Acute lymphocytic leukemia after fulminant varicella associated with severe neutropenia.

ABSTRACT

Acute lymphocytic leukemia developed within 3 weeks after a fulminant case of varicella complicated by pneumococcal sepsis and severe bone marrow suppression in a child treated with filgrastim (human granulocyte colony-stimulating factor).

VARICELLA is a common, usually benign, contagious childhood disease with relatively few side effects. Koumbourlis (1) described a 10-year-old child with severe varicella complicated by liver and central nervous system dysfunction. The child recovered completely without any sequelae. Our report details an unusual presentation of varicella with pancytopenia, pneumonia, and pneumococcal sepsis. The patient was treated with intravenous antibiotics, acyclovir, and appropriate doses of human granulocyte colony-stimulating factor (G-CSF). She responded well, with an increase in white blood cell (WBC) count and absolute neutrophil count (ANC) and resolution of infection. Three weeks later, she was readmitted with marked leukocytosis and was found to have acute lymphocytic leukemia.

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CASE REPORT

An 18-month-old white girl was transferred to the intensive care unit at Children's Hospital of New Orleans for treatment of disseminated varicella, pancytopenia, and respiratory distress. Physical examination showed an acutely ill infant with respiratory distress, high fever, hepatosplenomegaly, and oral candidiasis. She had no generalized lymphadenopathy. Laboratory values were hemoglobin 8 g/dL, hematocrit 23.6%, WBC 1,300/[mm.sup.3] with a differential of 7% segmented neutrophils, 3% band forms, 74% lymphocytes, 5% monocytes, 1% metamyelocytes for an ANC of 192, and platelet count 2,300/[mm.sup.3]. Chest x-ray film showed patchy infiltrates in the right upper lobe and left lower lobe. Liver function test values were alanine aminotransferase 126 U/L (normal, 7 to 56 U/L) and lactate dehydrogenase 5,020 U/L (normal, 297 to 737 U/L). Varicella titers were 1:6 by ELISA, and human immunodeficiency virus P24 antigen test was negative. Blood culture was positive for Streptococcus pneumoniae. She was treated with intravenous broad spectrum antibiotics, antifungal agents, and acyclovir. She also received fresh frozen plasma, packed red blood cells, and platelets as needed. Bone marrow aspirate and biopsy showed no morphologic evidence of leukemia but showed hypoplastic marrow with decrease in all cell lines (Table 1). Treatment was started with filgrastim (G-CSF) (Neupogen, Amgen Ltd), with excellent increase in WBC and ANC. At discharge, hematologic values were hemoglobin 12.5 g/dL, hematocrit 37.3%, WBC 4,700/[mm.sup.3], polymorphonuclear cells 49, 8% band forms, 34% lymphocytes, and 9% monocytes for an ANC of 2,679 and platelet count of 78,000/[mm.sup.3]. The patient was readmitted 2 weeks later when she was found to have marked lymphadenopathy, hepatosplenomegaly, and a WBC of 91,300/[mm.sup.3]. Bone marrow aspirate was diagnostic of early ALL, pre-B-cell type, CALLA-positive (Table 2). She was treated with the high-risk ALL protocol as advocated by our pediatric oncology group, completed chemotherapy, and has bee n in continuous remission for 3 years.

DISCUSSION

Neutropenia associated with viral infection is known to occur during the first 2 days of the illness. Viral-induced leukocyte damage leading to increased utilization and sequestration or direct bone marrow suppression may be factors leading to neutropenia. (2) Varicella infection is usually associated with mild leukocytosis and predominance of polyrnorphonuclear cells. (3) A case of varicella associated with leukopenia, neutropenia, and seizures that resolved without sequelae has been reported. (1)

Ours is the first reported case of ALL diagnosed immediately after an episode of varicella infection associated with severe pancytopenia. The severity of varicella and associated bacteremia may have been due to immune compromise related to a preleukemic state. The bone marrow aspirate and biopsy done during the varicella infection did not show morphologic evidence of ALL, and the cytogenetic analysis was also normal (Table 3). The significance of increased CD 10 cells in the absence of morphologic or chromosomal abnormalities is unclear. Increased CALLA-positive (CDIO) cells have been seen in viral infections and reactive bone marrow. (4,5) Results of bone marrow studies 3 weeks later were morphologically, immunophenotypically, and cytogenetically consistent with B-cell lineage ALL. Preleukemic hypoplastic state of the marrow may have aggravated the neutropenia that can occur with severe viral exanthema. Use of fligrastim (Neupogen) has not been associated with development or progression of ALL, and its role in the hyperleukocytosis in this case is unknown.

