Transient Erythroblastopenia of Childhood

The etiology of transient erythroblastopenia of childhood is unknown. However, researchers have proposed numerous viral and immunologic mechanisms. At least 2 separate case reports have noted pure red cell aplasia with concomitant human parvovirus B19 infection.[3, 4] However, a prospective case series of 10 patients failed to identify a single viral causative agent for transient erythroblastopenia of childhood.[5]

Human herpesvirus 6 (HHV-6) has been cited, albeit in only a few studies, as a source of transient erythroblastopenia of childhood. In vitro analysis has demonstrated suppression of erythroid-committed progenitor cells and multipotential hematopoietic colonies by the virus. In addition, Ogawa and Yanagisawa reported finding distinct erythroblast deformation, including the presence of pseudopodia and filamentous changes, in association with HHV-6–related transient erythroblastopenia of childhood.[6]

In vitro studies using serum and immunoglobulin G (IgG) from some patients with transient erythroblastopenia of childhood demonstrated erythroid colony suppression, suggesting an immunologic etiology. Transient erythroblastopenia of childhood is not caused by a lack of erythropoietin. Bone marrow from patients with transient erythroblastopenia of childhood exhibits an absence of red cell precursors.

A case report of half siblings with transient erythroblastopenia of childhood and the accompanying literature review suggests that predisposition to transient erythroblastopenia of childhood may be autosomal dominant in nature.[7]

Frequency

United States

Attempts to determine frequency of transient erythroblastopenia of childhood are limited by an unknown number of asymptomatic undiagnosed cases.

Mortality/Morbidity

Morbidity relates to the severity of the anemia and diagnostic workup. Children with transient erythroblastopenia of childhood have reportedly presented with high-output shock secondary to profound anemia.[8] Patients with atypical transient erythroblastopenia of childhood may require invasive tests such as bone marrow aspiration or biopsy. Association of transient neurologic deficits may lead the physician to pursue CNS imaging studies or a neurologic consultation.

A study by Schmidt et al of children under age 10 years indicated that a link may exist between breath-holding spells and TEC. The investigators found that nine out of 366 patients with anemia (2.5%) had breath-holding spells, including five out of the 41 anemia patients who specifically had TEC (12.2%). In comparison, there were 321 cases of breath-holding spells found in the total cohort of 443,470 children studied (0.07%). It was also reported that the breath-holding spells resolved in several of the patients treated for anemia.[9]

Sex

The male-to-female ratio is 1.4:1.

Age

The median age of presentation is 18-26 months; however, the disorder may occur in infants younger than 6 months and in children as old as 10 years. In contrast, Diamond-Blackfan anemia tends to present in child younger than 1 year, whereas human parvovirus B19–associated erythroblastopenia typically presents at an older age.

Most individuals with transient erythroblastopenia of childhood (TEC) present with gradually increasing pallor and no other symptoms despite the severity of the anemia. A case study by Mao et al supported the idea that transient erythroblastopenia of childhood can present very subtly, such as with conjunctival pallor alone.[10]

Occasionally, parents report increased fatigue or decreased energy levels in children with transient erythroblastopenia of childhood.

Some isolated incidents of transient neurologic events and breath-holding spells have been reported in association with transient erythroblastopenia of childhood.[11, 9]

Other differential considerations (eg, aplastic crises, hyperhemolytic crises, sequestrations) typically present more acutely than transient erythroblastopenia of childhood. Fatigue and pallor develop over the course of days and are often associated with nonspecific viral symptoms, such as fever, malaise, lethargy, abdominal pain, or upper respiratory symptoms. Jaundice may also be a presenting symptom, especially in the context of a preexisting hemoglobinopathy such as sickle cell disease or hereditary spherocytosis.

Family history may reveal siblings with a history of anemia.

Upon physical examination, patients are usually healthy except for findings commonly associated with anemia, such as skin and mucosal pallor, tachycardia, and, often, a cardiac flow murmur.[2] There is one isolated case report of TEC in association with ectopic atrial tachycardia.[12]

By contrast, the most common congenital anomalies associated with Diamond-Blackfan anemia include short stature, low birth weight, developmental delay, thumb malformations, craniofacial anomalies, and urogenital abnormalities. Examining for physical anomalies is important because they are found in as many as 70% of patients with Diamond-Blackfan anemia.

A complete neurologic examination is necessary because of case-report associations.

