YEXMP-03613; No of Pages 3 Experimental and Molecular Pathology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Experimental and Molecular Pathology
1
Dengue fever and bone marrow myelofibrosis☆
2Q1
Xin Qing a,⁎, Nora Sun a, James Yeh b, Changjun Yue a, Junchao Cai c
3 4 5
a
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a r t i c l e
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Article history: Received 6 July 2014 Accepted 9 July 2014 Available online xxxx
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Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition. © 2014 Published by Elsevier Inc.
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Department of Pathology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA Department of Internal Medicine, Division of Hematology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA Terasaki Foundation Laboratory, 11570 W Olympic Blvd, Los Angeles, CA 90064, USA
Keywords: Myelofibrosis Dengue fever Bone marrow
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1. Introduction
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Dengue fever is a rapidly spreading mosquito-borne viral disease with a worldwide incidence of 50 to 100 million cases annually. Symptoms include fever, headache, myalgias, arthralgias, and a characteristic rash. Thrombocytopenia is a constant manifestation of dengue fever, which may evolve into life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Myelofibrosis is an uncommon entity characterized by increased reticulin and/or collagen fibers in the bone marrow. Marrow fibrosis (myelofibrosis) may occur as primary disorder or secondary to other clinical conditions. It may also be classified as associated with neoplastic or non-neoplastic disorders. Primary myelofibrosis is a form of myeloproliferative neoplasms, whereas progression to myelofibrosis happens in about 10% of polycythemia vera and less than 1–2% of essential thrombocythemia patients over 10 years (Campbell and Green, 2011). Secondary myelofibrosis may be seen in a variety of diseases including leukemias, lymphomas, multiple myeloma, metastatic carcinoma, endocrine disorders, autoimmune diseases, radiation, and toxins. We describe a 52-year-old male who had bone marrow fibrosis associated with dengue virus infection. To our knowledge, this is the first reported case of dengue virus as an etiologic agent of myelofibrosis.
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2. Case report
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A previously healthy 52-year-old man was admitted to our hospital for anemia, thrombocytopenia, bilateral lower extremity rash and
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journal homepage: www.elsevier.com/locate/yexmp
☆ Financial support: N/A. ⁎ Corresponding author. E-mail address: [email protected] (X. Qing).
hematuria. He had traveled to Vietnam two months prior to admission to visit his family and developed fever, bilateral hemorrhagic bullae in his mouth and under his tongue less than one month following his trip. He recalled having mosquito bites while in Vietnam. He was evaluated in Vietnam for fevers and liver failure and was diagnosed with dengue fever. He received platelet transfusion support. Although his fever and hemorrhagic bullae were resolved, he had persistent thrombocytopenia, hematuria, jaundice and bilateral lower extremity rash, and was advised to go to the United States to have further workup. Physical examination was notable for gum bleeding and bilateral lower extremity petechial rash that extended to his trunk and back. Computed tomography scans of the chest, abdomen and pelvis revealed bilateral pleural effusions, ascites, extensive lymphadenopathy with the largest lymph node measuring 11 to 12 mm in maximum short axis diameter, kidney cysts and non-obstructive kidney stones, and irregularly thickened bladder. Hepatosplenomegaly was absent on imaging. The laboratory studies on admission included a white blood cell count of 9.4 K/mm3 (80% neutrophils, 14% lymphocytes, 4% monocytes and 2% eosinophils), a hemoglobin concentration of 8.1 g/dL, a hematocrit of 25.3%, a platelet count of 7 K/mm3, a D-dimer of 2655 ng/mL, an FDP of 337 μg/mL, and normal liver function tests. Urinalysis showed 3 + protein, 2 + blood, 115 white blood cells per high power field, and greater than 182 red blood cells per high power field. Tests for serum dengue fever antibodies performed at Focus Diagnostics (Cypress, CA) demonstrated elevated IgG (2.47, reference range: b 0.90) and normal IgM (0.83, reference range: b0.90). The patient was managed with packed RBC and platelet transfusion and prednisone at 1 mg/kg (60 mg daily) without any significant increase in platelets. The peripheral blood smear showed moderate anisopoikilocytosis with moderate hypochromia, some tear-drop cells and schistocytes (Fig. 1A). Rare circulating nucleated red
http://dx.doi.org/10.1016/j.yexmp.2014.07.004 0014-4800/© 2014 Published by Elsevier Inc.
Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
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X. Qing et al. / Experimental and Molecular Pathology xxx (2014) xxx–xxx
DENV-3, and DENV-4. The viruses are transmitted primarily to human through the bite of an infected Aedes species mosquito. The spectrum of illnesses can range from a mild, non-specific febrile syndrome to classic dengue fever (DF), to the severe forms of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The vast majority DHF/DSS occurs as the result of a secondary infection with a different serotype of the virus. Dengue infection is common in people living in tropical and subtropical countries. Several outbreaks happen in different countries in Southeast Asia, Latin America, even in Australia, Cuba, Puerto Rico and Hawaii (Gregory et al., 2010; Halstead, 2007; Jessie et al., 2004; Leong et al., 2007; Martina et al., 2009). With economic growth and globalization, dengue is the most frequent arbovirus infection with more than 100 million cases annually throughout the world nowadays (Leong et al., 2007). Clinical manifestations are protean, depending on the age of the patients, the stage of the illness, the genotypes and virulences of the virus, the geographic location of the occurrence, and the host responses. There is no vaccine available, and the current treatment is supportive care. Diagnosis is based on virus isolation, serologic tests for antibodies against dengue virus, especially sero-conversion, molecular tests for viral antigens, and histopathologic examination of diseased tissue with immunohistochemistry and in situ hybridization in addition to clinical suspicions of the disease (Chaterji et al., 2011; Gregory et al., 2010; Halstead, 2007; Jessie et al., 2004; Martina et al., 2009). Recently, a NS1 rapid test became also available (Chaterji et al., 2011). Although the 1997 and 2009 World Health Organization (WHO) Dengue Case Classification criteria are helpful for its diagnosis and management, it appears that refinement for case definition will be needed (Gregory et al., 2010; Hadinegoro, 2012). Gregory and colleagues suggested that the following clinical symptoms and signs were predictive of laboratory positive dengue infections: (1) for patients age 1–9 years, retro-orbital pain, low platelet count, and absence of cough; (2) in the 10–19 year age group, retro-orbital pain, rash, and absence of cough; and (3) for patients ≥ 20 years of age, retro-orbital pain, rash, absence of sore throat, and leukopenia. Further expanded studies may validate or dispute the above statement (Gregory et al., 2010). Hematologic abnormalities are common in patients with symptomatic DF, DHF, and DSS. The most common finding is thrombocytopenia; others include increased hematocrit (due to plasma leakage), leukopenia, varying degrees of hemorrhage, coagulopathy or even disseminated intravascular coagulation (Lin et al., 1989; Srichaikul and Nimmannitya, 2000). Unusual clinical presentations, such as hemophagocytosis/ hemophagocytic syndrome (Jain and Singh, 2008; Ray et al., 2011), severe aplastic anemia (Ramzan et al., 2012), and severe plasmacytosis mimicking plasma cell leukemia (Gawoski and Ooi, 2003) have been reported. However, myelofibrosis associated with dengue infection, as seen in our patient, has not been recorded in the literature (Gawoski and Ooi, 2003; Jain and Singh, 2008; Lin et al., 1989; Ramzan et al., 2012; Ray et al., 2011; Srichaikul and Nimmannitya, 2000). Marrow fibrosis (myelofibrosis) may be observed in a variety of clinical conditions (Table 1) (Campbell and Green, 2011; Faucar, 2010; Lorsbach, 2011). Myelofibrosis occurs more frequently with myeloid malignancies. Myelofibrosis secondary to infectious diseases is likely transient which often reverts to normal after infectious diseases have been treated, such as in our patient. Dengue virus has been detected in cells in the skin, liver, spleen, lymph node, kidney, bone marrow, endothelial cells, lung, thymus, brain and heart (De Araujo et al., 2009; Jessie et al., 2004; Martina et al., 2009). Bone marrow stromal cells and bone marrow progenitors have been shown to be susceptible to infection with dengue virus (Kyle et al., 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011; Nakao et al., 1989; Rothwell et al., 1996). It is believed that a high viral load and activation of a large number of T-cells and monocytes/macrophages result in a “storm” of inflammatory cytokines and other mediators (Gregory et al., 2010; Halstead, 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011). Cytokines and soluble factors, such as IL1β, IL-2, IL4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-18, TGF-1β,
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Dengue is caused by any of the four closely related single-stranded RNA viruses, dengue virus (DENV), serotypes called DENV-1, DENV-2,
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blood cells and plasma cells were noted. However, no immature myeloid cells were found. A bone marrow examination was performed on hospital day 4 which yielded a “dry tap” on aspiration. The trephine biopsy showed a hypercellular bone marrow with mucinous degeneration of fat cells and deposition of eosinophilic amorphous material (“damaged marrow”), erythroid and megakaryocytic hyperplasia (Figs. 1B and 2A) as well as moderate reticulin fibrosis (MF 2/3, WHO 2008 semiquantitative grading of bone marrow fibrosis) (Fig. 2B) (Thiele et al., 2008). There was no evidence of myelodysplastic changes, lymphoid aggregates, leukemia, lymphoma or metastatic carcinoma. The patient was discharged on hospital day 7 with prednisone 20 mg daily. Three days after discharge, his dose of prednisone was increased to 1 mg/kg due to continued thrombocytopenia (8 K/mm3, two days after discharge). A cystoscopy was performed approximately 1 week after discharge which showed recent stromal hemorrhage; concurrent bladder biopsy was negative for tumor. Three weeks after discharge, his anemia and thrombocytopenia began to recover, and a CBC two months following discharge showed resolution of anemia and thrombocytopenia.
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Fig. 1. A. Peripheral blood smear reveals moderate anisopoikilocytosis with some teardrop cells (arrow) and schistocytes. Romanowsky stain. B. A lower magnification of trephine biopsy displays hypercellular bone marrow. Periodic acid Schiff stain.
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Fig. 2. A. A higher magnification of trephine biopsy shows megakaryocytic and erythroid hyperplasia. Periodic acid Schiff stain. B. Reticulin stain shows moderate reticulin fibrosis (MF 2/3 according to WHO 2008 semiquantitative grading of bone marrow fibrosis).
Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
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Disclosure
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The authors have no disclosures.
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Campbell, P.J., Green, A.R., 2011. Myeloproliferative neoplasms, In: Hoffbrand, A.V., Catovsky, D., Tuddenham, E.G.D., Green, A.R. (Eds.), Postgraduate Haematology, 6th ed.Wiley-Blackwell, Oxford, UK, pp. 686–706. Chaterji, S., Allen Jr., J.C., Chow, A., Leo, Y.S., Ooi, E.E., 2011. Evaluation of the NS1 rapid test and the WHO Dengue Classification schemes for use as bedside diagnosis of acute dengue fever in adults. Am. J. Trop. Med. Hyg. 84 (2), 224–228. De Araujo, J.M., Schatzmayr, H.G., de Filippis, A.M., et al., 2009. A retrospective survey of dengue virus infection in fatal cases from an epidemic in Brazil. J. Virol. Methods 155 (1), 34–38. Faucar, K., 2010. Bone marrow stroma and bone disorders, In: Foucar, K., Reichard, K., Czuchlewski, D. (Eds.), Bone Marrow Pathology, 3rd editionASCP Press, Chicago, IL, pp. 653–685. Gawoski, J.M., Ooi, W.W., 2003. Dengue fever mimicking plasma cell leukemia. Arch. Pathol. Lab. Med. 127 (8), 1026–1027. Gregory, C.J., Santiago, L.M., Arguello, D.F., Hunsperger, E., Tomashek, K.M., 2010. Clinical and laboratory features that differentiate dengue from other febrile illnesses in an endemic area—Puerto Rico, 2007–2008. Am. J. Trop. Med. Hyg. 82 (5), 922–929. Hadinegoro, S.R.S., 2012. The revised WHO dengue case classification: does the system need to be modified? Paediatr. Int. Child Health 32 (Suppl. 1), 33–38. Halstead, S.B., 2007. Dengue. Lancet 370 (9599), 1644–1652. Jain, D., Singh, T., 2008. Dengue virus related hemophagocytosis: a rare case report. Hematology 13 (5), 286–288. Jessie, K., Fong, M.Y., Devi, S., Lam, S.K., Wong, K.T., 2004. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J. Infect. Dis. 189 (8), 1411–1418. Kyle, J.L., Beatty, R., Harris, E., 2007. Dengue virus infects macrophages and dendritic cells in a mouse model of infection. J. Infect. Dis. 195 (12), 1808–1817. Leong, A.S., Wong, K.T., Leong, T.Y., Tan, P.H., Wannakrairot, P., 2007. The pathology of dengue hemorrhagic fever. Semin. Diagn. Pathol. 24 (4), 227–236. Lin, S.F., Liu, H.W., Chang, C.S., Yen, J.H., Chen, T.P., 1989. Hematological aspects of dengue fever. Gaoxiong Yi Xue Ke Xue Za Zhi 5 (1), 12–16. Lorsbach, R.B., 2011. Myeloproliferative neoplasms. In: Proytcheva, M.A. (Ed.), Diagnostic Pediatric Hematopathology. Cambridge University Press, Cambridge, UK, pp. 217–244. Martina, B.E.E., Koraka, P., Osterhaus, A.D.M.E., 2009. Dengue virus pathogenesis: an integrated view. Clin. Microbiol. Rev. 22 (4), 564–581. Mota, J., Rico-Hesse, R., 2011. Dengue virus tropism in humanized mice recapitulates human dengue fever. PLoS One 6 (6), e20762 (1–10). Nakao, S., Lai, C.J., Young, N.S., 1989. Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines. Blood 74 (4), 1235–1240. Ramzan, M., Prakashyadav, S., Sachdeva, A., 2012. Post-dengue fever severe aplastic anemia: a rare association. Hematol. Oncol. Stem Cell Ther. 5 (2), 122–124. Ray, S1., Kundu, S., Saha, M., Chakrabarti, P., 2011. Hemophagocytic syndrome in classic dengue fever. J. Glob. Infect. Dis. 3 (4), 399–401. Rothwell, S.W., Putnak, R., La Russa, V.R., 1996. Dengue-2 virus infection of human bone marrow characterization of dengue-2 antigen-positive stromal cells. Am. J. Trop. Med. Hyg. 54 (5), 503–510. Srichaikul, T., Nimmannitya, S., 2000. Haematology in dengue and dengue haemorrhagic fever. Baillieres Best Pract. Res. Clin. Haematol. 13 (2), 261–276. Thiele, J., Kvasnicka, H.M., Tefferi, A., et al., 2008. Primary myelofibrosis. In: Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Vardiman, J.W. (Eds.), WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon, France, pp. 44–47.
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TNF-α, and IFN-γ lead to necrosis and apoptosis of cells and tissues, dysfunction of endothelial cells, increased plasma leakage, suppression of hematopoiesis, and development of coagulation disorders (Gregory et al., 2010; Halstead, 2007; Leong et al., 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011). All of these may contribute to the hematologic abnormalities including myelofibrosis seen in these patients. In summary, we describe a 52-year-old-man who contracted dengue virus infection and developed illness including myelofibrosis in the process. With prevalence of traveling in modern days, we would like to bring attention to such an occurrence.
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Neoplastic disorders Primary myelofibrosis Other myeloproliferative neoplasma: polycythemia vera, bcr-abl + chronic myeloid leukemia, essential thrombocythemia Acute myelofibrosis (acute megakaryoblastic leukemia, M7) Other acute myeloid leukemia (occasional) Myelodysplastic syndrome (occasional) Systemic mastocytosis Acute lymphoblastic leukemia/lymphoblastic lymphoma (occasional) Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Hairy cell leukemia Metastatic carcinoma, including neuroblastoma Langerhans cell histiocytosis Non-neoplastic disorders Infections: tuberculosis, leishmaniasis, histoplasmosis and other granulomatous infectious diseases Drugs/toxins: benzene, thorotrast, radiation exposure Vit D deficiency Bone disease: Paget disease, osteopetrosis, primary and secondary hyperparathyroidism, hypoparathyroidism Chronic renal failures (renal osteodystrophy) Storage disease, such as Gaucher disease Others: autoimmune myelofibrosis, gray platelet syndrome, familial hemophagocytic lymphohistiocytosis, healing fracture site, previous trephine biopsy site, status post bone marrow necrosis, collagen vascular diseases, such as systemic lupus and systemic sclerosis
References
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t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26 t1:27 t1:28 t1:29 t1:30
Table 1 Clinical conditions associated with marrow fibrosis. Adapted and modified from Refs. #1, 16 and 17.
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t1:1 t1:2
3
Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
Contents lists available at ScienceDirect
Experimental and Molecular Pathology
1
Dengue fever and bone marrow myelofibrosis☆
2Q1
Xin Qing a,⁎, Nora Sun a, James Yeh b, Changjun Yue a, Junchao Cai c
3 4 5
a
6
a r t i c l e
7 8 9 10
Article history: Received 6 July 2014 Accepted 9 July 2014 Available online xxxx
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i n f o
a b s t r a c t
Myelofibrosis is characterized by reticulin and/or collagen fibrosis in the bone marrow stroma resulting in secondary cytopenia. In addition to clonal hematologic neoplasms, myelofibrosis may also develop in association with other clinical conditions, including hematological disorders, solid malignancies, Down syndrome, autoimmune diseases and others. We report the first case to our knowledge of myelofibrosis associated with dengue fever. We briefly describe dengue infections and hypothesize the causes of myelofibrosis in this condition. © 2014 Published by Elsevier Inc.
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c
Department of Pathology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA Department of Internal Medicine, Division of Hematology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA Terasaki Foundation Laboratory, 11570 W Olympic Blvd, Los Angeles, CA 90064, USA
Keywords: Myelofibrosis Dengue fever Bone marrow
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1. Introduction
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Dengue fever is a rapidly spreading mosquito-borne viral disease with a worldwide incidence of 50 to 100 million cases annually. Symptoms include fever, headache, myalgias, arthralgias, and a characteristic rash. Thrombocytopenia is a constant manifestation of dengue fever, which may evolve into life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Myelofibrosis is an uncommon entity characterized by increased reticulin and/or collagen fibers in the bone marrow. Marrow fibrosis (myelofibrosis) may occur as primary disorder or secondary to other clinical conditions. It may also be classified as associated with neoplastic or non-neoplastic disorders. Primary myelofibrosis is a form of myeloproliferative neoplasms, whereas progression to myelofibrosis happens in about 10% of polycythemia vera and less than 1–2% of essential thrombocythemia patients over 10 years (Campbell and Green, 2011). Secondary myelofibrosis may be seen in a variety of diseases including leukemias, lymphomas, multiple myeloma, metastatic carcinoma, endocrine disorders, autoimmune diseases, radiation, and toxins. We describe a 52-year-old male who had bone marrow fibrosis associated with dengue virus infection. To our knowledge, this is the first reported case of dengue virus as an etiologic agent of myelofibrosis.
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2. Case report
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A previously healthy 52-year-old man was admitted to our hospital for anemia, thrombocytopenia, bilateral lower extremity rash and
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journal homepage: www.elsevier.com/locate/yexmp
☆ Financial support: N/A. ⁎ Corresponding author. E-mail address: [email protected] (X. Qing).
hematuria. He had traveled to Vietnam two months prior to admission to visit his family and developed fever, bilateral hemorrhagic bullae in his mouth and under his tongue less than one month following his trip. He recalled having mosquito bites while in Vietnam. He was evaluated in Vietnam for fevers and liver failure and was diagnosed with dengue fever. He received platelet transfusion support. Although his fever and hemorrhagic bullae were resolved, he had persistent thrombocytopenia, hematuria, jaundice and bilateral lower extremity rash, and was advised to go to the United States to have further workup. Physical examination was notable for gum bleeding and bilateral lower extremity petechial rash that extended to his trunk and back. Computed tomography scans of the chest, abdomen and pelvis revealed bilateral pleural effusions, ascites, extensive lymphadenopathy with the largest lymph node measuring 11 to 12 mm in maximum short axis diameter, kidney cysts and non-obstructive kidney stones, and irregularly thickened bladder. Hepatosplenomegaly was absent on imaging. The laboratory studies on admission included a white blood cell count of 9.4 K/mm3 (80% neutrophils, 14% lymphocytes, 4% monocytes and 2% eosinophils), a hemoglobin concentration of 8.1 g/dL, a hematocrit of 25.3%, a platelet count of 7 K/mm3, a D-dimer of 2655 ng/mL, an FDP of 337 μg/mL, and normal liver function tests. Urinalysis showed 3 + protein, 2 + blood, 115 white blood cells per high power field, and greater than 182 red blood cells per high power field. Tests for serum dengue fever antibodies performed at Focus Diagnostics (Cypress, CA) demonstrated elevated IgG (2.47, reference range: b 0.90) and normal IgM (0.83, reference range: b0.90). The patient was managed with packed RBC and platelet transfusion and prednisone at 1 mg/kg (60 mg daily) without any significant increase in platelets. The peripheral blood smear showed moderate anisopoikilocytosis with moderate hypochromia, some tear-drop cells and schistocytes (Fig. 1A). Rare circulating nucleated red
http://dx.doi.org/10.1016/j.yexmp.2014.07.004 0014-4800/© 2014 Published by Elsevier Inc.
Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
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14
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X. Qing et al. / Experimental and Molecular Pathology xxx (2014) xxx–xxx
DENV-3, and DENV-4. The viruses are transmitted primarily to human through the bite of an infected Aedes species mosquito. The spectrum of illnesses can range from a mild, non-specific febrile syndrome to classic dengue fever (DF), to the severe forms of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The vast majority DHF/DSS occurs as the result of a secondary infection with a different serotype of the virus. Dengue infection is common in people living in tropical and subtropical countries. Several outbreaks happen in different countries in Southeast Asia, Latin America, even in Australia, Cuba, Puerto Rico and Hawaii (Gregory et al., 2010; Halstead, 2007; Jessie et al., 2004; Leong et al., 2007; Martina et al., 2009). With economic growth and globalization, dengue is the most frequent arbovirus infection with more than 100 million cases annually throughout the world nowadays (Leong et al., 2007). Clinical manifestations are protean, depending on the age of the patients, the stage of the illness, the genotypes and virulences of the virus, the geographic location of the occurrence, and the host responses. There is no vaccine available, and the current treatment is supportive care. Diagnosis is based on virus isolation, serologic tests for antibodies against dengue virus, especially sero-conversion, molecular tests for viral antigens, and histopathologic examination of diseased tissue with immunohistochemistry and in situ hybridization in addition to clinical suspicions of the disease (Chaterji et al., 2011; Gregory et al., 2010; Halstead, 2007; Jessie et al., 2004; Martina et al., 2009). Recently, a NS1 rapid test became also available (Chaterji et al., 2011). Although the 1997 and 2009 World Health Organization (WHO) Dengue Case Classification criteria are helpful for its diagnosis and management, it appears that refinement for case definition will be needed (Gregory et al., 2010; Hadinegoro, 2012). Gregory and colleagues suggested that the following clinical symptoms and signs were predictive of laboratory positive dengue infections: (1) for patients age 1–9 years, retro-orbital pain, low platelet count, and absence of cough; (2) in the 10–19 year age group, retro-orbital pain, rash, and absence of cough; and (3) for patients ≥ 20 years of age, retro-orbital pain, rash, absence of sore throat, and leukopenia. Further expanded studies may validate or dispute the above statement (Gregory et al., 2010). Hematologic abnormalities are common in patients with symptomatic DF, DHF, and DSS. The most common finding is thrombocytopenia; others include increased hematocrit (due to plasma leakage), leukopenia, varying degrees of hemorrhage, coagulopathy or even disseminated intravascular coagulation (Lin et al., 1989; Srichaikul and Nimmannitya, 2000). Unusual clinical presentations, such as hemophagocytosis/ hemophagocytic syndrome (Jain and Singh, 2008; Ray et al., 2011), severe aplastic anemia (Ramzan et al., 2012), and severe plasmacytosis mimicking plasma cell leukemia (Gawoski and Ooi, 2003) have been reported. However, myelofibrosis associated with dengue infection, as seen in our patient, has not been recorded in the literature (Gawoski and Ooi, 2003; Jain and Singh, 2008; Lin et al., 1989; Ramzan et al., 2012; Ray et al., 2011; Srichaikul and Nimmannitya, 2000). Marrow fibrosis (myelofibrosis) may be observed in a variety of clinical conditions (Table 1) (Campbell and Green, 2011; Faucar, 2010; Lorsbach, 2011). Myelofibrosis occurs more frequently with myeloid malignancies. Myelofibrosis secondary to infectious diseases is likely transient which often reverts to normal after infectious diseases have been treated, such as in our patient. Dengue virus has been detected in cells in the skin, liver, spleen, lymph node, kidney, bone marrow, endothelial cells, lung, thymus, brain and heart (De Araujo et al., 2009; Jessie et al., 2004; Martina et al., 2009). Bone marrow stromal cells and bone marrow progenitors have been shown to be susceptible to infection with dengue virus (Kyle et al., 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011; Nakao et al., 1989; Rothwell et al., 1996). It is believed that a high viral load and activation of a large number of T-cells and monocytes/macrophages result in a “storm” of inflammatory cytokines and other mediators (Gregory et al., 2010; Halstead, 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011). Cytokines and soluble factors, such as IL1β, IL-2, IL4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-18, TGF-1β,
