Teaching Case 11

Clinical Summary

11-month-old male infant who presented with marked normochromic, normocytic anemia (Hb-9.5g/dL) and thrombocytosis (Plt-455K). A bone marrow biopsy was performed to rule out a congenital anemia or neoplastic process. The infant had no known history of immunosuppression.

Summary of Histologic Examination:

The bone marrow is normocellular for age and remarkable for a paucity of maturing erythroid cells. Abundant megakaryocytes are also appreciated, but in general show normal morphology. Occasional atypical pronormoblasts with prominent viral intranuclear inclusions are frequently identified. Many of the intranuclear inclusions are eosinophilic in nature and push the chromatin against the nuclear membrane.

H&E Images

Fig 1. Normocellular (for age) bone marrow	Fig 2. Normocellular bone marrow (low power)	Fig 3. Normocellular bone marrow with marked erythroid hypoplasia. Scattered pronormoblasts show intranuclear viral inclusions (arrows, medium power)
Fig 4. Pronormoblasts with prominent intranuclear viral inclusion (arrow) which are eosinophilic and compress the chromatin against the nuclear membrane. A single enlarged proerythroblast is also noted (highlighted by asterisks; high power)	Fig 5. Pronormoblasts with prominent intranuclear viral inclusion (arrow) which are eosinophilic and compress the chromatin against the nuclear membrane (high power)

Summary of Immunohistochemical Findings

Many of the pronormoblasts with prominent intranuclear viral inclusions show strong nuclear and cytoplasmic immunoreactivity with a monoclonal antibody to Parvovirus B19 capsid protein.

Fig 6. Bone marrow with scattered Parvovirus-positive erythroid precursors (low power)

Fig 7. Bone marrow with scattered Parvovirus-positive erythroid precursors (medium power)

Fig 8. Parvovirus-positive erythroid precursor showing both nuclear and cytoplasmic immunoreactivity (high power)

Final Diagnosis

Normocellular bone marrow with erythroid hypoplasia, secondary to Parvovirus B19 infection

Discussion

The patient's presentation (marked anemia) and bone marrow findings (marked erythroid hypoplasia, infrequent giant proerythroblasts, and frequent pronormoblasts often containing numerous intranuclear viral inclusions) raised the clinical suspicion of infection by Parvovirus B19. This suspicion was subsequently confirmed by immunohistochemistry studies, which highlighted scattered Parvovirus-positive erythroid precursors throughout the bone marrow. Although megakaryocytopenia has been described in patient's with Parvovirus B19 infection and may be related to viral infection of a common progenitor cell, the thrombocytosis seen in this patient is likely related to stimulation of megakaryocytes in response to cytokines released during an an ongoing Parvovirus infection.

Identification of parvovirus inclusions in marrow biopsies and subsequent confirmation of infection by immunohistochemistry can be important in the assessment of anemia in infants as well as immunosuppressed patients.1-5 Immunohistochemistry studies using the anti-Parvovirus B19 capsid monoclonal antibody, R92F6, have been found to be a useful, rapid, and sensitive method for confirming of Parvovirus B19 infection and show results comparable to that noted by polymerase chain reaction.1 Confirmatory immunohistochemistry is particularly useful in infants and immunosuppressed patients in which serologic studies can frequently be negative.^1-3

Parvovirus B19 is the causative agent for a spectrum of disease in humans including acute/chronic red cell aplasia as well as fifth disease (Parvoviral infection typically found in children with characteristic facial viral exanthem with "slapped cheek" appearance accompanied by lacy, reticular, maculopapular viral eruption over the trunk and proximal extremities). Parvovirus B19 is a highly contagious single stranded DNA virus, which has a particular tropism for erythroid precursors. Although most Parvovirus B19 infections in immunocompetent patients are typically self-limited (lasting only 2-3 weeks) and without clinical symptoms, patients with compromised immune systems often develop anemia as they are unable to mount a neutralizing anti-viral antibody response which is needed to clear the virus effectively. In addition, patients with underlying chronic hemolytic disorders (such as red blood cell membrane defects, sickle cell anemia, or thalassemias) can often develop transient aplastic crisis, due to acute Parvovirus B19 infection.

References

1. Vadlamudi G, Rezuke WN, Ross JW, Cartun RW, Ackroyd R, Knibbs DR, Tsongalis GJ. The use of monoclonal antibody R92F6 and polymerase chain reaction to confirm the presence of parvovirus B19 in bone marrow specimens of patients with acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1999 Sep;123(9):768-73.
2. Nagai K, Morohoshi T, Kudoh T, Yoto Y, Suzuki N, Matsunaga Y. Transient erythroblastopenia of childhood with megakaryocytopenia associated with human parvovirus B19 infection. Br J Haematol. 1992 Jan;80(1):131-2.
3. Crook TW, Rogers BB, McFarland RD, Kroft SH, Muretto P, Hernandez JA, Latimer MJ, McKenna RW. Unusual bone marrow manifestations of parvovirus B19 infection in immunocompromised patients. Hum Pathol. 2000 Feb;31(2):161-8.
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. Liu W, Ittmann M, Liu J, Schoentag R, Tierno P, Greco MA, Sidhu G, Nierodzik M, Wieczorek R. Human parvovirus B19 in bone marrows from adults with acquired immunodeficiency syndrome: a comparative study using in situ hybridization and immunohistochemistry. Hum Pathol. 1997 Jul;28(7):760-6.