Pure red cell aplasia

What every physician needs to know:

Pure red cell aplasia (PRCA) is defined as anemia with absent reticulocytes and marrow erythroid precursor cells. This rare aregenerative anemia has a number of interesting clinical associations and is also usually responsive to treatment.

PRCA in children is very rare. Furthermore, the differential diagnosis is restricted predominantly to only a few syndromes, namely:

The congenital forms (Diamond Blackfan anemia and Pearson syndrome)
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The acquired forms (transient erythroblastopenia of childhood [TEC] and those related to parvovirus B19 infection)

A variety of predominantly adult diagnoses such as thymoma, certain malignancies, infections, autoimmune and lymphoproliferative disorders, drug/chemical-related, pregnancy, and renal failure may have associated PRCA. These may also be observed occasionally in children.

The “pure” red cell aplasia, Diamond Blackfan anemia, felt by many to be the “sine qua non” of pediatric hematology, is one of a rare group of inherited bone marrow failure syndromes (IBMFS) distinguished by the variable presence of congenital anomalies and a predisposition to cancer.

Are you sure your patient has pure red cell aplasia? What should you expect to find?

Anemia symptoms (fatigue, headache, shortness of breath, exertional dyspnea) and signs (pallor, tachycardia).

Associated findings with specific syndromes:

Congenital anomalies in DBA
Acidosis in Pearson syndrome

Beware of other conditions that are associated with or can mimic pure red cell aplasia:

Acquired:

Antibody-dependent PRCA
Transient erythroblastopenia of childhood (TEC)
PRCA mediated by T and NK cells
B19 parvovirus-associated
PRCA associated with myelodysplastic syndrome (MDS)
PRCA associated with thymoma
Other causes: autoimmune disorders, malignancy, nutritional, renal failure, drugs or toxins, infection

Congenital:

DBA
Pearson syndrome

Which individuals are most at risk for developing pure red cell aplasia:

Clinical associations include thymoma (but probably less than 10% of PRCA cases), collagen-vascular syndromes, myasthenia gravis, chronic lymphocytic leukemia, and large granular lymphocytic (LGL) leukemia. PRCA may also be seen in MDS, especially with 5q- syndrome.

Immunodeficient host: Persistence of parvovirus B19 can occur in an immunodeficient host, in congenital immunodeficiencies (Nezelof syndrome), iatrogenic immunosuppression (immunosuppressive drugs and cytotoxic chemotherapy), and HIV infection-induced immunodeficiency.

DBA is sporadic (new autosomal dominant) in approximately 60% of cases, and is inherited as an autosomal dominant in about 40% of cases.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Tests required

Reticulocytes are severely depressed
Red blood cell (RBC) size may be normocytic or macrocytic
Liver and renal function tests (creatinine) may be abnormal and suggest secondary causes
Bone marrow biopsy and aspirate with cytogenetic analysis

– Erythroid precursor cells are usually absent but a few normoblasts may be present in the marrow. Giant pronormoblasts signal B19 parvovirus; uninuclear micromegakaryocytes, 5q- syndrome. Other blood counts are typically normal, as are cytogenetics (except for PRCA associated with MDS).

Lymphoid abnormalities

– B-cell or LGL proliferation

T-cell receptor analysis
Flow cytometry immunophenotyping (CD2, CD3, CD4, CD5, CD8, CD16, CD56, CD57)
Erythrocyte adenosine deaminase activity (eADA) elevated in approximately 85% of patients with DBA
Secondary causes of PRCA
Tests for autoantibodies (antinuclear antibody, anti-erythropoietin antibody)
B19 parvovirus

– B19 parvovirus antibodies are usually absent, or only immunoglobulin M (IgM) may be observed; virus can be detected in the blood by DNA hybridization or polymerase chain reaction (PCR)

What imaging studies (if any) will be helpful in making or excluding the diagnosis of pure red cell aplasia?

Computed tomography (CT) or magnetic resonance imaging (MRI) scan to rule out thymoma or lymphoid neoplasms.

Appropriate imaging for congenital anomalies associated with DBA (for example, orofacial, orthopedic, genitourinary, cardiac).

If you decide the patient has pure red cell aplasia, what therapies should you initiate immediately?

Secondary causes treated: identify and stop drug or toxin.

Transfusion of red blood cells, as clinically indicated.

More definitive therapies?

For acquired PRCA, corticosteroids in moderate doses are usually first therapy. Followed by either other immunosuppressives such as: cyclosporine, anti-thymocyte globulin (ATG), and more recently (in a few case reports): monoclonal antibodies to CD20 (rituximab), or cytotoxic drugs such as moderate doses of azathioprine or cyclosphosphamide, administered orally. Anti-interleukin-2 receptor (Daclizumab) has been shown to be safe and effective in a case series of 15 patients, in which hematologic response was observed in 6 (see Sloand reference below).

Persistent parvovirus B19 infection responds to intravenous immunoglobulins at 0.4g/kg daily for 5 to 10 days. Patients with large viral loads, especially in the acquired immunodeficiency syndrome, may relapse and require periodic retreatment.

In the special case of PRCA due to MDS and del(5q), the immunomodulatory drug lenalidomide may induce remissions.

For DBA, corticosteroids are standard (usually commenced at 9 to 12 months of age), after a period of red cell transfusions; patients may be dependent on exquisitely low doses, and relapse may not always be responsive to reinstitution of treatment. Despite transfusions and adequate iron chelation, patients may develop fatal late complications.

What other therapies are helpful for reducing complications?

Thymomas should be excised as they are locally invasive; surgery does not necessarily resolve the anemia.

What should you tell the patient and the family about prognosis?

Remission is usually achieved, but relapse can occur.

"What if" scenarios.

Relapse can occur.

Iron overload from transfusions is common, and iron chelation therapy must be instituted early when the iron burden is increased.

DBA is a genetic syndrome that predisposes to leukemia and solid tumors.

Pathophysiology

Antibody-dependent PRCA

Krantz and Kao first reported that plasma from a patient with PRCA could inhibit heme synthesis by the patient’s own bone marrow cells in vitro. The serum of patients with antierythropoietin antibody-related PRCA also inhibited the growth of erythroid progenitor cells in vitro.

PRCA caused by autoantibodies against endogenous erythropoietin could occur, but is rare in patients never treated with recombinant human erythropoietin. Recombinant human erythropoietin–related PRCA reached peak incidence in 2001-2002, related to manufacturing changes in a particular recombinant human erythropoietin product. Antibody-dependent PRCA can also occur in allogeneic hematopoietic stem cell transplantation.

Delayed hemolysis and PRCA have been reported in patients receiving allogeneic hematopoietic stem cell grafts from ABO major mismatched donors. PRCA results from the pre-existing isohemagglutinin antibodies, anti-IgA isoagglutinin in particular, reacting with incompatible blood antigens on erythroid progenitors. Incompatible isohemagglutinin can also be produced by long-lived plasma cells derived from the host. TEC is caused by a short-lived anti-erythroid antibody likely post-infectious. Rarely persists for more than a few months.

T cell/NK cell

The expansion of LGLs is the disorder most commonly associated with PRCA. These LGLs may be of T-cell type or of NK-cell type. T-LGLs express CD3 and a T-cell receptor of αβ-type in most cases or gd-type. In contrast, NK-LGLs, recently defined as chronic lymphoproliferative disorders of NK cells, are CD3, and do not express a T-cell receptor at the cell surface.

B19 parvovirus

Parvovirus B19 infection is often asymptomatic, but may cause erythema infectiosum (fifth disease) in children and transient aplastic crisis in patients with underlying hemolysis. Virus infection is ordinarily terminated by production of neutralizing antibodies. Persistence of parvovirus results from failure to mount a neutralizing antibody response, leading to chronic erythroid precursor destruction and anemia.

DBA

DBA is now also categorized as one of an emerging group of disorders known as ribosomopathies. The molecular biology of DBA is being extensively explored and, in 50 to 60% of cases, the syndrome appears to result from haploinsufficiency of either a small or large subunit-associated ribosomal protein. How ribosomal protein haploinsufficiency results in erythroid failure, as well as the other clinical manifestations of DBA, remains uncertain. However, genetic testing for a mutated DBA-associated ribosomal protein gene has become an important diagnostic tool in differentiating DBA from other types of PRCA.

Myelodysplastic syndrome (MDS): MDS can be associated with an isolated deletion of the long arm of chromosome 5 [del(5q] as the sole cytogenetic abnormality, sometimes referred to as the 5q- syndrome, and presenting with pure red cell aplasia. The deletion of 5q has been found to cause haploinsufficiency of the small ribosomal protein, RPS14: the pathophysiology of this acquired form of MDS appears to be analogous to the genetic haploinsufficiency of ribosomal proteins seen in DBA (with both leading to pure red cell aplasia).
Thymoma
Other causes

What other clinical manifestations may help me to diagnose pure red cell aplasia?

History of drug use or infections
Family history
DBA associated anomalies

What other additional laboratory studies may be ordered?

DBA: Genetic testing for mutated genes encoding the known DBA-associated ribosomal proteins.

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