J MEDICINE 2020; 21: 123-126

Haemophagocytic Lymphohistiocytosis Associated with Dengue

Fever - A case series
Quazi Tarikul Islam1, Hirinmoy Barman Sagor2, Tasmina Chowdhury Tuli3

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by
hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that
driven by excessive cytokines production which resulted in cellular destructions. Dengue induced
hemophagocytic lymphohistiocytosis (HLH) is a serious condition and may prove fatal if not detected early
and treated appropriately. Diagnosis of HLH is challenging and usually missed as clinical and laboratory
findings are nonspecific. It should be suspected with prolonged fever beyond seven days associated with
splenomegaly, hyperferritinemia, worsening cytopenias and development of multiorgan dysfunction. A
proportion of patients recovered with supportive therapy, however most required interventions with
corticosteroids, intravenous immunoglobulin or chemotherapy. We report 3 cases of dengue associated
HLH . Among them 2 patients were treated with steroid with good outcome, and one died from MODS.
Key words : Haemophagocytic Lymphohistiocytosis, Dengue, Methylprednisolone, MODS

DOI: [Link]
Copyright: © 2020 Islam QT et al. This is an open access article published under the Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited, is not changed in any way and it
is not used for commercial purposes.
Received: 01 August, 2020 Accepted: 16 August 2020

Introduction: cytomegalovirus infection, adenovirus infection, and viral

Dengue, transmitted by the mosquito Aedes aegypti affects [Link] report 3 cases of dengue associated HLH with
millions of people worldwide every year. Hemophagocyticl their management and outcome. The following cases were
ymphohistiocytosis (HLH), a potentially fatal condition that diagnosed during the outbreak of Dengue Fever between
is often under recognised contributing to its high mortality the month of June and September, 2019 admitted at Popular
and morbidity. Early recognition is crucial for any efforts at Medical College Hospital.
curative therapy. Virus-associated hemophagocytic syndrome
is a disorder characterized by a benign histiocytic Description of cases
proliferation with marked hemophagocytosis in the Patient 1
background of a systemic viral infection. Infection-associated A 40 year old diabetic female from Hazaribag, Dhaka with
hemophagocytic syndrome carries a high mortality1
Dengue NS1 positive presented in August 2019 with fever
.Hemophagocytic lymphohistiocytosis (HLH) has a
for 6 days and vomiting, loose motion, pain abdomen for 3
prominent link with a variety of viral, bacterial, fungal, and
parasitic infections. It may be diagnosed in association with days. Significant findings on examination were fever of
autoimmune diseases and malignancies such as T-cell 103oF, hypotension, epigastric and right hypochondriac
lymphomas. 2 Viral infections mostly implicated in tenderness, and dullness over both lung bases.
association with HLH are Epstein-Barr virus infection, Routine laboratory parameters revealed hemoglobin 10.2gm/
dl, Leukopenia with presence of reactive lymphocytes (WBC
1. Professor of Medicine, Popular Medical College, Dhaka, count 3.4 K/µL; Lymphocyte 57%) and low platelet count
Bangladesh (18,000 /mm3. There were significant derangements of the
2. Assistant Registrar of Medicine, Popular Medical College biochemical parameters as well. Liver enzymes were
Hospital, Dhaka, Bangladesh
elevated, AST 727 U/L and ALT 498 U/L. Serum lipase levels
3. Registrar of Medicine, Popular Medical College Hospital,
was high 465U/L, hyponatraemia (127mmol/L).
Dhaka, Bangladesh
Corresponding author: Prof. Quazi Tarikul Islam, Professor of The platelet count dropped to 10 K/ on day two of admission
Medicine, Popular Medical College, Dhaka, Bangladesh, with per rectal bleeding. The patient subsequently received
[Link]@[Link] one units of single donor platelet.
Haemophagocytic Lymphohistiocytosis Associated with Dengue Fever - A case series JOM Vol. 21, No. 2

