Abstract
Infection-associated hemophagocytosis is a diagnostic challenge. The varied presentation makes timely diagnosis difficult. We report two cases with unusual presentation of well-established secondary triggers for hemophagocytic lymphohistiocytosis.
Keywords: HLH, Infectious causes, leishmaniasis, EBV infection in HLH, Hepatic failure in HLH
Dear Editor,
Various infections are known to present with hemophagyctosis without triggering the immune dysregulation associated with HLH. Pediatric secondary HLH may be triggered by various tropical infections. We report two cases with unusual presentation of well-established secondary causes of HLH in terms of age and disease course. Hemophagocytic lymphohistiocytosis is a complex hyper immunity either genetic/primary or secondary/Acquired disorder, with a hyperactivity immune system and evidence of hemophagocytosis [1]. Timely diagnosis is the key to the favorable outcome when triggered by tropical infections like EBV, leishmaniasis, malaria, CMV, herpes simplex virus (HSV), varicella-zoster (VZV), Tuberculosis etc. [2–4].
Case 1: Leishmaniasis with Hemophagocytosis Meeting HLH Criteria
A 6-month-old child, presented with high-grade fever with chills and rigors abdominal distension for three months with severe pallor, and hepatomegaly. All tests for endemic chronic febrile tropical illness, - malaria, dengue, kala-azar, typhoid, urinary tract infection, TB and rickettsia were negative. With persistent high fever spikes, splenomegaly and pancytopenia, the possibility of secondary HLH were considered. Fasting high serum triglycerides 692 mg/dL and serum ferritin 1650ng/mL, and bone marrow examination showing intracellular and extracellular LD Bodies with hemophagyctosis suggested a diagnosis of kala-azar with infection associated hemophagyctosis. The child was treated with injectable liposomal amphotericin B At 2 weeks of follow-up, counts had recovered except for mild thrombocytopenia and regressing or organomegaly. The child currently asymptomatic at two years of follow-up.
Case 2: Spontaneous Remission of EBV Infection with Fatal Reactivation:
Two years male, with complaints of fever for 20 days, generalized swelling. Examination showed bilateral submandibular and cervical lymph nodes, hepatosplenomegaly, and bilateral testicular enlargement. Investigations revealed anemia with thrombocytopenia with deranged liver enzymes and increased LDH. A differential diagnosis of tuberculosis, hematolymphoid malignancy and Ebstein Bar virus (EBV) infection was considered. Epstein bar virus antibody panel showed VCA (Viral capsid antigen) IgM positive indicating an early stage of primary EBV infection. Bone marrow biopsy revealed scattered foci of erythrophagocytosis – suggestive of hemophagocytosis. CECT chest & abdomen showed hepatosplenomegaly with multiple small ill-defined hypodense lesions in the liver, spleen, lungs & kidney with bilateral pleural effusion. multiple generalized lymphadenopathies. Serum ferritin and Triglycerides were raised s. fibrinogen 378 mg/dl, s. triglycerides 425 mg/dl, s. ferritin 6459ng/dl. The child was started on oral steroids awaiting the final diagnosis with marked improvement in clinical condition. Genetic testing for HLH was negative. A diagnosis of EBV-associated HLH vs. systemic T cell lymphoproliferative disorder was considered. Flow cytometry screening for SAP and XIAP was negative. On follow-up at 8 weeks, he had spontaneous resolution (steroid was stopped at 2 weeks) & asymptomatic with imaging showing complete resolution. There was a loss to follow-up for 18 months when Child presented with fulminant hepatic failure with laboratory features of HLH and EBV reaction was considered as a possible cause.
We highlight the need for a detailed investigation of secondary causes of HLH and timely diagnosis as key to improving outcomes in settings with a high incidence of tropical infection.
Declarations
Conflict of Interest
All authors wish to declare no conflict of interests.
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References
- 1.Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: An update on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139:713–727. doi: 10.1309/AJCP4ZDKJ4ICOUAT. [DOI] [PubMed] [Google Scholar]
- 2.Marsh RA, Haddad E. How i treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182(2):185–199. doi: 10.1111/bjh.15274. [DOI] [PubMed] [Google Scholar]
- 3.Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017;129(22):2993–2999. doi: 10.1182/blood-2016-12-753830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–131. doi: 10.1002/pbc.21039. [DOI] [PubMed] [Google Scholar]