7,8,9 Most mutations are whole gene deletions, translocations or truncations; this pattern suggests a mechanism of haploinsufficiency, and RPS19 behaves as a dominant gene.¹⁶ (Disruption of both copies of the gene in the mouse prevents implantation.¹⁷) RPS19 mutations occur in approximately 25 percent of patients with inherited red cell aplasia^16,18; and mutations subsequently have been identified in multiple other ribosomal biogenesis genes (RPS10, RPS26 particularly) in other cases.^16,19,20 More recently, a globin transcription factor 1 (GATA1) gene mutation was identified in a Diamond-Blackfan kindred, implicating a signal transduction pathway of erythroid differentiation as also causative of the syndrome.²¹ Experiments have implicated RPS14 in one of the myelodysplastic syndromes characterized by loss of 5q.²²

Precisely how defects in ribosomal protein genes cause constitutional red cell aplasia is uncertain. Historically, Diamond-Blackfan anemia has been characterized by diminished erythroid progenitor cell numbers (colony forming unit–erythroid [CFU-E] and burst-forming unit–erythroid [BFU-E]).^23,24 In cell culture, early, erythropoietin-independent erythropoiesis is relatively normal; the major defect is in the late stage of erythropoietin-dependent erythroid cell expansion and maturation.²⁵ A defect in late erythroid differentiation is compatible with the classic findings of macrocytosis and increased hemoglobin F expression in inherited red cell aplasia. Granulopoiesis in the colony-forming unit–granulocyte-macrophage assay and the earlier hematopoietic progenitors as measured in vitro by long-term culture-initiating cell assay (an assay for an early multipotential hematopoietic progenitor) frequently are abnormal, but to a lesser degree than are CFU-E and BFU-E.²⁶ In a zebrafish model, deficiency of rps19 in early embryogenesis caused a decrease in erythrocytes and also physical anomalies.²⁷ In tissue culture experiments, silencing of RPS19 profoundly affects erythropoietic differentiation and, to lesser degrees, myelopoiesis.^28,29 Both in vivo and in vitro models have implicated accumulation in the cell of free ribosomal proteins, which modulates the inhibitory activity of regulators of tumor protein p53, leading to p53 stabilization and apoptosis.³⁰ The specificity of this molecular defect for the erythroid pathway may be a result of the extreme requirement of red cell progenitors and precursors for ribosome biogenesis.

Despite responsiveness of patients to glucocorticoids, there is little evidence of an immune mechanism, cellular or humoral, underlying inherited red cell aplasia.

CLINICAL FEATURES

Approximately one-third of patients are diagnosed at birth or within a few weeks of delivery, and almost all are identified within the first year of life.³¹ Considerable variations are noted with regard to severity of phenotype, ranging from hydrops fetalis^32,33 to presentation in adulthood, when diagnosis is inferred from associated physical anomalies.^5,34 No sex predominance exists. Increased rates of prematurity in patients and of miscarriages in families have been inferred from collected cases.³⁵ Symptoms of anemia in early childhood include pallor, apathy, poor appetite, and “failure to thrive.” Physical anomalies occur in about a third of cases; most frequent is craniofacial dysmorphism, the classic appearance described by Cathie³⁶ is “tow-colored hair, snub nose, wide set eyes, thick upper lips, and an intelligent expression.” Malformations of the thumbs and short stature are frequent, followed by abnormalities of the urogenital system, web neck, and skeletal and cardiac defects.^11,31,37 These physical anomalies are less prevalent than the abnormalities seen in Fanconi anemia (FA).

LABORATORY FEATURES

The degree of anemia is highly variable at diagnosis. Erythrocytes may be macrocytic or normocytic. Reticulocytopenia is profound. The marrow, which usually is devoid of red blood cell precursors, may show small numbers of megaloblastoid early erythroid cells with apparent “maturation arrest.” Platelets are normal or elevated. Leukocytes may be normal or slightly decreased at presentation. Neutrophils often decline with age, and in adult survivors neutropenia occasionally is severe enough to predispose to fatal infection.³⁸

Erythrocyte adenosine deaminase level is elevated in approximately 75 percent of patients but also may be increased in other aregenerative anemias of childhood.³⁹ Serum erythropoietin level, serum iron level, and total iron-binding capacity are high. Ferritin level increases as patients receive multiple transfusions and develop iron overload if they are not treated with chelation therapy.