On day 3 of admission patient developed breathlessness and symptoms and normalization of all blood results occurred.
patient WBC count was 19.5 K/. Ultrasound imaging showed No oral substitution of Prednisolone was given to the patient.
mild splenomegaly (measured length13.5 cm), free fluid in
abdomen and edematous pancreas and bilateral pleural Patient 3
effusion. Chest X-ray showed pneumonitic changes in both A 60 year old diabetic and hypertensive male from
lung fields. Maniknagor , Dhaka with Dengue NS1 positive presented
in august 2019 with fever for 5 days and yellow
Serum ferritin level done at day 3 of admission was 8040 discoloration sclera , vomiting, disorientation , pain abdomen
ng/ml . Serum procalcitonin level was 3 ng/dl which indicate for 2 days . Significant findings on examination were fever
sepsis . D- dimer was slightly high but APTT was normal. of 103 , hypotension, epigastric and right hypochondriac
Serum Triglyceride was 456 mg/dl (<150 mg/dL). tenderness, deeply icteric and feature of hepatic
Urine and blood cultures were negative. Negative Weil Felix encephalopathy ( Flapping tremor ,disorientation).
screening test for rickettsial infections, Rapid-test anti- Initial laboratory investigations showed bicytopenia
dengue virus IgM antibody was positive but anti-dengue IgG
(Leukopenia 3.60 K/ and thrombocytopenia 13,000 /) ),
was nonreactive, which is suggestive of primary dengue
transaminase (ALT 5200 U/L, AST 6873 U/L), bilirubin
infection.
19.10 mg/dL, s. albumin 2.86g/dL, renal impairment
Although bone marrow examination was not done , (creatinine 6.08 mg/dL, urea 160 mg/dL ), Lipase 5461 u/L
diagnostic criteria of HLH were met: fever, splenomegaly, PT 18 sec (control 12sec), APTT 43sec (control 32 sec), D-
cytopenia, hypertriglyceridaemia and hyperferritinaemia dimer 4.17 , FDP 13.68 (RV -<5 ) , Fibrinogen was normal
.Diagnosis was made Dengue Fever Group C complicated and ABG showed metabolic acidosis.
with HLH with pancreatitis and pneumonitis. Intravenous
Methylprednisolone was initiated on 10th day of illness Ultrasound imaging showed mild splenomegaly (measured
(500mg/ daily), was continued for 3 days and then was length12.7 cm), free fluid in abdomen and edematous
changed to oral methylprednisolone 16 mg twice daily for gallbladder. Chest X-ray showed bilateral pleural effusion.
another 5 days. After good clinical improvement the patient Serum procalcitonin level was 95.21ng/dl and lactate was
was discharged after 8 days of hospital stay. A follow up 108.1mg/Dl which indicate severe sepsis.
checkup after 2 weeks showed all results of blood tests were Dengue serology IgM antibody was positive but anti-dengue
normal. IgG was non reactive , which is suggestive of primary dengue
Patient 2 infection. All microbiological investigations for secondary
A 24 year old male from Cumilla with Dengue NS1 infection (Blood, urine and stool culture) were negative.
positive presented in September 2019 with fever for 6 days Viral screening (HAV, HBV, HCV and HEV) were negative.
and respiratory distress for 3 [Link] laboratory
investigations showed bicytopenia (Leukopena 3.67 K/ and Serum ferritin and Serum Triglyceride level were 4524ng/
Thrombo-cytopenia 26,000) and transamiases (ALT 399 U/ ml and 365 mg/dL respectively.
L, AST 673 U/L). Diagnosis was made as Dengue Fever Group C complicated
Ultrasound imaging showed hepatomegaly (15 cm) and mild with Expanded Dengue Syndrome and MOD (hepatitis,
splenomegaly (measured length 12.6 cm. Chest X-ray pancreatitis, AKI) and HLH on the basis of, splenomegaly,
showed feature of pneumonitis. He received empirical cytopenia, hypertriglyceridaemia and hyperferritinaemia .
antibiotics although later all microbiological investigations Patent was managed at intensive care unit with board
were negative. Dengue serology was positive for both IgG spectrum antibiotic, steroid (Methyle Prednisolone 500 mg
and IgM, indicative of secondary dengue infection. IV daily for 3 days), aphaeretic platelet transfusion,
Serum ferritin and Serum Triglyceride level were 6620 ng/ Haemodialysis. But patient condition deteriorated further
ml and 332 mg/dl respectively. and patient died after 9 days of hospital admission.
Diagnosis was made Dengue Fever Group C complicated Discussion:
with pneumonitis and HLH on the basis of fever,
HLH is a disease with major therapeutic and diagnostic
splenomegaly, cytopenia, hypertriglyceridaemia and
difficulties. The diagnosis HLH was based on five criteria
hyperferritinaemia.
(fever, splenomegaly, bicytopenia, hypertriglyceridemia and/
Three days course of Inj. Methyl Prednisolone 250 mg IV or hypofibrinogenemia, and hemophagocytosis).4 In 2004
daily was given. Resolution of fever, followed by other three additional criteria were introduced by the Histiocyte

124
JOM Vol. 21, No. 2 Haemophagocytic Lymphohistiocytosis Associated with Dengue Fever - A case series

Society; low or absent NK-cell-activity, hyperferritinemia, different serotypes) is also a risk for severe dengue. We found
and high-soluble interleukin-2-receptor levels.5 Five of these one case was associated with secondary infection.
eight criteria must be fulfilled for a diagnosis of HLH. The Some studies observed that primary dengue infections were
NK cell activity and soluble IL2 receptor quantitation tests as much at risk of severe DHF and dengue associated
are not done in routine clinical practice. HLH.4,7,9 Case 1 and 3 were associated with primary
Bone marrow examination could not be done in our 3 cases. infection. So, both primary and secondary infection with DF
These patients fulfilled five out of the eight criteria - high can cause HLH.
grade fever, splenomegaly, cytopenia, hypertri- It would be important to differentially diagnose dengue-
glyceridaemia, hyperferritinaemia and accordingly were associated HLH from severe dengue hemorrhagic fever.
diagnosed as case of secondary HLH clinically and Early recognition and initiation of steroid would be crucial
biochemically. HLH may be primary (familial) and for the successful treatment of dengue fever complicated by
secondary. Secondary HLH develop due to over activation HLH. Dengue virus needs to be investigated as an important
of immune system. Secondary HLH has been associated with triggering factor for HLH.
a variety of viral, bacterial, fungal and parasitic infections
as well as collagen vascular diseases and malignancies Conclusion:
particularly T-cell lymphomas 6. The term reactive HLH has Dengue associated HLH must be suspected in the presence
been suggested when HLH is associated with an identifiable of persistent fever beyond day 7, splenomegaly , worsening
infectious or non-infectious etiology to distinguish it from cytopenias, shock and MOD beyond plasma leakage phase.
the familial form. Infection has been found to be associated Exclusion of SIRS and secondary infection is important
with HLH in half of all reported cases.7 before initiation of corticosteroids. Early recognition has a
significant impact on the management and outcome. Dengue
Early recognition and diagnosis of HLH might enable
associated HLH may indicate a severe form of dengue
physicians to start the steroid treatment in optimal time,
infection, and dengue virus needs to be recognized as an
leading to better clinical outcome.8 Although the mechanism
important causative agent for HLH.
of HLH remains unclear, current accepted theory suggests
that inappropriately proliferating and activated T-cells may Limitation:
induce macrophage activation with inadequate intracellular BM biopsy needs to be performed to demonstrate
killing of phagocytes.9 Many studies suggested the important hemophagocytosis.
roles of perforin and natural killer (NK) cells in the HLH
subtypes.10 Identification of Dengue virus serotype is very crucial to
determine the relationship .
In DF the febrile phase lasts up to seven days. With prolonged
fever, secondary bacterial infection should be excluded and Conflict of interest: None declared.
dengue associated HLH should be suspected. Steroid and Funding: There were no sources of funding.
immunoglobulin are the mainstay of treatment of HLH.
Severe or fatal complications may ensue if dengue associated Consent: The patient’s informed signed consent was
HLH is unrecognized. Cases received methyl prednisolone obtained.
due to early recognition of dengue associated HLH based References:
on the presence of persistent fever, splenomegaly, cytopenia, 1. Sullivan JL, Woda BA. Lymphohistiocytic Disorders. In:
hypertriglyceridaemia and hyperferritinaemia . Case 1 and David GN, Ginsburg D, Orkin SH, Look AT, editors. Nathan
and Oski’s Hematology of Infancy and Childhood. 6th ed.
2 were successfully recovered with treatment but case 3 did
Philadelphia: Saunders; 2003. pp. 1380–81. [Google
not survived due to development of MOD and Expanded Scholar]
dengue syndrome which encountered the aggressiveness of
2. Fisman DN. Hemophagocytic syndromes and
HLH if not early detected and treated accordingly.
infection. Emerg Infect Dis. 2000;6:601–8. [PMC free
Defervescence occurs between D3 and D7 and in DHF this article] [PubMed] [Google Scholar]
period is associated with critical phase and plasma leakage. 3. Karras A, Hermine O. Macrophage activation syndrome. Rev
Secondary dengue infection (two sequential infections by Med Interne. 2002;23:768–78. [PubMed] [Google Scholar]

125
Haemophagocytic Lymphohistiocytosis Associated with Dengue Fever - A case series JOM Vol. 21, No. 2

4. Henter JI, Horne A, Aricó M, Egeler M, Filipovich A, 7. Reiner AP, Spivak JL. Hematophagichistiocytosis. A report
Imashuku S, et al. HLH2004: diagnostic and therapeutic of 23 new patients and a review of the literature. Medicine
guidelines for hemophagocyticlymphohistiocytosis. Pediatr
(Baltimore) 1988;67(6):369–88.
Blood Cancer 2007;48:124–31.
5. Henter JI, Elinder G, Ost A. Diagnostic guidelines for 8. George MR. Hemophagocyticlymphohistiocytosis: review
hemophagocyticlymphohistiocytosis. the FHL study group of etiologies and management. J Blood Med 2014;5:69–86.
of the histiocyte society. SeminOncol 1991;18(1):29–33.
9. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW,
6. Fishman DN. Hemophagocytic syndromes and infection. Moyes CL, et al. The global distribution and burden of
Emerg Infect Dis 2000;6:601–8. dengue. Nature 2013;496:504–7.

126
 © 2020. This work is licensed under
[Link] (the “License”).
Notwithstanding the ProQuest Terms and Conditions, you may use this content
in accordance with the terms of the License.