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   Table of Contents     
CASE REPORT  
Year : 2011  |  Volume : 3  |  Issue : 4  |  Page : 399-401
Hemophagocytic syndrome in classic dengue fever


1 Department of Medicine, Medical College and Hospital, West Bengal, India
2 Department of Hematology (Institute of Haematology and Transfusion Medicine), Medical College, Kolkata, West Bengal, India

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Date of Web Publication21-Dec-2011
 

   Abstract 

A 24-year-old previously healthy girl presented with persistent fever, headache, and jaundice. Rapid-test anti-dengue virus IgM antibody was positive but anti-dengue IgG was nonreactive, which is suggestive of primary dengue infection. There was clinical deterioration during empiric antibiotic and symptomatic therapy. Bone marrow examination demonstrated the presence of hemophagocytosis. Diagnosis of dengue fever with virus-associated hemophagocytic syndrome was made according to the diagnostic criteria of the HLH 2004 protocol of the Histiocyte Society. The patient recovered with corticosteroid therapy. A review of literature revealed only a handful of case reports that showed the evidence that this syndrome is caused by dengue virus. Our patient is an interesting case of hemophagocytic syndrome associated with classic dengue fever and contributes an additional case to the existing literature on this topic. This case highlights the need for increased awareness even in infections not typically associated with hemophagocytic syndrome.

Keywords: Hemophagocytic lymphohistiocytois, Primary dengue infection, Virus-associated hemophagocytic syndrome

How to cite this article:
Ray S, Kundu S, Saha M, Chakrabarti P. Hemophagocytic syndrome in classic dengue fever. J Global Infect Dis 2011;3:399-401

How to cite this URL:
Ray S, Kundu S, Saha M, Chakrabarti P. Hemophagocytic syndrome in classic dengue fever. J Global Infect Dis [serial online] 2011 [cited 2015 Jul 3];3:399-401. Available from: http://www.jgid.org/text.asp?2011/3/4/399/91068



   Introduction Top


Virus-associated hemophagocytic syndrome is a disorder characterized by a benign histiocytic proliferation with marked hemophagocytosis in the background of a systemic viral infection. Infection-associated hemophagocytic syndrome carries a high mortality. [1] Hemophagocytic lymphohistiocytosis (HLH) has a prominent link with a variety of viral, bacterial, fungal, and parasitic infections. It may be diagnosed in association with autoimmune diseases and malignancies such as T-cell lymphomas. [2] Inappropriate stimulation of macrophages in bone marrow and resultant phagocytosis of blood cells with the production of high amounts of proinflammatory cytokines are the pathologic hallmarks of HLH. [3] Viral infections mostly implicated in association with HLH are Epstein-Barr virus infection, cytomegalovirus infection, adenovirus infection, and viral hepatitis. We describe a 24-year-old girl who had hemophagocytic syndrome associated with dengue virus infection. What is most intriguing in our case is that here the disorder is encountered with classic dengue fever while most of the case reports are in the setting of dengue hemorrhagic fever.


   Case Report Top


A 24-year-old previously healthy girl presented with a 4-day history of fever along with myalgia, headache, and retro-orbital pain. Fever was low grade and continuous. Physical examination revealed morbilliform rash over trunk and mild hepatosplenomegaly, but no edema or lymphadenopathy. The clinical diagnosis of dengue fever was made, and NS1 antigen (NS1 Ag) detection for dengue virus was performed. NS1Ag was detected. The patient started to improve with a conservative management but fever returned after 3 days. This time the fever was high grade and intermittent with chill and rigor, and she also had developed yellowish discoloration of eyes and urine. There was history suggestive of menorrhagia. A general survey revealed moderate pallor and icterus and maculopapular skin rashes over the shinbone. Lymphadenopathy was absent. Abdominal examination revealed tender hepatomegaly and moderate splenomegaly. An initial peripheral blood picture showed pancytopenia as evidenced by a hemoglobin concentration of 6.6 g/dl and a leukocyte count of 1.3 Χ 10 9 /L with 44% neutrophils (<1 Χ 10 9 /L) and platelet counts (105 Χ 10 9 /L), but no feature of hemoconcentration was found. The erythrocyte sedimentation rate was slightly raised (40 mm/h). Serum lactate dehydrogenase (LDH) was raised (2461 units/l) and serum ferritin was very high (2161 ΅g/l). Fasting serum triglyceride measured 534 mg/dl (normal range < 150 mg/dl). Liver function tests revealed hyperbilirubinemia with raised serum aminotransferases as well as alkaline phosphatase and hypoalbuminemia. Renal parameters and electrolytes were within the normal limit. Blood and urine culture were sterile. Chest X-ray showed no detectable abnormality. An ultrasound of abdomen revealed hepatosplenomegaly and mild ascites. Serological tests for conventional hepatotropic viruses were negative. Rapid-test anti-dengue virus IgM antibody was positive but anti-dengue IgG was nonreactive, which is suggestive of primary dengue infection. Bone marrow aspiration showed depressed granulopoiesis and dyshematopoiesis and increased number of macrophages with gross hemophagocytosis compatible with reactive HLH [Figure 1]a and b. No malignant cells or infiltration was found. The patient's condition met the diagnostic criteria of HLH, which include clinical, laboratory, and histopathological features. There was clinical deterioration during empiric antibiotic and symptomatic therapy. We then kept the patient on intravenous dexamethasone 16 mg/day (starting dose 10 mg/m 2 ). Fever subsided from day 2; spleen size started regressing from day 5; and normalization of peripheral blood counts noted 1 week later. Since she responded dramatically to dexamethasone, no further chemotherapy was added. Serum ferritin after 2 weeks of treatment initiation showed more than 25% decline of the ferritin level. The initial therapy continued for 8 weeks with the tapering schedule as per the HLH 2004 protocol. Despite the presence of most of the signs of resolution at the end of 8 weeks, she was put on continuation therapy with dexamethasone pulses to sustain resolution and keep the disease nonactive over weeks 9-40.She was on her 6-month follow-up (including the period of therapy) at the time of this writing. No further signs of reactivation have been detected.
Figure 1: (a) Hemophagocytosis in the bone marrow of a 24-year-old girl with dengue virus-associated HLH (Leishman's staining technique). (b) The macrophage at the center of the image with engulfed red blood cells (white arrow), leukocytes (black arrow), and platelets (dotted arrow) [Original photomicrograph 100×; oil immersion].

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   Discussion Top


Hemophagocytic lymphohistiocytosis is a rare hyperinflammatory disorder related to macrophage activation and usually presents as prolonged fever and a sepsis-like syndrome. [2],[4] Two types of HLHs are seen: The primary (familial) form is a fatal autosomal recessive disorder that typically affects young children, whereas the secondary or reactive form is associated with viral, bacterial, fungal, or parasitic infections as well as with connective tissue disorders and malignancy. The importance of the association between HLH and infection lies in the fact that both forms of HLH may be preceded by infection. HLH may also mimic infectious diseases such as overwhelming bacterial sepsis. [2],[5] Most of the secondary HLH cases are associated with viral infection, and Epstein-Barr virus has been implicated as the most common cause. [6] Virus-associated hemophagocytic syndrome presents with nonspecific clinical signs such as fever, cachexia, hepatosplenomegaly, and lymphadenopathy. Typical laboratory findings include bicytopenia or pancytopenia, hepatic impairment with coagulopathy, hypofibrinemia, elevation of serum LDH and triglyceride levels, and ferritinemia. Diagnosis is confirmed by cytological or pathological examination of bone marrow or tissue specimens. [3],[7] As regards diagnosis and treatment, the criteria of the HLH 2004 protocol proposed by the Histiocyte Society are followed. Dengue fever, caused by flavivirus, is an important mosquito-transmitted disease. Rapid serologic diagnosis made by using capture ELISA can distinguish between primary and secondary dengue infections. [8] Dengue NS1 Ag test has a significantly higher sensitivity for primary infections than for secondary infections. [9] Hyperproduction of cytokines, including interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin 6 by virus-infected T lymphocytes may play a role in the pathogenesis of HLH. In the context of virus-associated HLH, higher levels of IFN-γ and TNF-α correlate with poor clinical outcome.[10] Very few cases of dengue associated HLH have been reported so far. According to the published data, there are fewer than 20 case reports, which showed evidence of dengue virus causing this syndrome. [11],[12] However, in one study from India, dengue virus has been found to be the most common agent causing HLH in children. [13]