DIFFERENTIAL DIAGNOSIS

The characteristic triad consists of the clinical diagnostic features of anemia, reticulocytopenia, and a paucity or absence of erythroid precursors in the marrow. These findings may be supplemented by increased activity of red cell adenosine deaminase and ribosomal gene mutation analysis. FA can be excluded by cytogenetic analyses under clastogenic stress and determination of FA gene mutations (Chap. 35). Transient erythroblastopenia of childhood, which unusually occurs in the first year of life, is established by spontaneous recovery. When presentation occurs at older ages, the distinction between inherited and acquired aplastic anemia can be difficult⁴⁰: family history, physical anomalies, and characteristic cytogenetic enzymatic, or genetic findings implicate and indicate an inherited disorder.

THERAPY, COURSE, AND PROGNOSIS

Untreated inherited pure red cell aplasia is fatal; death results from severe anemia and congestive heart failure. Transfusions, glucocorticoids, and allogeneic stem cell transplantation are of proven efficacy.^9,41 Predictors of glucocorticoid administration in glucocorticoid responsive patients include older age at presentation, a family history, and a normal platelet count. Younger age at presentation and premature birth correlate with continued red cell transfusion dependence.⁴² Supportive care consists of red cell transfusions. To avoid transfusional hemosiderosis, chelation with desferrioxamine should be initiated early (Chap. 43). Injury to visceral organs from iron overload has been a major cause of death in the past.

Red cell transfusions should be leukocyte depleted to avoid alloimmunization (see Chap. 138). Erythrocytes are administered with the goal of eliminating symptoms and permitting normal growth and sexual development, usually achieved by maintaining hemoglobin levels between 7 and 9 g/dL (70 to 90 g/L).

Glucocorticoids are effective in many patients.⁴³ Although the mechanism of action of glucocorticoids in this disease is not understood, their toxicities are substantial, and a response is not predictable. Once the diagnosis is established, prednisone is administered orally at 2 mg/kg daily in three or four divided doses.^35,44,45 A reticulocyte response is seen in the majority of patients 1 to 4 weeks later, followed by a rise in hemoglobin level. Once the hemoglobin level reaches 9 to 10 g/dL (90 to 100 g/L), very slow reduction of the glucocorticoid dose is undertaken by decreasing the number of daily doses. When a single daily dose is achieved, an alternate-day schedule is adopted. In general, severe anemia can be avoided with continued glucocorticoid administration. The maintenance dose may be low (1 to 2 mg/day). Some patients may tolerate complete withdrawal of prednisone, but relapse is frequent and most responders become glucocorticoid dependent. A variety of patterns of response have been described, ranging from prompt recovery and apparent cure to refractoriness after a long period of responsiveness.³⁵ Conversely, a second trial of glucocorticoids years after an apparent therapeutic failure may be successful. In a series of 76 patients followed for many years, 59 were treated with prednisone; 31 initially responded, and two of the 25 who initially failed later responded.⁴⁴ Glucocorticoid responsiveness is strongly associated with better survival, and patients who require low doses of prednisone, or those few who spontaneously remit, may have normal life expectancies. Long-term use of high-dose prednisone results in significant toxicity, including some combination of growth retardation, cushingoid facies, buffalo hump, osteoporosis, aseptic necrosis of the hip and fractures, diabetes, hypertension, and cataracts. Red cell transfusions with iron chelation may be preferable to such an outcome.

Allogeneic stem cell marrow transplantation, when successful, is curative (Chap. 23), but the procedure has not been widely applied to children responding to medical measures. The median life expectancy of patients requiring transfusions and iron chelation is 30 to 40 years. A less-favorable outcome is related to poor compliance and cardiac and hepatic disease from iron overload.⁴⁶ Because of the morbidity and mortality associated with allogeneic stem cell transplant, most patients have been transplanted late in their disease course, after large numbers of transfusions, accumulation of heavy iron loads, and alloimmunization. Despite the poor predictive factors, 15 of 19 patients of the first published series of cases survived 5 months to many years posttransplant.³⁷ Comparable survival rates have been reported from European⁴⁷ and Japanese registries.⁴⁸ Stem cell transplantation from unrelated stem cell donors or use of cord blood stem cells^47,49 has been less successful. Recurrent red cell aplasia despite full engraftment was reported in one child after transplantation.⁵⁰

Other therapies have not gained wide acceptance despite promising pilot studies, including interleukin-3 (IL-3),⁵¹ high-dose methylprednisolone,⁵² cyclosporine and other immunosuppressive agents,^53,54 and prolactin induction by metoclopropamide.⁵⁵ Leucine, which is effective in animal models,⁵⁶ is in clinical trials.

