Primary (familial/hereditary) and secondary (non-familial/hereditary) 
hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and 
hypercytokinemic syndromes. Secondary HLH includes infection- (eg 
viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or 
malignancy) related diseases. Viral HLH is the major type among all age groups. 
Secondary viral HLH and primary HLH must be differentiated carefully because 
primary HLH can be associated with viral infection(s), and the outcome is dismal 
without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). 
Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral 
HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, 
followed by immunomodulatory agent(s) such as corticosteroids, intravenous 
immunoglobulin or cyclosporine A, is usually successful; however, recent 
SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur 
heterogeneously associated with the primary infection, with chronic active EBV 
infection or with underlying primary HLH. Although immunomodulatory agent(s) are 
effective in the majority of EBV-HLH cases, management differs from that of 
non-EBV-HLH because severe and refractory cases may require etoposide-containing 
HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab 
(an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid 
the risk of secondary malignancy due to etoposide. Finally, HSCT is required for 
refractory EBV-HLH cases and can also be curative in some other cases.