101
Dengue is caused by any of the four closely related single-stranded RNA viruses, dengue virus (DENV), serotypes called DENV-1, DENV-2,
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3. Discussion
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blood cells and plasma cells were noted. However, no immature myeloid cells were found. A bone marrow examination was performed on hospital day 4 which yielded a “dry tap” on aspiration. The trephine biopsy showed a hypercellular bone marrow with mucinous degeneration of fat cells and deposition of eosinophilic amorphous material (“damaged marrow”), erythroid and megakaryocytic hyperplasia (Figs. 1B and 2A) as well as moderate reticulin fibrosis (MF 2/3, WHO 2008 semiquantitative grading of bone marrow fibrosis) (Fig. 2B) (Thiele et al., 2008). There was no evidence of myelodysplastic changes, lymphoid aggregates, leukemia, lymphoma or metastatic carcinoma. The patient was discharged on hospital day 7 with prednisone 20 mg daily. Three days after discharge, his dose of prednisone was increased to 1 mg/kg due to continued thrombocytopenia (8 K/mm3, two days after discharge). A cystoscopy was performed approximately 1 week after discharge which showed recent stromal hemorrhage; concurrent bladder biopsy was negative for tumor. Three weeks after discharge, his anemia and thrombocytopenia began to recover, and a CBC two months following discharge showed resolution of anemia and thrombocytopenia.
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Fig. 1. A. Peripheral blood smear reveals moderate anisopoikilocytosis with some teardrop cells (arrow) and schistocytes. Romanowsky stain. B. A lower magnification of trephine biopsy displays hypercellular bone marrow. Periodic acid Schiff stain.
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Fig. 2. A. A higher magnification of trephine biopsy shows megakaryocytic and erythroid hyperplasia. Periodic acid Schiff stain. B. Reticulin stain shows moderate reticulin fibrosis (MF 2/3 according to WHO 2008 semiquantitative grading of bone marrow fibrosis).
Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
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Campbell, P.J., Green, A.R., 2011. Myeloproliferative neoplasms, In: Hoffbrand, A.V., Catovsky, D., Tuddenham, E.G.D., Green, A.R. (Eds.), Postgraduate Haematology, 6th ed.Wiley-Blackwell, Oxford, UK, pp. 686–706. Chaterji, S., Allen Jr., J.C., Chow, A., Leo, Y.S., Ooi, E.E., 2011. Evaluation of the NS1 rapid test and the WHO Dengue Classification schemes for use as bedside diagnosis of acute dengue fever in adults. Am. J. Trop. Med. Hyg. 84 (2), 224–228. De Araujo, J.M., Schatzmayr, H.G., de Filippis, A.M., et al., 2009. A retrospective survey of dengue virus infection in fatal cases from an epidemic in Brazil. J. Virol. Methods 155 (1), 34–38. Faucar, K., 2010. Bone marrow stroma and bone disorders, In: Foucar, K., Reichard, K., Czuchlewski, D. (Eds.), Bone Marrow Pathology, 3rd editionASCP Press, Chicago, IL, pp. 653–685. Gawoski, J.M., Ooi, W.W., 2003. Dengue fever mimicking plasma cell leukemia. Arch. Pathol. Lab. Med. 127 (8), 1026–1027. Gregory, C.J., Santiago, L.M., Arguello, D.F., Hunsperger, E., Tomashek, K.M., 2010. Clinical and laboratory features that differentiate dengue from other febrile illnesses in an endemic area—Puerto Rico, 2007–2008. Am. J. Trop. Med. Hyg. 82 (5), 922–929. Hadinegoro, S.R.S., 2012. The revised WHO dengue case classification: does the system need to be modified? Paediatr. Int. Child Health 32 (Suppl. 1), 33–38. Halstead, S.B., 2007. Dengue. Lancet 370 (9599), 1644–1652. Jain, D., Singh, T., 2008. Dengue virus related hemophagocytosis: a rare case report. Hematology 13 (5), 286–288. Jessie, K., Fong, M.Y., Devi, S., Lam, S.K., Wong, K.T., 2004. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J. Infect. Dis. 189 (8), 1411–1418. Kyle, J.L., Beatty, R., Harris, E., 2007. Dengue virus infects macrophages and dendritic cells in a mouse model of infection. J. Infect. Dis. 195 (12), 1808–1817. Leong, A.S., Wong, K.T., Leong, T.Y., Tan, P.H., Wannakrairot, P., 2007. The pathology of dengue hemorrhagic fever. Semin. Diagn. Pathol. 24 (4), 227–236. Lin, S.F., Liu, H.W., Chang, C.S., Yen, J.H., Chen, T.P., 1989. Hematological aspects of dengue fever. Gaoxiong Yi Xue Ke Xue Za Zhi 5 (1), 12–16. Lorsbach, R.B., 2011. Myeloproliferative neoplasms. In: Proytcheva, M.A. (Ed.), Diagnostic Pediatric Hematopathology. Cambridge University Press, Cambridge, UK, pp. 217–244. Martina, B.E.E., Koraka, P., Osterhaus, A.D.M.E., 2009. Dengue virus pathogenesis: an integrated view. Clin. Microbiol. Rev. 22 (4), 564–581. Mota, J., Rico-Hesse, R., 2011. Dengue virus tropism in humanized mice recapitulates human dengue fever. PLoS One 6 (6), e20762 (1–10). Nakao, S., Lai, C.J., Young, N.S., 1989. Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines. Blood 74 (4), 1235–1240. Ramzan, M., Prakashyadav, S., Sachdeva, A., 2012. Post-dengue fever severe aplastic anemia: a rare association. Hematol. Oncol. Stem Cell Ther. 5 (2), 122–124. Ray, S1., Kundu, S., Saha, M., Chakrabarti, P., 2011. Hemophagocytic syndrome in classic dengue fever. J. Glob. Infect. Dis. 3 (4), 399–401. Rothwell, S.W., Putnak, R., La Russa, V.R., 1996. Dengue-2 virus infection of human bone marrow characterization of dengue-2 antigen-positive stromal cells. Am. J. Trop. Med. Hyg. 54 (5), 503–510. Srichaikul, T., Nimmannitya, S., 2000. Haematology in dengue and dengue haemorrhagic fever. Baillieres Best Pract. Res. Clin. Haematol. 13 (2), 261–276. Thiele, J., Kvasnicka, H.M., Tefferi, A., et al., 2008. Primary myelofibrosis. In: Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Vardiman, J.W. (Eds.), WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon, France, pp. 44–47.
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TNF-α, and IFN-γ lead to necrosis and apoptosis of cells and tissues, dysfunction of endothelial cells, increased plasma leakage, suppression of hematopoiesis, and development of coagulation disorders (Gregory et al., 2010; Halstead, 2007; Leong et al., 2007; Martina et al., 2009; Mota and Rico-Hesse, 2011). All of these may contribute to the hematologic abnormalities including myelofibrosis seen in these patients. In summary, we describe a 52-year-old-man who contracted dengue virus infection and developed illness including myelofibrosis in the process. With prevalence of traveling in modern days, we would like to bring attention to such an occurrence.
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Neoplastic disorders Primary myelofibrosis Other myeloproliferative neoplasma: polycythemia vera, bcr-abl + chronic myeloid leukemia, essential thrombocythemia Acute myelofibrosis (acute megakaryoblastic leukemia, M7) Other acute myeloid leukemia (occasional) Myelodysplastic syndrome (occasional) Systemic mastocytosis Acute lymphoblastic leukemia/lymphoblastic lymphoma (occasional) Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Hairy cell leukemia Metastatic carcinoma, including neuroblastoma Langerhans cell histiocytosis Non-neoplastic disorders Infections: tuberculosis, leishmaniasis, histoplasmosis and other granulomatous infectious diseases Drugs/toxins: benzene, thorotrast, radiation exposure Vit D deficiency Bone disease: Paget disease, osteopetrosis, primary and secondary hyperparathyroidism, hypoparathyroidism Chronic renal failures (renal osteodystrophy) Storage disease, such as Gaucher disease Others: autoimmune myelofibrosis, gray platelet syndrome, familial hemophagocytic lymphohistiocytosis, healing fracture site, previous trephine biopsy site, status post bone marrow necrosis, collagen vascular diseases, such as systemic lupus and systemic sclerosis
References
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Table 1 Clinical conditions associated with marrow fibrosis. Adapted and modified from Refs. #1, 16 and 17.
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Please cite this article as: Qing, X., et al., Dengue fever and bone marrow myelofibrosis, Exp. Mol. Pathol. (2014), http://dx.doi.org/10.1016/ j.yexmp.2014.07.004