With better survival, the risk of late development of leukemia has become apparent.^14,43 Four of 76 patients followed at Children’s Hospital in Boston died of acute myelogenous leukemia, with a calculated relative risk of greater than 200 times expected.⁴⁴

Gene transfer in vitro has functionally corrected cells defective in RSP19,⁵⁷ and in animal models corrected cells show improved erythropoiesis and a survival advantage in vivo⁵⁸ offering the possibility of gene therapy.

TRANSIENT APLASTIC CRISIS AND TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD

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DEFINITION AND HISTORY

Temporary failure of erythropoiesis is clinically identical to pure red cell aplasia except for spontaneous resolution of symptoms and of the laboratory findings of normocytic and normochromic anemia and marrow erythroid hypoplasia, usually over the course of a few weeks. Erythrocyte production is halted: (1) by acute primate erythroparvovirus 1 (B19 parvovirus) infection, typically in the context of underlying hemolytic disease (called transient aplastic crisis); (2) in normal children, usually after an infection by another [unknown] childhood virus (transient erythroblastopenia of childhood); or (3) as a transient reaction to a drug.

An anemic crisis was described in the 1940s first by Lyngar⁵⁹ and then by Owren,⁶⁰ Gasser,³ and Dameshek and Bloom⁶¹ in kindreds with hereditary spherocytosis. Several children within a family suffered anemic crises and exhibited low, rather than the usually high, reticulocyte numbers. Transient aplastic crisis also was noted as a complication of sickle cell disease.^62,63 Marrow examination showed decrease or absence of erythroid precursor cells, and often giant erythroblasts.^60,61 An infectious etiology was suspected from the history of a preceding febrile illness in families and its simultaneous occurrence in siblings. After the serendipitous discovery of B19 parvovirus in a normal blood donor, Pattison and colleagues screened large numbers of stored sera for evidence of recent infection. Immunoglobulin (Ig) M antibody or viral antigen was found in the blood of Jamaican children in London, all of whom had transient aplastic crisis of sickle cell disease.⁶⁴ B19 parvovirus later was established as the agent also responsible for fifth disease.⁶⁵ In the large cohort of sickle cell patients in Jamaica reported by Serjeant and colleagues,^66,67 virtually all episodes of transient aplastic crisis could be linked to B19 parvovirus. In retrospect, red cell aplasias blamed on kwashiorkor, vitamin deficiency, bacterial infections, and chemical exposures likely represented parvovirus infection.

Gasser³ described erythroblastopenia in normal children who ultimately recovered⁶⁰; the disease was recognized as an entity by Wranne⁶⁸ in the 1970s. Transient erythroblastopenia of childhood has an unclear etiology but may represent a postviral immune-mediated syndrome. The syndrome is rare and may be declining in incidence.⁶⁹

ETIOLOGY AND PATHOGENESIS

B19 parvovirus, a small DNA virus, commonly infects humans. Most of the adult population has IgG antibodies specific to B19.⁶⁵ The virus is tropic for erythroid progenitor cells,⁷⁰ mainly because of their P antigen or globoside, the receptor for entry of B19 into the cell^71,72 (Fig. 36–1). Infection lyses the target cell and abrogates erythropoiesis in vitro and in vivo. Reticulocytopenia probably accompanies B19 parvovirus infection in all infected persons.⁷³ Anemia only manifests if red cell survival is decreased. Infection ordinarily is terminated by production of neutralizing antibodies to the virus (when such antibodies are absent, persistence of the virus produces chronic pure red cell aplasia). B19 parvovirus may appear in epidemics of fifth disease in the normal population and of transient aplastic crisis, for example, in hematology clinics specializing in sickle cell disease.^74,75 In fifth disease, IgM antibody is present in the blood, and virus levels are either low or are not detectable. Symptoms and signs of a typical “slapped cheek” cutaneous eruption and arthralgia or arthritis are secondary to antibody–virus immune complex deposition.

