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Year : 2016  |  Volume : 9  |  Issue : 5  |  Page : 639-641  

Neonatal-onset hemophagocytic lymphohistiocytosis associated with primary dengue infection

1 Department of Pediatrics, NRS Medical College, Kolkata, West Bengal, India
2 Department of Pediatrics, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
3 Department of Pathology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India

Date of Web Publication13-Oct-2016

Correspondence Address:
Madhumita Nandi
6/6, Naren Sarkar Road, Barisha, Kolkata - 700 008, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-2870.192154

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A 40-day-old baby presented with prolonged fever, petechial spots, hepatosplenomegaly, generalized lymphadenopathy, and pancytopenia. Investigations revealed positive anti-dengue virus IgM antibody, and bone marrow examination demonstrated the presence of hemophagocytes. The diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made according to HLH-2004 guidelines. HLH associated with primary dengue in an infant who was symptomatic from neonatal age has hitherto not been reported in the literature.

Keywords: Hemophagocytic lymphohistiocytosis, infection-associated hemophagocytic syndrome, primary dengue virus infection

How to cite this article:
Nandi M, Roy SM, Das MK, Datta C. Neonatal-onset hemophagocytic lymphohistiocytosis associated with primary dengue infection. Med J DY Patil Univ 2016;9:639-41

How to cite this URL:
Nandi M, Roy SM, Das MK, Datta C. Neonatal-onset hemophagocytic lymphohistiocytosis associated with primary dengue infection. Med J DY Patil Univ [serial online] 2016 [cited 2020 Oct 22];9:639-41. Available from:

  Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition resulting from an uncontrolled and ineffective immune response. The predominant clinical findings are prolonged fever, splenomegaly, cytopenias, and liver dysfunction, and the characteristic biochemical markers include elevated triglycerides, ferritin, and low fibrinogen with evidence of hemophagocytosis in the reticuloendothelial systems. This disorder is potentially fatal and hence, an early diagnosis is required to start life-saving therapy in time.[1],[2] It could be associated with various types of infection, some collagen vascular diseases, and also some malignancies.[3] We hereby report a case of HLH with primary dengue virus infection having onset in the neonatal age.

  Case Report Top

A 40-day-old female infant born to nonconsanguineous healthy parents as their first baby presented with history of moderate grade intermittent fever for the past 2 weeks along with generalized petechial spots for the past 4 days. The family came from the same city as our Institute. Her mother had an uneventful antenatal period. Immediate perinatal period was also uneventful with normal birthweight. The baby was given occasional bottle feeds in addition to breastfeeding. On examination, her weight was 4.5 kg, and length was 53 cm (within 2 Z scores). There was pallor with significant generalized lymphadenopathy and petechial rashes over the trunk and extremities, but no icterus or pedal edema was seen. Abdomen was distended, and liver and spleen were palpable 2cm and 3 cm below the costal margins, respectively.

Investigations revealed hemoglobin of 7.6 g/dL, white blood cell count of 2600/mm 3 (absolute neutrophil count [ANC] 546/mm 3, N-21%, L-72%, M-6%, E-1%), and platelet count of 16,000/mm 3. Reticulocyte count was 2.8%. Malaria parasite and dual antigen were negative. Blood culture did not show any growth. Widal test was nonreactive, and serology for TORCH panel of both the patient and the mother was negative. Total serum protein, albumin, and globulin were 6.7, 3.2, and 3.5 g/dl, respectively, and serum cholesterol was 124 mg/dl. Anti-hepatitis C virus, hepatitis B virus surface antigen, and venereal diseases reference laboratory were nonreactive. Urine examination was within normal limits.

The baby was treated empirically with broad-spectrum intravenous (IV) antibiotics and repeated platelet and red blood cell transfusions. However, there was persistent fever with worsening of general condition and progressively increasing size of liver and spleen. There was appearance of generalized edema and seizure episodes on day 5 of the admission. The cause of this sudden onset of seizures could not be ascertained as the electrolyte and blood sugar levels were maintained. Cranial imaging studies could not be performed in the critically ill baby. Considering congenital leukemia as one of the possibilities, we did bone marrow aspiration study. The marrow revealed normocellularity for age along with a fair number of histiocytes with features of hemophagocytosis [Figure 1]. Further investigations included that serum ferritin was 20,000 µg/L, triglyceride was 410 mg/dL, and plasma fibrinogen level was 67.6 mg/dL. Before consideration of familial HLH, the serological investigations for some viral infections were done. EB-VCA IgM was negative. Dengue IgM was reactive and dengue IgG was nonreactive, suggesting primary dengue infection. No laboratory evidence of capillary leak was found.
Figure 1: Bone marrow aspirate smear showing erythrophagocytosis (Leishman, ×400). Black arrow indicates normoblast within cytoplasm of macrophages (blue arrow)

