Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an 
acute and rapidly progressive systemic inflammatory disorder characterized by 
cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical 
manifestations of HLH are acute unremitting fever, lymphadenopathy, 
hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, 
this clinical condition is considered as a cytokine storm syndrome. HPS has 
primary and acquired (secondary, reactive) forms. Its primary form is mostly 
seen in childhood and caused by various mutations with genetic inheritance and, 
therefore, is called familial HLH. Secondary HLH may be caused in the presence 
of an underlying disorder, that is, secondary to a malignant, infectious, or 
autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis 
and the clinical picture of HLH, and its severe complication, the cytokine 
storm, with a special emphasis on the developed classification criteria sets for 
rheumatologists, since COVID-19 infection has clinical symptoms resembling those 
of the common rheumatologic conditions and possibly triggers HLH. 
MED-LINE/Pubmed was searched from inception to April 2020, and the following 
terms were used for data searching: "hemophagocytic syndrome" OR "macrophage 
activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine 
storm". Finally, AND "COVID-19" was included in this algorithm. The selection is 
restricted to the past 5 years and limited numbers of earlier key references 
were manually selected. