Transient Erythroblastopenia of Childhood

Transient erythroblastopenia of childhood (TEC) is the most common acquired red cell aplasia occurring in children. It is more prevalent than congenital hypoplastic (Diamond-Blackfan) anemia. This syndrome of severe, transient hypoplastic anemia occurs mainly in previously healthy children between 6 mo and 3 yr of age, and most of the children are older than 12 mo at onset. Only 10% of affected patients are >3 yr of age. The annual incidence is estimated to be up to 4.3 cases per 100,000 children, although it is likely higher, because many cases might go undiagnosed and resolve spontaneously. The suppression of erythropoiesis has been linked to immunoglobulin (Ig)G, IgM, and cell-mediated mechanisms. Familial cases have been reported, suggesting a hereditary component. TEC often follows a viral illness, although no specific virus has been implicated consistently. A study of acute cases found no proof that human herpesvirus (HHV)-6, parvovirus B19, Epstein-Barr virus (EBV), or cytomegalovirus (CMV) is a causative agent.

The temporary suppression of erythropoiesis results in reticulocytopenia and moderate to severe normocytic anemia. Some degree of neutropenia occurs in up to 20% of cases. Platelet numbers are normal or elevated. Similar to the situation observed in iron-deficiency anemia and other red blood cell (RBC) hypoplasias, thrombocytosis is presumably caused by increased erythropoietin, which has some homology with thrombopoietin. Mean corpuscular volume (MCV) is characteristically normal for age, and fetal hemoglobin (HbF) levels are normal before the recovery phase. RBC adenosine deaminase (ADA) levels are normal in this disorder, thus contrasting with the elevation noted in most cases of congenital hypoplastic anemia (Table 444-1). Differentiation from the latter disease is sometimes difficult, but differences in age at onset and in age-related MCV, HbF, and ADA are usually helpful. The peak occurrence of TEC coincides with that of iron-deficiency anemia in infants receiving milk as their main caloric source; differences in MCV should help to distinguish between these 2 disorders.

Table 444-1 COMPARISON OF DIAMOND-BLACKFAN ANEMIA AND TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD

DBA, Diamond-Blackfan anemia; HbF, fetal hemoglobin; MCV, mean cell volume; TEC, transient erythroblastopenia of childhood; WBC, white blood cell.

From Nathan DG, Orkin SH, Ginsburg D, et al, editors: Nathan and Oski’s hematology of infancy and childhood, ed 6, vol 1, Philadelphia, 2003, WB Saunders, p 329. Adapted from Alter BP: The bone marrow failure syndromes. In Nathan DG, Oski FA, editors: Hematology of infancy and childhood, ed 3, Philadelphia, 1987, WB Saunders, p 159; and Link MP, Alter BP: Fetal erythropoiesis during recovery from transient erythroblastopenia of childhood (TEC), Pediatr Res 15:1036–1039, 1981.

Virtually all children recover within 1-2 mo. RBC transfusions may be necessary for severe anemia in the absence of signs of early recovery. The anemia develops slowly, and significant symptoms usually develop only with severe anemia. Corticosteroid therapy is of no value in this disorder. Any child with presumed TEC who requires >1 transfusion should be re-evaluated for another possible diagnosis. In rare instances, a prolonged case of apparent TEC may be caused by parvovirus-induced RBC aplasia, occurring in children with congenital or acquired immunodeficiencies.

Red Cell Aplasia Associated with Parvovirus B19 Infection

Parvovirus B19 is a common infectious agent that causes erythema infectiosum (fifth disease) (Chapter 243). It is also the best-documented viral cause of RBC aplasia in patients with chronic hemolysis, patients who are immunocompromised, and fetuses in utero. The virus is particularly infective and cytotoxic in marrow erythroid progenitor cells, interacting specifically with the RBC P antigen. In addition to decreased or absent erythroid precursors, characteristic nuclear inclusions in erythroblasts and giant pronormoblasts may be seen under the light microscope in bone marrow specimens.

Chronic Hemolysis

Because parvovirus infection is usually transient, with recovery occurring in <2 wk, anemia is either not present or not appreciated in otherwise normal children whose peripheral RBC life span is 100-120 days. The RBC life span is much shorter in patients with hemolysis secondary to conditions such as hereditary spherocytosis or sickle cell disease. In these children, a brief cessation of erythropoiesis can cause severe anemia, a condition known as an aplastic crisis. When a definitive diagnosis is required, the work-up should include serum parvovirus IgM and IgG titers and, if needed, viral detection using polymerase chain reaction (PCR) techniques. Recovery from moderate to severe anemia is usually spontaneous, heralded by a wave of nucleated RBCs and subsequent reticulocytosis in the peripheral blood. A RBC transfusion may be necessary if the anemia is associated with significant symptoms. Notably, parvovirus-induced aplastic crisis usually occurs only once in children with chronic hemolysis. In families with >1 child affected with a hemolytic disorder, parents should be warned that a similar aplastic episode can occur in the other children if they have not been previously infected.

Immunodeficiency

Persistent parvovirus infection rarely occurs in children with congenital immunodeficiency diseases, those being treated with immunosuppressive agents, and those with HIV/AIDS, because these children may be unable to mount an adequate antibody response. The resultant pure RBC aplasia may be severe, and affected children often are thought to have TEC. This type of RBC aplasia differs from TEC in that there is no spontaneous recovery and >1 transfusion is often needed. The diagnosis of parvovirus infection is made by PCR of peripheral blood or bone marrow DNA because the usual serologic responses, reflected by parvovirus serum Ig M or Ig G titers, are impaired in immunodeficient children. In chronically infected patients, the disease may be treated with high doses of intravenous immunoglobulin (IVIG), which contains neutralizing antibody to parvovirus.

Miscarriage and Hydrops Fetalis

Parvovirus infection and destruction of erythroid precursors can also occur in utero. Such events are associated with increased fetal wastage in the first and second trimesters. Infants may be born with hydrops fetalis (Chapter 97) and viremia. The presence of persistent congenital parvovirus infection is detected by PCR of peripheral blood and/or bone marrow DNA, because immunologic tolerance to the virus can prevent the usual development of specific antibodies.

Other Red Cell Aplasias in Children

Acquired red cell aplasia in adults is usually mediated by a chronic antibody and often associated with disorders such as chronic lymphocytic leukemia, lymphoma, thymoma, lymphoproliferative disorders, and systemic lupus erythematosus. This chronic antibody-mediated type of RBC aplasia is extremely rare in childhood. Alemtuzumab (humanized anti-CD52 antibody) has been used to treat adult-onset pure red cell aplasia when treatment with corticosteroids and other immunosuppressive agents was unsuccessful.

Certain drugs, such as chloramphenicol, also can inhibit erythropoiesis in a dose-dependent manner. Reticulocytopenia, erythroid hypoplasia, and vacuolated pronormoblasts in the bone marrow are reversible effects of this drug. These effects are distinct from the idiosyncratic and rare development of severe aplastic anemia in chloramphenicol recipients. Acquired antibody-mediated pure red cell aplasia is also a rare complication in patients who are chronically treated with recombinant human erythropoietin (EPO), usually for chronic renal failure. In addition to discontinuing EPO, treatment may include immunosuppression and renal transplantation.