TABLE 1.

Results of Bone Marrow Studies

                  Initial Admission               3 Weeks Later
                    With Varicella                   With ALL

Cellularity     Decreased                    100% increased
Morphology      Decreased in all cell lines  Total replacement by
                                               ALL-L, blasts
Blast count     0%                           82%
Megakaryocytes  Decreased                    Absent

ALL = Acute lumphocytic leukemia.
TABLE 2.

Immunophenotyping Flow Cytometry

                                                       Bone Marrow
                             Initial Bone              Aspirate at
                           Marrow Aspirate           Diagnosis of ALL

Viability            99 (85%-100%) *                     96
Bone marrow          CD45 96[up arrow] (54-60) *         96[up arrow]
                     CD2 32[up arrow] (4-22) *           4
                     CD3 32[up arrow] (4-15) *           3
                     CD5 33[up arrow] (2-20) *           4
                     CD7 33[up arrow]                    4
Bone marrow          CD19 61[up arrow] (0-25) *          86[up arrow]
  B Cells            CD20 10 (0-12) *                    13[up arrow]
Bone marrow          CD13 <1 (18-99) *                   1
  monocytic/
  myelocytic cells
Lymphocytes          CD33 <1 (11-39) *                   <1
                     CD14 <1 (1-11) *                    <1
Miscellaneous cell.  CD10 58[up arrow] (7-19) *          95[up arrow]
  markers            HLA-DR 68 (lymphocytes)             95
Impression           No evidence of                      Compatible
                     monoclonality or                    with CALLA-
                     leukemia. [up arrow] in CALLA-      positive B-cell
                     positive B-cells could              ALL
                     be due to viral infection
                     or reactive bone marrow

ALL=Acute lymphocytic leukemia.

* Normal.
TABLE 3.

Cytogenetic Studies

             At Diagnosis           At Diagnosis
             of Varicella             of ALL

Chromosomes  46 xx         Numerous anomalies, balanced
             No abnormal   5:19 translocation, unbalanced
             karyotypes    7:9t. Rearrangement involving
                           short arm of 9. 9t (7,9)
                           (q11,p13)--found in 10% of
                           B precursor ALL

ALL = Acute lymphocytic leukemia.

References

(1.) Koumbourlis AC: Varicella infection with profound neutropenia, multisystemic involvement and no sequelae. J Pediatr Infect Dis 1988; 7:429-430

(2.) Curnulte JT, Boxer LA: Disorders of granulocytosis and granulocyte function. Hematol Infancy Childhood 1987; 3:797842

(3.) Feigin RD, Chemy JD: Varicella-Zoster infection. textbook of Pediatric Infectious Disease. Philadelphia, WB Saunders Go, 1987, pp 1602-1607

(4.) Caldwell CW, Poje E, Helikson M: B-cell precursors in normal pediatric bone marrow. Am J Clin Pathol 1991; 95:816823

(5.) Kobyashi SD, Seki K, Suwa N, et al: The transient appearance of small blastoid cells in the marrow after bone marrow transplantation. Am J Clin Pathol 1991; 96:191-195

Reprint requests to R. P. Warrier, MD, Children's Hospital, Department of Pediatric Hematology/Oncology, 200 Henry Clay Aye, Suite 408 ACC, New Orleans, LA 70118.

RELATED ARTICLE: KEY POINTS

* Varicella can be fulminant and lead to pancytopenia and secondary sepsis.

* Acute lymphocytic leukemia developed within 3 weeks after diagnosis of varicella.

* Immunologic and chromosomal studies are essential in all cases of leukemia and highlighted the leukemic changes in the bone marrow.

From the Departments of Pediatrics and Pediatric Hematology/Oncology, Children's Hospital of New Orleans, and Louisiana State University Health Sciences Center, New Orleans.