Hemophagocytic lymphohistiocytosis: a rare and fatal manifestation of dengue fever

INTRODUCTION

Dengue fever is a common acute febrile illness in tropical countries. It is caused by Dengue virus of the Flaviviridie family, transmitted by the Aedes aegypti mosquito. Dengue fever can present with a wide spectrum of clinical manifestations, ranging from self-limiting febrile illness to life threatening haemorrhagic fever and shock syndrome. Rare and atypical manifestations have also been reported.¹

Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening hyper inflammatory syndrome, characterized by excessive, although ineffective, stimulation of the immune system. It is classified as familial (primary), which manifests in early life and has high mortality without treatment, and acquired (secondary), associated with various infectious etiologies, autoimmune disorders and hematological malignancies.² Among the viral infections, Epstein Bar virus has been most commonly associated with HLH, although it has also been reported with other viral infections like dengue fever.^3-5

Authors describe the case of a 26-year-old man who had Dengue fever complicated by the development of hemophagocytosis. This report adds to the limited number of adult cases of dengue-associated hemophagocytic syndrome described in the literature.

CASE REPORT

A 26-year-old male presented to the medical emergency with complaints of high-grade fever since 4 days, and loose stool (10-12 episode), vomiting (10-15 episode) and reduced urine output since 1 day. On examination he was conscious, oriented and hemodynamically stable. He was diagnosed as a case of acute gastroenteritis with acute kidney injury and admitted in the ward.

On the next day he developed respiratory distress (respiratory rate of 45/min), tachycardia (heart rate-150 bpm) and a fall in Oxygen saturation (SpO2 88% on 15 Lt of O2 by Non-rebreathing mask). Auscultation revealed crepitations in bilateral lung fields. The patient was intubated and shifted to ICU.

On further evaluation in ICU his laboratory values were: hemoglobin 6.7 gm/dL, total leucocyte count 3600/mm³, platelet count 29000/mm³, blood urea 136 mg/dL, serum creatinine 4.8 mg/dL, serum pro-calcitonin 10.03 ng/ml. Liver function tests revealed: albumin 2.2 g/dL, total bilirubin 3.2 mg/dL, prothrombin time International Normalized Ratio of 1.21, Alanine Aminotransferase 312 U/L, and Aspartate Aminotransferase 475 U/L. Viral markers for Human Immunodeficiency Virus, Hepatitis B and C were negative. Fever panel workup showed negative results for malaria, typhoid, leptospirosis and chikungunya, but positive for Anti-dengue IgM antibody. Ultrasound abdomen examination revealed mild hepatomegaly and moderate splenomegaly. Ultrasound chest showed massive pleural effusion.

Taking into account worsening clinical condition, persist fever, and a falling trend in total leucocyte and platelet counts, the possibility of Hemophagocytic lymphohistiocytosis (HLH) was considered. Further testing on day 9 of admission revealed low fibrinogen (150 mg/dL), and raised triglycerides (161 mg/dL), Lactic Dehydrogenase (4031 U/L) and ferritin (7211 ng/ml). Bone marrow biopsy was done on the 10th day of admission, which demonstrated phagocytosis of red and white blood cells by macrophages (Figures 1 and 2).

Hence the diagnosis of HLH was confirmed according to criteria given by Histocyte Society (Table 1)6. Along with general supportive care including multiple blood and platelet transfusions, and hemodialysis, corticosteroid therapy was started after diagnosis of HLH. In spite of all these measures, the condition of the patient did not improve. He died on day 28 of hospital admission.

DISCUSSION

HLH is typically characterized by fever, pancytopenia, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia and presence of hemophagocytes in bone marrow, spleen or lymph nodes.³ Pathophysiology of HLH includes excessive and uncontrolled immune response by macrophages and monocytes, leading to the overproduction of inflammatory cytokines like interferon-γ, tissue necrosis factor-α, interleukin-6, interleukin-10 and macrophage colony stimulating factor. These activated macrophages engulf red blood cells, white blood cells and platelets leading to pancytopenia. Decreased NK cell activity is also a feature of HLH.

Pathophysiology of HLH in dengue infection is not well established but association of HLH in dengue fever has been reported.^4,5 Dengue Haemorrhagic fever and Dengue Shock Syndrome with multiorgan failure has been proposed as predisposing factor in HLH.⁷ It is difficult to diagnose whether dengue is associated with HLH or not because haemophagocytic activity and increased ferritin levels may be present in dengue without HLH.⁸

Due to poor prognosis in most of the cases, HLH should be treated promptly with a combination of corticosteroids and chemotherapeutic agents like etoposide and cyclosporine.⁹

In this case, the patient had atypical presentation of dengue fever, without features of DHF or DSS. He presented with fever, acute gastroenteritis and signs of sepsis (raised procalcitonin). The overlap between reactive HLH and sepsis has been reported with common features like fever, hypotension, thrombocytopenia and multi-organ failure resulting from cytokine mediated multi-organ dysfunction.¹⁰ Patient did not survive due to the initial diagnostic dilemma and the rapid, fatal course of the disease. Because of rarity of HLH in dengue fever, this potentially fatal, yet treatable complication may be often overlooked. Authors hope that by adding another report of HLH in dengue fever to existing literature, clinicians will hold a higher clinical suspicion for this condition.

Authors hereby conclude that HLH is an atypical, life-threatening, yet potentially treatable presentation of dengue fever and should be considered early in patients presenting with dengue fever with pancytopenia and increased serum ferritin levels.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Simmons CP, Farrar JJ, Nguyen VC, Wills B. Dengue. N Engl J Med. 2012;366:1423-32.
2. 2. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014 Apr 26;383(9927):1503-16.
3. 3. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infe Dis. 2000 Nov;6(6):601.
4. 4. Lei HY. Transient hemophagocytic activity in dengue immunopathogenesis. J Form Med Assoc. 2009 Aug 1;108(8):595-8.
5. 5. Nelson ER, Bierman HR, Chulajata R. Hematologic Phagocytosis in Postmortem Bone Marrows of Dengue Hemorrhagic Fever. (Hematologic Phagocytosis in Thai Hemorrhagic Fever.)(Pediatric Dengue.). Am J Med Sci. 1966;252(1):68-74.
6. 6. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. ASH Edu Prog Book. 2009;2009(1):127-31.
7. 7. Tan LH, Lum LC, Omar SF, Kan FK. Hemophagocytosis in dengue: comprehensive report of six cases. J Clin Virol. 2012 Sep 1;55(1):79-82.
8. 8. Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996 Feb;10(2):197-203.
9. 9. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood, J Am Soci Hematol. 2011 Oct 13;118(15):4041-52.
10. 10. Robert A. Raschke and Roxanne Garcia-Orr. Hemophagocytic Lymphohistiocytosis A Potentially Underrecognized Association with Systemic Inflammatory Response Syndrome, Severe Sepsis, and Septic Shock in Adults. Chest. 2011;140:933-8.