OVERVIEW: What every practitioner needs to know
Are you sure your patient has transient erythroblastopenia of childhood? What are the typical findings for this disease?
Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited, benign disorder characterized by a temporary suppression of erythropoiesis, resulting in reticulocytopenia in the blood and development of moderate to severe normochromic, normocytic anemia. The most common manifestation of the anemia is pallor. Other symptoms, such as anorexia and lethargy, may also be present. On examination, a murmur or tachycardia may be evident. In severe cases, hemodynamic instability may be present.
What other disease/condition shares some of these symptoms?
Few diseases and conditions share symptoms with TEC.
Diamond-Blackfan anemia (DBA) can share some of the symptoms. TEC is differentiated from DBA in that the latter is usually diagnosed in infants less than 6 months of age, and frequently responds to steroid therapy. At the time of presentation, DBA is usually associated with elevated erythrocyte mean corpuscular volume (MCV), fetal hemoglobin and i antigen score, and increased levels of certain erythrocyte enzymes, such as erythrocyte adenosine deaminase (eADA). These laboratory studies are typically normal in TEC, although the MCV can be elevated during the recovery phase. In contrast to DBA, the reticulocyte count in recovery phase TEC is high. Patients with DBA tend to have short stature and low birthweight, and can have developmental delay and congenital anomalies, such as thumb malformations, craniofacial anomalies, and urogenital abnormalities.
Transient aplastic crisis due to parvovirus B19 can also mimic symptoms of TEC. Children with chronic hemolytic disorders such as sickle cell anemia and hereditary spherocytosis are prone to developing severe anemia during infection with parvovirus B19. In contrast, TEC is rarely caused by parvovirus.
TEC symptoms may also suggest other causes of pure red cell aplasia. Therefore, TEC must be differentiated from chronic disorders associated with decreased red cell production, such as renal failure, hypothyroidism and other chronic states of infection or inflammation.
Malignancy can usually be differentiated from TEC by the presence of second cell line depression, or symptoms such as bone pain, hepatosplenomegaly, lymphadenopathy, or fever. When TEC is discovered during the recovery phase when the reticulocyte count and MCV are high, it may be confused with hemolytic disease. In contrast to hemolytic disorders, TEC is not associated with jaundice or peripheral destruction of red blood cells.
What caused this disease to develop at this time?
TEC was first described in 1970. It is the most common cause of decreased erythrocyte production in children and should be suspected in an otherwise healthy child with anemia and reticulocytopenia. On occasion, it is preceded by an upper respiratory tract infection, although this is not seen in all cases. TEC has been reported in siblings, and a family history increases the likelihood of the disease. The genetic reason for this predisposition is currently unknown. Pallor is often the only presenting symptom of TEC. TEC is often discovered on a complete blood count that was done for some other reason.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
An extensive workup is not usually necessary, provided the MCV is normal and the blood smear does not suggest an erythrocyte disorder or leukemia. In many cases, a CBC with differential, peripheral blood smear, and reticulocyte count are sufficient to evaluate TEC.
If the diagnosis is unclear, obtaining a bone marrow aspirate or other tests may be warranted. CBC often reveals a normocytic, normochromic anemia with a low reticulocyte count. Mild neutropenia may be noted in addition to a normal or slightly elevated platelet count. MCV is usually low in iron deficiency; therefore, iron studies are not necessary in most cases. Hemoglobin electrophoresis will frequently be normal, in contrast to DBA which frequently shows an elevated hemoglobin F level. Elevated hemoglobin F levels have been reported during the recovery phase of TEC. Erythrocyte adenosine deaminase (eADA) activity and i antigen score should be normal but are frequently elevated in DBA. Recovery phase TEC can be differentiated from hemolysis by demonstration of a normal lactate dehydrogenase, indirect bilirubin, and haptoglobin.
Bone marrow aspirate can be helpful in distinguishing TEC from malignancy. However, malignancy can often be excluded based on the absence of depression of a second cell line, or typical signs and symptoms such as bone pain, lymphadenopathy, or hepatosplenomegaly.
Would imaging studies be helpful? If so, which ones?
Imaging studies are usually not indicated for the diagnosis or management of TEC.
Confirming the diagnosis
There are several things to consider when differentiating TEC from other causes of anemia:
1. A patient is usually between the ages of six months to four years old.
2. Anemia usually begins around the time of birth.
3. Patient with TEC usually have normal height and no congenital anomalies.
4. The spleen is not enlarged, there are no enlarged lymph nodes, and there is no evidence of blood loss or renal dysfunction.
5. Lab results during the acute phase show reticulocytes as low to normal, leukocyte counts are usually normal, and platelet counts are normal to high. During recovery the reticulocyte count will be high.
6. MCV is normal accept in the recovery phase.
7. There are normal levels of folic acid, vitamin B12, serum iron, and ferritin.
8. Spontaneous recovery typically occurs in 2 months.
If you are able to confirm that the patient has TEC, what treatment should be initiated?