Figure 36–1.

A and B. Giant early erythroblast precursors in the marrow aspirate of a patient with chronic pure red cell aplasia secondary to persistent B19 parvovirus infection. Note the nuclear inclusions (darker nuclear shading) representing parvovirus infection. C. Marrow biopsy section. The arrows point to binucleate erythroid precursor cell with nuclear inclusions representing parvovirus infection. (Reproduced with permission from Lichtman's Atlas of Hematology, www.accessmedicine.com.)

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In contrast, in transient aplastic crisis, high concentrations of virus are present in the circulation, and patients do not develop fifth disease. In children with sickle cell disease, the incidence of B19 parvovirus infection was estimated at approximately 11 percent, and 75 percent of patients were infected by age 20 years.⁷⁶ In this setting, parvovirus infection was associated with transient aplastic crisis, a higher frequency of fever, pain, acute chest syndrome, and acute splenic sequestration syndrome.⁷⁶ As in normal individuals, parvovirus infection can be asymptomatic in sickle cell disease.⁷⁷

The origins of transient erythroblastopenia of childhood are poorly understood. An apparent viral prodrome is typical,⁷⁸ and temporal and seasonal clustering of cases may occur.^79,80,81 With rare exception,⁸² B19 parvovirus is not the etiology,^83,84 and no other virus has been consistently implicated.⁷⁸ Erythroid colony numbers (Chap. 32) usually are low.⁸⁵ An immune pathophysiology has been inferred from in vitro experiments in which IgG from sera of patients inhibited erythropoiesis⁸⁶ in the majority of cases.⁸⁷ Cell-mediated mechanisms also may play a causal role. In one report, T-cell depletion led to a dramatic increase in CFU-E formation.⁸⁸ A possible relationship between transient erythroblastopenia of childhood and inherited red cell aplasia has been suggested by the clustering of polymorphic alleles in familial transient erythroblastopenia.⁸⁹

The same drugs implicated in chronic pure red cell aplasia apply to transient erythropoietic failure.⁹⁰ Laboratory investigations of red cell aplasia secondary to diphenylhydantoin⁹¹ and rifampicin⁹² are consistent with a hapten mechanism, in which serum antibody affects erythroid progenitor cells only in the presence of drug.

CLINICAL FEATURES

Transient aplastic crisis typically occurs in younger patients who are chronically anemic as a result of hereditary spherocytosis, sickle cell disease, or another hemolytic anemia. The decrease in erythropoiesis results in more evident pallor, fatigue on exertion or at rest, lassitude, and dyspnea on exertion. Gastrointestinal complaints or headache may be associated.⁹³ Parvovirus infection can unmask previously undiagnosed underlying hemolytic anemia. Physical examination may reveal signs of anemia, such as pallor, tachycardia, and a flow murmur. No rash or joint swelling is seen. Elevated serum bilirubin or overt icterus may be a clue to underlying hemolysis.

Transient erythroblastopenia of childhood presents as an acute anemia in a previously well child. The syndrome has an estimated incidence rate of 4 to 5 cases per 1 million children.^94,95,96 Transient erythroblastopenia is a frequent diagnosis in children with severe anemia,^95,97 and is the most common cause of acquired red cell aplasia in pediatric patients.^94,98 Most patients are 1 to 3 years old,^97,98 but transient erythroblastopenia of childhood can occur in the first year of life and through adolescence. Rare complications include seizures and transient neurologic abnormalities.^99,100,101

LABORATORY EVALUATION

In both syndromes, anemia is the hallmark, and hemoglobin levels may be markedly depressed. Reticulocytes usually are absent from the blood, and erythroid precursor cells are not present or markedly decreased in the marrow. Red cell indices are normal. White blood cell and platelet counts are normal or elevated. Occasionally, neutropenia and thrombocytopenia of mild or moderate degree are present (especially if splenic function is intact, as in hereditary spherocytosis and in transient erythroblastopenia of childhood).⁹⁷ If the episode is brief and diagnosed during marrow recovery, patients may present with reticulocytosis, and nucleated red blood cells may be seen on the blood film.