HLH should be considered in the differential diagnosis of children and adolescents with prolonged fever, hepatosplenomegaly, and cytopenia. Prompt recognition and early institution of appropriate therapy may result in good outcome, particularly in infection-associated HLH. In the absence of a proven definitive therapy, supportive therapy and maximal diagnostics for the detection of curable underlying diseases are essential. Clinicians should work closely with pathologists and microbiologists to clearly define precipitating or underlying illnesses. Our patient is an unusual case of dengue-related hemophagocytic syndrome and contributes an additional case to the existing literature on this topic. The occurrence of reactive infection-associated hemophagocytosis is rare and that too in the setting of classic dengue fever, making the case stand apart. Clinicians should be aware of the fact that the occurrence of hemophagocytosis and dyserythropoiesis could be due to dengue virus infection in areas where the disease prevalence is more.


   Conclusion Top


Hemophagocytic syndrome can occur even in the setting of infections not typically associated with it, such as classic dengue fever as in our case. This case highlights the need for increased awareness of such an association. Clinicians should be aware of this disorder in appropriate clinical settings because prompt recognition and early institution of appropriate therapy is the most important factor for recovery.

 
   References Top

1.Sullivan JL, Woda BA. Lymphohistiocytic Disorders. In: David GN, Ginsburg D, Orkin SH, Look AT, editors. Nathan and Oski's Hematology of Infancy and Childhood. 6 th ed. Philadelphia: Saunders; 2003. p.1380-81.   Back to cited text no. 1
    
2.Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 2
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3.Karras A, Hermine O. Macrophage activation syndrome. Rev Med Interne 2002;23:768-78.   Back to cited text no. 3
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4.Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 4
    
5.Janka GE. Hemophagocytic syndromes. Blood Rev 2007;21:245-53.  Back to cited text no. 5
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6.Janka G, Zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program 2005:82-8.  Back to cited text no. 6
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7.Imashuku S, Hlbi S, Todo S. Hemophagocytic lymphohistiocytosis in infancy and childhood. J Pediatr 1997;130:352-7.  Back to cited text no. 7
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8.Vaughn DW, Nisalak A, Solomon T, Kalayanarooj S, Nguyen MD, Kneen R, et al. Rapid serologic diagnosis of dengue virus infection using a commercial capture ELISA that distinguishes primary and secondary infections. Am J Trop Med Hyg 1999;60:693-8.  Back to cited text no. 8
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9.Chaterji S, Allen JC, Jr., Chow A, Leo YS, Ooi EE. 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 2011;84:224-8.  Back to cited text no. 9
    
10.Ohga S, Matsuzaki A, Nishizaki M, Nagashima T, Kai T, Suda M, et al. Inflammatory cytokines in virus-associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of disease activity. Am J Pediatr Hematol Oncol 1993;15:291-8.  Back to cited text no. 10
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11.Veerakul G, Sanpakit K, Tanphaichitr VS, Mahasandana C, Jirarattanasopa N. Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology and outcome. J Med Assoc Thai 2002;85 Suppl 2:S530-41.  Back to cited text no. 11
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12.Jain D, Singh T. Dengue virus related hemophagocytosis: A rare case report. Hematology 2008;13:286-8.  Back to cited text no. 12
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13.Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. Indian Pediatr 2011;48:31-5.  Back to cited text no. 13
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Correspondence Address:
Sayantan Ray
Department of Medicine, Medical College and Hospital, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-777X.91068

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    Abstract
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