In most cases, spontaneous resolution occurs in two to eight weeks without intervention. Observation is sufficient in most cases, and erythrocyte transfusion is rarely needed except when there is hemodynamic instability or interference with quality of life.
What are the adverse effects associated with each treatment option?
Because observation is the mainstay of treatment, there are typically no adverse effects. In cases where transfusion is necessary, hemolytic, allergic and infectious transfusion-related reactions may occur.
What are the possible outcomes of TEC?
The prognosis for TEC is excellent. Anemia typically persists one to two months and is followed by complete recovery. Even though the vast majority of patients recover within 2 months, anemia can rarely last as long as one year. Most patients spontaneously recover. Erythrocyte transfusions are rarely needed except for patients with hemodynamic instability, exercise intolerance, or altered mental status.
What causes this disease and how frequent is it?
The exact etiology is uncertain. Studies suggest that TEC may be caused by certain viral illnesses, serum inhibitors against erythroid progenitor cells, and cell-mediated suppression of erythropoiesis. Viruses that have been implicated include parvovirus B19, human herpes virus type 6, and echovirus 11; however, in most cases no virus is detected.
The incidence of TEC has been reported to be 4.3 cases per 100,000 children. The true incidence may be higher because many cases remain undiagnosed and resolve spontaneously. The median onset occurs at 18 to 26 months, with the majority of cases occurring at 1 to 4 years of age. TEC has been seen in all ethnicities and may be slightly more common in males than females. No seasonal predominance is reported. Genetics may play a role in TEC, but the exact genes involved remain unknown.
How do these pathogens/genes/exposures cause the disease?
TEC is thought to be caused by the direct effect of viral infections or autoimmune suppression of erythropoiesis.
Other clinical manifestations that might help with diagnosis and management
What complications might you expect from the disease or treatment of the disease?
Due to the benign and transient nature of TEC and spontaneous resolution within two months, there are typically no complications. If the anemia is severe enough, TEC may produce symptoms requiring a blood cell transfusion, although this is rare.
Are additional laboratory studies available; even some that are not widely available?
Viral titers or cultures are usually not helpful. There are no additional laboratory studies that are necessary to diagnose TEC.
How can TEC be prevented?
Because the cause of TEC in an individual patient varies and cannot be predicted, there are no ways to prevent TEC.
What is the evidence?
Wegelius, R, Weber, TH. “Transient erythroblastopenia in childhood”. A study of 15 cases. Acta Paediatr Scand. vol. 67. 1978. pp. 513-8. (One of the early descriptions of TEC.)
Wranne, L. “Transient erythroblastopenia in infancy and childhood”. Scand J Haematol. vol. 7. 1970. pp. 76-81. (One of the early descriptions of TEC.)
Prassouli, A, Papadakis, V, Tsakris, A. “Classic transient erythroblastopenia of childhood with human parvovirus B19 genome detection in the blood and bone marrow”. J Pediatr Hematol Oncol. vol. 27. 2005. pp. 333-6. (this paper is the inital report of Parvovirus B19 as a cause of TEC.)
Skeppner, G, Kreuger, A, Elinder, G. “Transient erythroblastopenia of childhood: prospective study of 10 patients with special reference to viral infections”. J Pediatr Hematol Oncol. vol. 24. 2002. pp. 294-8.
Shaw, J, Meeder, R. “Transient erythroblastopenia of childhood in siblings: case report and review of the literature”. J Pediatr Hematol Oncol. vol. 29. 2007. pp. 659-60. (This article describes 2 cases in half-siblings diagnosed approximately 10 years apart, along with 11 other sibling pairs identified in the literature, suggesting an autosomal dominant pattern of inheritance. )
Skeppner, G, Forestier, E, Henter, JI, Wranne, L. “Transient red cell aplasia in siblings: a common environmental or a common hereditary factor”. Acta Paediatr. vol. 87. 1998. pp. 43-7. (Another paper raising the possibility of an hereditary susceptibility to TEC) (The authors found no proof of any single agent causing TEC. Parvovirus B19, HHV-6, EBV, and cytomegalovirus were each found but none were a common causative agent of TEC in this study. )
Ongoing controversies regarding etiology, diagnosis, treatment
Parvovirus B19 has been implicated as frequently causing TEC. However, when assays for parvovirus are performed, evidence of infection is lacking in most cases. In many patients, TEC may be due to transient autoimmune suppression of early erythrocyte progenitors. Sera from some patients with TEC contains IgG that suppresses the proliferation of erythroid progenitor cells. Purified IgG from these patients inhibits the production of erythroid colony-forming units (CFU-E) and granulocyte-macrophage colony-forming units (CFU-GM).
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has transient erythroblastopenia of childhood? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has TEC, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of TEC?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- Other clinical manifestations that might help with diagnosis and management
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can TEC be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment