A Case Report of Hemophagocytic Lymphohistiocytosis Syndrome Due to Dengue Virus Infection

Abstract

Hemophagocytic lymphohistiocytosis syndrome due to dengue virus infection (HLH), is a rare but severe complication of dengue fever. The diagnosis of HLH is based on clinical and laboratory findings. We report here a case of dengue who developed HLH syndrome during hospitalization. A 42-yr-old woman presented with high fever for one week with abdominal discomfort for three days duration. On admission vitals were stable except for liver enlargement of about 2cm. Dengue virus infection was confirmed by serological tests. Investigations revealed bicytopenia with absolute neutrophil count 0.8 x 109 /L and platelet count of 48 x 10⁹/L with high CRP 150mg/ml, ferritin >40000 ug/L and liver enzymes AST 6715 units, ALT 1733 units. Because of persistent high fever with bicytopenia, very high CRP, ferritin in recovery phase of dengue infection, HLH was suspected and bone marrow examination was done. HLH was confirmed since there was obvious triggering infection for HLH and patient was clinically stable, we opted for conservative treatment rather than HLH specific therapy. Recover was uneventful during hospitalization and the patient was discharged after two weeks although HLH is a deleterious disease with high fatality rate. Clinicians need to be aware of HLH in dengue patient who still have high fever with very high acute phase reactant in recovery phase. Dengue-induced HLH diagnosis is challenging but it is very important to be recognized as early recognition is associated with better outcomes.

Introduction

Haemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory syndrome that can develop secondary to numerous conditions.¹ HLH is sporadically seen in daily clinical practice and is also a rare complication of dengue viral infection characterized by persistent fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin level. In this syndrome, the immune system becomes hyperactivated, leading to excessive inflammation and cytokine production. This can result in the destruction of blood cells and organs, leading to symptoms like fever, cytopenia, liver dysfunction, and coagulopathy. The overlap in clinical features makes diagnosing HLH in a dengue patient difficult, requiring bone marrow examination sometimes.²

Table. 1 Infectious causes of HLH³

Case report

A 42-yr-old previously healthy woman from Yangon presented to the Department of Tropical and Infectious Diseases, YGH with high fever for one week and abdominal discomfort for three days duration. On examination, the patient was febrile, vitals were stable and apart from hepatomegaly about 3 cm, no significant finding was detected. Secondary dengue infection was confirmed by dengue serology (NS1, Ig M and Ig G all positive). Investigations on admission revealed Hb 9 g/dL, Hct 41%, MCV 85 fl, WBC 3x 10⁹/l, absolute neutrophil count 1×10⁹/l, absolute lymphocyte count 1.2x 10⁹/l , Plt 128x 10³/ul, CRP 133ug/ml, procalcitonin 0.06ng/ml, AST 6715 U/L, ALT 1733 U/L, GGT 1356 U/L, serum bilirubin 62mcg/dL, INR 1.8 sec with normal renal function. Hepatitis antibodies for B, C and A were negative. Mild right sided pleural effusion was detected on CXR and USG (abdomen) revealed diffuse oedema of gallbladder wall, mild ascites with mild right sided pleural effusion. Severe dengue/ expanded dengue syndrome (acute hepatitis) was diagnosed according WHO classification (2011). During hospitalization, high fever was still persisted although she was in dengue recovery phase. No vegetation was detected on echocardiogram and ANA, ENA were negative. And serial investigations showed Hb level, total WBC count and absolute neutrophil count were dropped to 8, 2 and 0.4 respectively. CRP 130 mg/L and ferritin >40000 and triglyceride 3.1 mmol/L level were also very high at the same time. Therefore, secondary haemophagocytic lymphohistiocytosis (HLH) due to dengue virus infection was suspected and bone marrow examination was proceeded. And bone marrow result evaluated highly concerned for haemophagocytic lymphohistiocytosis due to macrophage activation and engulfing haemopoietic cells in the marrow. All necessary criteria were fulfilled according to 2004 criteria and expanded dengue syndrome (HLH) was finally diagnosed. Regarding treatment, she was clinically stable and there was obvious triggering dengue infection, we opted conservation treatment rather than HLH specific therapy. She was clinically stable, bicytopenia became improved on day 16 of fever and successfully discharged on 2 weeks after hospitalization.

