Final Diagnosis -- Anemia, neutropenia, and lymphopenia

FINAL DIAGNOSIS:

• Peripheral blood:
  Anemia, neutropenia, and lymphopenia
• Bone marrow biopsy and aspirate:
  Marked erythroblastopenia associated with parvovirus infection

The bone marrow also demonstrated dyspoietic changes in the granulocytic and megakaryocytic lineages. These changes could be related to cyclosporin therapy or an underlying myelodysplastic process but could not be accurately assessed during active parvovirus infection.

Note: The term pure red cell aplasia (PRCA) is used to describe severe anemia associated with absence of reticulocytes, absence or near absence of bone marrow erythroid precursors, and presence of normal numbers of granulocytic and megakaryocytic elements that are morphologically normal. In this case, the more inclusive term erythroblastopenia was used to describe the dyserythropoiesis; the dysplastic changes seen in the granulocytic and megakaryocytic lineages, which are most likely unrelated to parvovirus infection, do not fit the more specific diagnosis of pure red cell aplasia.

DISCUSSION:

Pure red cell aplasia (PRCA) is a condition of severe anemia associated with absence of reticulocytes and virtual absence of erythroid precursors in the bone marrow. The other hematopoietic lineages seem morphologically normal and are present in normal numbers. The disease can be either acquired or congenital; the congenital form is associated with other anomalies and is called Diamond-Blackfan syndrome.

Multiple causes of acquired PRCA have been described.

 

Causes of Acquired Pure Red Cell Aplasia
Drugs      Azathioprine      Chloramphenicol      Isoniazid      Phenytoin      Zidovudine      Recombinant erythropoietin   Idiopathic   Infection          HHV-6      HIV      Parvovirus B19      Viral hepatitis	Immune Disorders      Systemic lupus erythematosus      Rheumatoid arthritis      Sjogren’s syndrome   Malignancies      Chronic lymphocytic leukemia      LGL leukemia      Hodgkin lymphoma      Non-Hodgkin lymphoma      Prodrome to myelodysplastic syndrome      Lung cancer      Thymoma

In PRCA, suppression of normal erythroid maturation has been demonstrated to occur at a point between progression of the Colony Forming Unit erythroid (CFUe) cell to the pronormoblast stage. Several mechanisms have been described, including neutralizing immunoglobulins (described with recombinant erythropoietin administration), suppression mediated by T-lymphocytes (described with thymoma), and direct toxicity (described with phenytoin and chloramphenicol). Direct attack and toxicity is also the mechanism of PRCA associated with parvovirus B19 infection.

Human parvovirus B19 is a small, non-enveloped, single-stranded DNA virus belonging to the Parvoviridae family. It was discovered in 1975 while screening units of blood from asymptomatic donors for hepatitis B virus. It is mainly transmitted by respiratory secretion and, rarely, by blood products. B19 selectively infects and replicates within erythroid precursor cells; the blood group P antigen system serves as the receptor by which the virus enters the pronormoblast. Rare individuals whose erythrocytes lack P antigens (p phenotype) are inherently resistant to parvovirus B19 infection.

Neither cytotoxic immunoglobulins nor evidence of T-lymphocyte-mediated suppression have been described with parvovirus-associated PRCA. Severe anemia is most likely to occur in immunocompromised individuals or patients with an underlying hemolytic disease, such as sickle cell disease, hereditary spherocytosis, thalassemia, or deficiencies of glucose-6-phosphate dehydrogenase or pyruvate kinase.

PRCA associated with parvovirus B19 infection often produces giant pronormoblasts in the marrow, which is a characteristic morphologic finding useful for diagnosis. It is thought that these giant pronormoblasts represent very early regenerating erythroid precursors that appear after clearance of the virus. Positive immunohistochemical staining for parvovirus in an affected erythroid precursor, or virocyte, is represented by a nuclear inclusion surrounded by a dense ring of chromatin. In non-immunocompromised patients, stainable virocytes are present only very briefly in the early phase of the infection and are rapidly cleared.

REFERENCES

1. Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol. 2000 Dec; 111(4): 1010-22.
2. Erslev AJ, Soltan A. Pure red-cell aplasia: a review. Blood Rev. 1996 Mar; 10 (1):20-8.
3. Ahsan N, Holman MJ, Gocke CD, Groff JA, Yang HC. Pure red cell aplasia due to parvovirus B19 infection in solid organ transplantation. Clin Transplant. 1997 Aug; 11(4):265-70.
4. Geetha D, Zachary JB, Baldado HM, Kronz JD, Kraus ES. Pure red cell aplasia caused by Parvovirus B19 infection in solid organ transplant recipients: a case report and review of literature. Clin Transplant. 2000 Dec; 14(6):586-91.
5. Dessypris EN. The biology of pure red cell aplasia. Semin Hematol. 1991 Oct; 28(4):275-84.
6. Thompson DF, Gales MA. Drug-induced pure red cell aplasia. Pharmacotherapy. 1996 Nov-Dec; 16(6):1002-8.
7. Penchansky L, Jordan JA. Transient erythroblastopenia of childhood associated with human herpesvirus type 6, variant B. Am J Clin Pathol. 1997 Aug; 108(2):127-32.
8. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002 Feb 14; 346(7):469-75.
9. Brown KE, Hibbs JR, Gallinella G, Anderson SM, Lehman ED, McCarthy P, YoungNS. Resistance to parvovirus B19 infection due to lack of virus receptor (erythrocyte P antigen). N Engl J Med. 1994 Apr 28;330(17):1192-6.
10. Charles RJ, Sabo KM, Kidd PG, Abkowitz JL. The pathophysiology of pure red cell aplasia: implications for therapy. Blood. 1996 Jun 1; 87(11):4831-8.

Contributed by J Manuel Zarandona, MD, and Sandra S Kaplan, MD