Neonate with haemophagocytic lymphohistiocytosis secondary to dengue infection: a case report

Introduction

Haemophagocytic lymphohistiocytosis (HLH) is a clinical and immunological syndrome characterised by an excessive inflammatory response due to defective inflammatory signalling, resulting in hyperactivation of macrophages and cytotoxic T lymphocytes leading to cellular damage. Haemophagocytosis in the reticuloendothelial system causes pancytopenia, hepatosplenomegaly and lymphadenopathy, progressive multi-organ failure and death if not treated. Owing to the resurgence of the Dengue epidemic, Dengue fever is no longer an uncommon presentation in neonates. Dengue fever, however, found in association with neonatal HLH, has not been heretofore reported.

Case summary

A term, male infant, of birth weight 2.5 kg, delivered by emergency Caesarean section for fetal distress to a second degree consanguineously married couple with a previous healthy baby, presented to our emergency room aged 16 days with fever, refusal of feeds and seizures. The baby had otherwise been thriving. On examination he was lethargic, pale, with cold peripheries, prolonged capillary refilling time and poor respiratory effort. There was no jaundice, petechiae or purpura and no dysmorphic features. The abdomen was distended with hepatomegaly of 10 cm and a palpable spleen of 5 cm. He was intubated, treated for shock with fluid boluses and inotropes and was started on intravenous antibiotics for probable late-onset septicaemia.

Initial full blood count, CSF and urine examination, blood and urine culture, C-reactive protein (CRP) and coagulation profile, renal function and lactate levels were unremarkable. Subsequently, however, an anaemia (Hb 7.2 gm/dl), leucocytosis (29,500 cells/cu mm) and thrombocytopenia (30,000 cells/cu mm) developed. The CRP rose. Liver transaminases became abnormal and a chest radiograph showed minimal bilateral pleural effusions. Abdominal ultrasonography confirmed hepatosplenomegaly with bilateral pleural effusions and minimal ascites.

The baby’s clinical condition did not improve, and so other differential diagnoses were considered. Investigations for scrub typhus, malaria, HIV and RSV were negative. IgM for Dengue virus was, however, positive. Further tests revealed low fibrinogen (<0.45 g/L) elevated triglycerides (2.22 mmol/L) and markedly elevated serum ferritin levels (16,500 µg/L). Bone marrow biopsy showed many haemophagocytes (Figure 1). The diagnostic criteria for HLH were fulfilled treatment with dexamethasone and etoposide as per HLH protocol 2004 ¹ was commenced. However, the neonate succumbed on the 11th day of illness. OPEN IN VIEWER

Discussion

Dengue infection results in a clinical spectrum varying from self-limiting Dengue fever to severe Dengue haemorrhagic fever or Dengue shock syndrome. Vertical transmission of the Dengue virus and anti-Dengue virus IgG are responsible for the pathogenesis of Dengue in neonates and infants, though primary Dengue with the presence of Dengue IgM in neonates has also been described.

HLH can be classified based on the underlying aetiology into primary or genetic and secondary or acquired. Primary HLH is caused owing to defective target action of cytotoxic lymphocytes. The primary form is familial and has an incidence of 1 in 50,000 births and the secondary form is found in association with infections, malignancies and rheumatologic conditions. ² In an Indian study, among 156 cases of HLH, 93 were children, of whom 24% were familial HLH. ² Neonatal HLH is rare and accounts for only 4% of all HLH cases. ³

Infection is the common trigger for secondary HLH in the tropics (44%). Viruses were identified in 56% of paediatric HLH, Epstein Barr virus being the commonest, while Dengue constituted 26%. ² The youngest case to be reported with HLH and Dengue was a 50-day-old male infant. ⁴ Our report is the first newborn case of HLH secondary to Dengue.

HLH is a fatal syndrome with non-specific but highly characteristic symptoms and laboratory findings. Children usually present with prolonged fever, hepatosplenomegaly, bleeding, skin rash, CNS abnormalities, jaundice, and the laboratory findings of bicytopenia or pancytopenia, coagulopathy, hyperlipidemia, hypofibrinogenemia, hyperferritinemia, raised transaminase levels, hyperbilirubinemia, hypoalbuminemia and hyponatremia.

Serum ferritin levels of >10,000 µg/L is pathognomonic of HLH. ⁵ The demonstration of haemophagocytes in the bone marrow is confirmatory.

The treatment of HLH aims to suppress the exaggerated immune response using immunosuppressive drugs. The 2004 HLH treatment protocol recommends an 8-week induction therapy with corticosteroids, etoposide and cyclosporine A. Corticosteroids are used to suppress the hypercytokinemia, cyclosporine A causes the inhibition of T-cell activation, and etoposide blocks cell division and cell proliferation. Despite treatment, mortality is very high. Haematopoietic stem cell transplantation is the only curative treatment for primary HLH. In cases of infection-associated HLH, the immediate treatment of the underlying disease is indicated. Our patient clearly had HLH secondary to Dengue infection though it was not possible to rule out familial HLH through molecular analysis as the parents did not consent.

Conclusion

In endemic areas, Dengue and a catastrophic haemophagocytic response should be considered when a neonate takes an unusual clinical course. The presence of hyperferritinemia and cytopenias warrants a bone marrow examination.