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Considering the clinical, biochemical, and hematological features, a diagnosis of infection-associated hemophagocytic syndrome (IAHS) was made based on Histiocytic Society Protocol Entitled HLH 2004 Criteria.[4] Persistent fever (>3 weeks), pancytopenia with worsening of general condition, appearance of generalized edema, repeated convulsions, and progressive splenohepatomegaly led us to start IV pulse methyl prednisolone 30 mg/kg/day along with other supportive care on day 8. However, unfortunately, the baby succumbed with sudden development of pulmonary hemorrhage on the next day.

  Discussion Top

HLH is a rare and potentially fatal syndrome associated with a variety of genetic, malignant, autoimmune disorder, and infection-associated conditions.[3] The pathological hallmark of the disease HLH is uncontrolled and nonmalignant hyperinflammation, caused by unremitting activation of CD8+ T-cells and macrophages, and excessive levels of cytokines.[3] The spleen, liver, lymph nodes, bone marrow, skin, and neural membranes are the preferential sites of involvement.[4]

According to the Histiocyte Society Protocol Entitled HLH 2004, the diagnosis of HLH can be established if five out of the following eight diagnostic criteria:

  1. Fever (>7 days),
  2. Splenomegaly,
  3. Cytopenia (>2 lineages) — anemia (haemoglobin <9 g/dL), thrombocytopenia (<100,000/mm 3), and neutropenia (ANC <1000/mm 3),
  4. Hypertriglyceridemia (>265 mg/dL) and/or hypofibrinogenemia (<1.5 g/L),
  5. Hemophagocytosis (bone marrow, spleen, lymph node),
  6. Low/absent NK-cell activity,
  7. Hyperferritinemia (>500 mcg/L), and
  8. Increased soluble CD25 >2400 units/mL are met.[4]

The index case fulfilled 6 out of these 8 criteria (fever, splenomegaly, cytopenia, hypertriglyceridemia and hypofibrinogenemia, hemophagocytosis in bone marrow, and hyperferritinemia). NK-cell activity and CD25 could not be done due to lack of facilities.

HLH comprises two different conditions: primary or genetic and secondary or acquired form. The acquired (secondary) form may be associated with infections (IAHS), malignancies (malignancy-associated hemophagocytic syndrome), and rheumatologic disorders (macrophage activation syndrome). IAHS is associated with viral infections as well as with several bacterial, fungal, rickettsial, and parasitic infections. Viral infections mostly implicated in association with HLH are Epstein–Barr virus, enterovirus, herpes simplex virus, cytomegalovirus, adenovirus, and also dengue virus.[2] Dengue fever, caused by Flavivirus, is an important mosquito-transmitted disease in many countries. Although a few cases of dengue-associated HLH have been reported,[3],[5] but none so far in an infant with onset in the neonatal age. Extensive search in literature has not yielded any result for HLH associated with primary dengue in such a young infant.

  Conclusion Top

The chances of complicated or severe dengue in infants increase in the presence of passive anti-dengue IgG antibody acquired from the mother transplacentally. However, we need to be aware of the fact that even in the absence of transplacental transfer of IgG antibodies, serious complications such as HLH can occur in neonates with consequent lethality as in our patient. Awareness about such a possibility is of utmost importance so that appropriate management can be given early within the salvageable window period.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Aricò 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;10:197-203.  Back to cited text no. 1
Sullivan JL and Woda BA. Lymphohistiocytic disorders. In: Nathan DG, Orkin SH, Ginsburg D, Look AT (eds) Nathan and Oski's Hematology of Infancy and Childhood, 6th ed. vol 2. Philadelphia: W.B. Saunders Co., 2003. 1375-95.  Back to cited text no. 2
Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am 2008;28:293-313, viii.  Back to cited text no. 3
Henter JI, Horne A, Aricó 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
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. 5


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