DIFFERENTIAL DIAGNOSIS

The reticulocyte count readily distinguishes the cause of increasing anemia in a patient with hemolytic disease as transient aplastic crisis. The most important differential diagnosis for transient erythroblastopenia of childhood is inherited pure red cell aplasia. For the former, the age at presentation is older, the patient usually has no family history (but transient erythroblastopenia of childhood may be familial and can occur simultaneously in siblings),¹⁰² physical anomalies are absent, and the syndrome resolves spontaneously.

In transient erythroblastopenia of childhood (in contrast to inherited red cell aplasia), erythrocyte adenosine deaminase levels are normal, and red cells do not show “stress” patterns of fetal hemoglobin and i antigen (red cell antigen expressed primarily on feral erythrocytes) expression. The patient’s medical history, the red cell indices, and appropriate serum assays should allow prompt exclusion of more common causes of anemia in children, such as iron deficiency or other nutritional deficiencies. When transient erythroblastopenia is associated with neutropenia, acute lymphoblastic leukemia and aplastic anemia may be suspected: marrow examination clarifies the diagnosis.¹⁰³ A record of current medications, more important in adults, may provide the basis for a tentative diagnosis of drug-induced rather than idiopathic disease.

THERAPY, COURSE, AND PROGNOSIS

Transient aplastic crisis resolves as neutralizing antibodies to B19 parvovirus are made, usually within 1 to 2 weeks of infection. Ensuing reticulocytosis may be brisk, and the hemoglobin may transiently rise to higher-than-normal values. White cell and platelet numbers may “rebound,” and some bone pain from marrow expansion may be present. Severe anemia may require transfusion of red blood cells (Chap. 138). No established role for administration of immunoglobulin exists.

Transient erythroblastopenia of childhood typically terminates after a few weeks, but anemia may persist occasionally for months.⁹⁸ Transfusions may be required during that interval. Overtreatment of a self-limited illness and misdiagnosis of a more serious disease are to be avoided.

For drug-associated transient failure of erythropoiesis, the suspected offending drug is discontinued and the diagnosis established from subsequent clinical improvement.

ACQUIRED PURE RED CELL APLASIA

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DEFINITION AND HISTORY

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

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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

Acquired

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

Idiopathic

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 aplasia^130,131,132 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

Medications

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.

CLINICAL FEATURES

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.

LABORATORY FEATURES

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.

DIFFERENTIAL DIAGNOSIS

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

Treatment

Transfusion Therapy

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).

Immunosuppression

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 Plasmapheresis^186,187 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

Other Therapies

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.

Figure 36–2.

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.

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Chapter 36: Pure Red Cell Aplasia

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INTRODUCTION

INHERITED PURE RED CELL APLASIA (DIAMOND-BLACKFAN ANEMIA)

DEFINITION AND HISTORY

ETIOLOGY AND PATHOGENESIS

CLINICAL FEATURES

LABORATORY FEATURES

DIFFERENTIAL DIAGNOSIS

THERAPY, COURSE, AND PROGNOSIS

TRANSIENT APLASTIC CRISIS AND TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD

DEFINITION AND HISTORY

ETIOLOGY AND PATHOGENESIS

Figure 36–1.

CLINICAL FEATURES

LABORATORY EVALUATION

DIFFERENTIAL DIAGNOSIS

THERAPY, COURSE, AND PROGNOSIS

ACQUIRED PURE RED CELL APLASIA

DEFINITION AND HISTORY

ETIOLOGY AND PATHOGENESIS

Immune-Mediated Erythropoietic Failure

Persistent B19 Parvovirus Infection

Intrinsic Cellular Defects Leading to Failed Red Blood Cell Production

Medications

CLINICAL FEATURES

LABORATORY FEATURES

DIFFERENTIAL DIAGNOSIS

THERAPY, COURSE, AND PROGNOSIS

Treatment

Transfusion Therapy

Immunosuppression

Other Therapies

Immunoglobulin for Persistent B19 Parvovirus Infection

Figure 36–2.

REFERENCES

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