The Haemophagocytic Syndrome Re-Visited: A Unique Asian Perspective.
Authors: Tan Daryl C.L. , Loh Yvonne , Hwang William , Linn Y.C. , Wong G.C. , Lim L.C. , Lee L.H. , Goh Y.T. , Koh Mickey 
Published: October 2019

Abstract
Introduction: Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by fever, hepatosplenomegaly, cytopenia and liver dysfunction due to dysregulated activation of non-neoplastic histiocytes. It is associated with a myriad of different causes, commonly resulting in an unfavourable outcome. Data pertaining to its approach is scarce. The link with various infectious agents results in geographical differences in the incidence and etiology. Advances in immunophenotyping has allowed it be better delineated. We report the clinical spectrum and outcome of 49 cases of HPS in an adult Asian population in a single institution over 5 years. Gaining a better insight into its etiology will help us adopt a better management approach.
Method: This is a retrospective analysis. Patients with findings of hemophagocytosis on bone marrow morphology were identified and clinical records of such patients were reviewed. Only patients who fulfil the criteria of having HPS were included.
Results: Of the 49 cases, 32 (65%) were due to malignant lymphoproliferative diseases (LPD), of which 22 (70%) were of NK/T and 10 (30%) were of B-cell lineages. The former group consisted peripheral T-cell lymphoma (PTCL) (n=10), hepatosplenic γδ TCL(n=2), anaplastic large TCL(n=2) and NK-cell LPD(n=8). Amongst cases of NK LPD, 3 started as extranodal nasal type, while 5 presented as aggressive NK-cell leukemia. Common to both the PTCL and NK-cell LPD was the demonstration of EBV involvement by EBER ISH or PCR for EBV DNA and the absence of serological evidence of an active EBV infection. Tumour masses were however not striking. Bone marrow, skin and liver biopsies appear to be of great importance for diagnosis. The distinct entity of fulminant EBV associated NK/T LPD, which typically affected young and seemingly immunocompetent patients was seen in 10 patients. Mortality was uniform, with MS of only 29 days. An immunomodulatory approach prior to ablative chemo seemed to prolong the survival. Cases of B-cell LPD (7 DLBCL, 2 lymphoplasmacytoid lymphoma and 1 MALT lymphoma) with HPS had a less ominous course. Advanced stages at presentation was peculiar. Other malignancies included metastaic gastric ca (n=1)and acute leukemia (n=1). Non-malignant causes of HPS (30%) included disseminated TB (n=5), SLE (n=3), HIV (n=2), bacterial (n=1) and dengue fever (n=1). Despite similar presenting features, the prognosis of non-malignant causes of HPS was good once appropriate treatment was instituted. Two patients with disseminated TB who did not receive anti-TB treatment due to a delay in diagnosis succumbed to HPS. Etiological cause of HPS could not be elucidated in only 3.
Discussion: The clinical spectrum is broad. Vigorous search for an underlying etiology is crucial. Infectious disease screening have to be guided by epidemiological data. Benign viral causes are not common compared to western data. Delay in diagnosis may compromise the outcome of a treatable infection. EBV-associated NK/T LPD accounts for a disproportionate number of cases unique to the Asian perspective and prognosis remains dismal. An important pitfall in their diagnosis is the lack of serological evidence of EBV, possibly implying a lack of humoral response to acute EBV infection. Reasons for the epidemiologic predisposition remain elusive, but one may speculate that high prevalence of EBV infection, together with a yet unidentified defect in immune response to EBV may play a role. Immunomodulation has a role in controlling the cytokine storm which may have a more detrimental effect than the LPD initially.