Table 2. Investigations summary

Fig.1 Bone marrow result of the patient

Fig. 2 HLH criteria 2004⁴

Discussion

Dengue has emerged as the most widespread and rapidly increasing vector-borne disease in the world. Dengue viral infection is also one of the most important vector-borne disease in Myanmar. HLH syndrome is a rare complication of dengue virus infection and also known as expanded dengue syndrome with hematological manifestation. There are two main types of HLH; primary or familial HLH associated with genetic predisposition and secondary or sporadic HLH associated with other medical conditions, including infective, autoimmune, and malignant conditions.⁵ Fever should be resolved during recovery phase of dengue infection. Persistent fever following dengue infection may occur due to sepsis and expanded dengue syndrome.^6,7,8 HLH is an unusual hematological manifestation of expanded dengue syndrome, whereas other manifestations include disseminated intravascular coagulopathy and cytopenias.⁹ There are several reported cases of HLH as a secondary manifestation of dengue infection in adult populations, where most have occurred in patients without any other comorbidities, mean age was 34 year (range 19-65) , slightly female predominant like our case.¹⁰ The exact mechanism is less precise for the secondary HLH.¹¹ The inability to clear the antigenic stimulus to turn off the inflammatory response leads to hypercytokinemia is seen in HLH.¹² The presenting symptoms of HLH are nonspecific and may overlap with other inflammatory or hematopoietic diseases, and so the diagnosis of HLH is based on the diagnostic criteria as revised for HLH-2004.^5,13 According to HLH-2004, there are two main criteria; Criterion 1 and 2. The diagnosis of HLH can be established if Criterion 1 or 2 is fulfilled. Criterion 1 included a molecular diagnosis consistent with HLH. Criterion 2 included fulfilling five of the eight criteria, namely fever, splenomegaly, cytopenias (affecting 2 of 3 lineages in the peripheral blood, hemoglobin < 9 g/dL, platelets < 100 × 10⁹/L, and neutrophils < 1.0 × 10⁹/L), hypertriglyceridemia, or hypofibrinogenemia (fasting triglycerides ≥ 3.0 mmol/L (i.e., ≥ 265 mg/dL), fibrinogen ≤ 1.5 g/L). Hemophagocytosis in bone marrow or spleen, or lymph nodes, no evidence of malignancy, low or no NK cell activity (according to local laboratory reference), ferritin ≥ 500 mg/L, and CD25 (i.e. Soluble IL-2 receptor) ≥ 2400 U/mL are also included in Criterion 2. ⁵Our patient fulfilled 6 out of 8 criteria for Criterion 2. In studying treatment for secondary HLH due to dengue infection, there were cases who opted steroid sparing treatment like our cases and most were recovered well. There were also reported which used HLH specific therapy like steroid, cyclosporin, immunoglobulin or etoposide.10 Our case was treated with injection antibiotics for neutropenic fever with liver supportive vitamin. She was clinically stable, bone marrow recovered and acute phase reactant parameters improved gradually and discharged 2 weeks after hospitalization.

Conclusion

Hemophagocytic lymphohistiocytosis is a rare complication of dengue virus infection. But the outcome is poor if the diagnosis of HLH is delayed or left untreated. Since cytopenias can occur in uncomplicated dengue infection, bone marrow examination is sometimes necessary to confirm the diagnosis of HLH and exclude other possibilities like hematological malignancies. In conclusion, a high degree of clinical suspicion is paramount in diagnosing HLH especially when high fever with very high CRP, ferritin in recovery phase of dengue infected patient.

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Author Information

Aye-Mya-Theingi-Win¹, Khin-Rupar-Ko², Aye-Aye-Win³, May-Zabe⁴, Nyunt Thein⁵

1. Consultant Physician, Tropical and Infectious Diseases Department, Yangon General Hospital
2. Professor, Tropical and Infectious Diseases Department, Yangon General Hospital
3. Associated Professor, Tropical and Infectious Diseases Department, University of Medicine (1), Yangon
4. Consultant Physician, Tropical and Infectious Diseases Department, Yangon General Hospital
5. Senior Consultant Physician, Former Head of Department of Medicine, Emeritus Professor of Medicine, University of Medicine (1), Yangon