In patients with symptoms such as splenomegaly and icterus, consider other diagnoses such as a hemolytic-associated anemia or sequestration-associated anemia. A characteristic "slapped cheek" rash is often associated with parvovirus B19 infection and aplastic anemia.[13]

There is one isolated case report of transient erythroblastopenia of childhood in association with neonatal hepatitis.[14]

The cause of transient erythroblastopenia of childhood is unknown. Viral and immunologic mechanisms may be involved.

Reports of seasonal clusters of incidents of transient erythroblastopenia of childhood, although suggestive of a viral etiology, are not statistically significant.

Only a handful of familial transient erythroblastopenia of childhood cases have been reported, and no apparent genetic link has been elucidated.

The following studies are indicated in patients with suspected transient erythroblastopenia of childhood (TEC):

• Complete blood count (CBC)

  • CBC results demonstrate a normochromic normocytic anemia, with a red cell morphology within the reference range on the peripheral smear.

  • Mean corpuscular volume (MCV) is usually within the reference range; however, MCV may be elevated if the patient has begun to recover and has reticulocytosis.

• Hemoglobin studies

  • The hemoglobin level is usually 5-7 g/dL but may be as low as 2 g/dL.

  • Transient erythroblastopenia of childhood is frequently accompanied by clinically insignificant neutropenia that spontaneously resolves with the onset of reticulocytosis. Some series report the incidence of associated neutropenia to be as much as 64%.

  • In contrast, Diamond-Blackfan anemia is characterized by fetal-like hematopoiesis with an increased fetal hemoglobin, I antigen, and MCV.

• Viral studies: A search for a viral etiology, such as cytomegalovirus, Epstein-Barr virus, and parvoviral immunoglobulin (Ig)G and immunoglobulin M, may be useful.

• Reticulocyte count: Initial reticulocyte count is less than 0.1%, and a spontaneous increase heralds the recovery phase.

• Iron studies: Iron studies are not indicated unless microcytosis is present. Serum iron levels may be elevated because of underuse.

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• In individuals with suspected Diamond-Blackfan anemia, imaging studies may be helpful in revealing occult malformations; however, they are unnecessary for the diagnosis or treatment of transient erythroblastopenia of childhood.

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• Bone marrow aspiration

  • Consider bone marrow studies when clinical history, physical findings, or CBC is inconsistent with classic transient erythroblastopenia of childhood.

  • In patients with transient erythroblastopenia of childhood, findings include decreased or absent RBC precursors.

  • Evidence of marrow recovery precedes a rapid rise in hemoglobin levels; thus, bone marrow studies may help determine if a patient with transient erythroblastopenia of childhood who is severely anemic is likely to recover before requiring a blood transfusion.

  • In vitro studies have suggested that bone marrow cultures may have a future role in determining potential responsiveness of RBC aplasia to immunosuppressive therapy. In patients with classic presentations of transient erythroblastopenia of childhood, bone marrow cultures and immunosuppressive agents do not currently play a role.

• Enzyme levels: Red cell adenosine deaminase levels have been used to differentiate Diamond-Blackfan anemia from transient erythroblastopenia of childhood and other anemias. Enzyme levels are typically elevated in Diamond-Blackfan anemia, whereas levels found in persons with transient erythroblastopenia of childhood are normal or depressed.

Packed red cell transfusions are required in patients with severe transient erythroblastopenia of childhood (TEC) when signs of clinical decompensation are evident. Conditions in which transfusion may be necessary include hemodynamic instability, exercise intolerance, and altered mental status.

Refractory incidents of transient erythroblastopenia of childhood may be associated with a failure to thrive and also may require packed red cell transfusion.

Perform nonemergent transfusions in consultation with a pediatric hematologist.

Consultation with a pediatric hematologist is recommended in nonclassic presentations of transient erythroblastopenia of childhood or if the patient with transient erythroblastopenia of childhood has severe anemia that requires transfusion.

No special dietary requirements are necessary.

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• Treatment with corticosteroids and erythropoietin is unnecessary. Difficulty in distinguishing Diamond-Blackfan anemia (a corticosteroid-responsive condition) from transient erythroblastopenia of childhood (TEC) has led to corticosteroid treatment and subsequent resolution in some individuals with transient erythroblastopenia of childhood.

• Whether these isolated reports are true incidents of corticosteroid-responsive transient erythroblastopenia of childhood or whether the anemia can resolve independently of corticosteroid treatment is unclear.

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• Until resolution of anemia, advise patients with transient erythroblastopenia of childhood (TEC) to undergo regular follow-up care with CBC count.

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• All patients with transient erythroblastopenia of childhood completely recover, usually within 1-2 months. Occasionally, spontaneous recovery may occur as long as 12 months after onset.