Acute myeloid leukemia precipitated by dengue virus infection in a patient with hemoglobin H disease.
Wing Y. Au, Edmond S.K. Ma*,
Yok-Lam Kwong.
Departments of Medicine and Pathology*, University of Hong Kong,
Queen Mary Hospital, Hong Kong
Correspondence to Dr Au, Professorial Block, Queen Mary Hospital,
Pokfulam Road, Hong Kong. Tel +852.28554792. Fax +852. 29741165.
Email: auwing@hotmail.com
Abstract
We report a unique case of refractory acute myeloid leukemia (AML) precipitated by dengue virus induced marrow aplasia in a Chinese patient with hemoglobin (Hb) H disease. The quick temporal sequence of the three marrow abnormalities: hereditary hemoglobinopathy, reactive viral induced marrow change and malignant neoplastic process is highly unusual. Neither HbH disease nor viral induced marrow aplasia has known associations with AML. We propose that this unique case of AML may be caused by cytokine hyperstimulation in a stressed marrow.
Introduction
The underlying causes for most cases of acute myeloid leukemia (AML) remained unknown. Documented associations including radiation exposure(1), chemotherapy (1, 2), solvent and pesticide exposure(3), smoking(4), and underlying genetic disorders e.g. Down's syndrome(5), Fanconi's anemia(6). There have been several reports of AML following marrow aplasia or severe aplastic anemia, especially after paroxysmal nocturnal hemoglobinuria (PNH)(7). It is not known, however, whether previous case reports represents a myelodysplastic or a pure hypoplastic process(8, 9). Epidemiological evidence suggested seasonal and socio-economic variations, which have not been verified in detail(10-12). Preliminary data does not suggest any racial or geographical predisposition, except may be for acute promyelocytic leukemia in Hispanics(13). There is no proven link between AML and human viral infection or hemoglobinopathy. We present a unique case of AML in a patient with hemoglobin (Hb) H disease occurring immediately after dengue virus induced marrow hypoplasia.
Case report and results
A 35-year-old Southern Chinese man has family history of alpha-thalassaemia. He was asymptomatic all along, but an older brother has splenectomy performed for splenomegaly due to HbH disease. His baseline complete blood picture (CBP) showed: Hb 10.1g/dl, mean corpuscular volume (MCV): 70.2fl, white cell count (WCC): 3.7x109/l and platelet count (Plt): 108x109/l. Physical examination showed a palpable spleen 4 cm below costal margin. A Hb electrophoresis showed 42.9% HbH with numerous HbH granules seen on methylene blue staining. Molecular investigation on the family confirmed an SEA deletion a codon 30 mutation, reported in HbH non-hydrops (14, 15). Splenectomy was performed which showed simple congestion on histology examination. Post-operatively, there was no change in the CBP. Four months later, he contracted febrile illness after mosquito exposure on a trip to Indonesia. This was accompanied by fall in Hb and WCC, with a nadir level of Hb: 8.1g/dl, reticulocytes:0.2%, WCC: 1.1x109/l (37% neutrophils, 58% lymphocytes) and Plt: 83x109/l. Serum investigation showed an 8 fold increase in specific antiviral titre (ELISA test) against dengue virus serotype 2, which was confirmed by haemagglutinin inhibition (HAI) testing. He was treated for marrow aplasia secondary to dengue virus infection, with antibiotics, intravenous immunglobulins and transfusion support. Marrow examination was refused and the fever subsided. Two months later, there was still persistent pancytopenia, with a CBP of Hb 6.1g/dl, WCC 6.1x109/l (12% neutrophils) and Plt 90x109/l. A marrow examination showed extreme erythroid hyperplasia, with an increase in blast cells in the background non-erythroid component, and dysplastic micro-megakaryocytes (Figure 1A, B, C). Subsequently, a peripheral blood film showed circulating blast cells, and marrow examination confirmed the development of AML (M2) (Figure 1D). The blast cells were cytochemically positive for myeloperoxidase and Sudan Black B and showed CD13, CD33, MPO as well as CD7 expression by flow cytometry. Platelet markers and glycophorin A were negative. Cytogenetic investigation yielded only normal metaphases. The disease persisted after two courses of induction therapy (daunorubicin 50mg/m2x3, cytosine arabinoside (AraC) 100 mg/m2x7 and idarubicin 8 mg/m2x5, AraC 500 mg/m2x5, etoposide150 mg/m2x3), and remained refractory to conventional treatment. Allogeneic bone marrow transplantation (BMT) was performed in refractory disease with an HLA matched brother, also with HbH disease, as donor, but the patient died of severe graft versus host disease eight weeks after engraftment.
Discussion
Our patient followed a highly unusual clinical course, with three hematological diseases, hereditary, infective and neoplastic, occurring in quick succession. Although acquired HbH disease is known to be associated with AML(16), the family history and the molecular findings showed that the patient has a long-standing hemoglobinopathy. This results in a stressed marrow, prone to marrow aplasia (17). Splenectomy per se has been reported cause an increased incidence of AML(18), but this has not been verified by epidemiology (19). Dengue fever is very rare in Hong Kong, and most cases are imported. It is however, a common disease in South East Asia (20). The dengue virus is an RNA virus, which infects endothelial cells as well as primitive hematopoieitic progenitor cells in vitro and in vivo. Dengue virus predominant infects the reticulo-endothelial cells of the marrow (20), resulting in a cytokine storm, especially of interleukin (IL) 8(21). This causes transient marrow aplasia, hence protecting precursor haematopoietic cells from infection. The clinical course is self-limiting. Although Dengue virus can infect human myeloblasts in vitro(22), unlike retro-viruses or DNA viruses, it does not integrate into human genome or causes in vivo transformation. It is however, apparent that AML in our patient was triggered by dengue virus infection. The marrow aplasia produced by dengue virus may provide a growth advantage for the malignant clone, similar to reported cases of acute leukemia after parvovirus B19 infection (23) or aplastic anemia (24, 25). Indeed, clonal hemopoietic recovery is a recognized event after various forms of marrow aplasia (7, 26, 27). Alternatively, the IL-8 cytokine storm in the marrow may provide the stimulatory signal, similar to G-CSF induced leukemia in hypoplastic marrows (28). Autocrine, IL-8 dependent AML cell lines have been described (29). It is also unclear how much the underlying stressed marrow of HbH disease contributed to the dengue induced marrow aplasia, or subsequent AML. There has not been any reported association between dengue infection, thalassemia or AML, apart from scattered case reports(30, 31). Since several animal models of dengue virus infection have recently been created, it would be interesting to observe whether a similar pathogenetic effect can be implied in the laboratory setting.
Acknowledgements
The authors would like to thank Dr Derek Wong of the virus unit of the Department of Health for details on the virology diagnostic tests.
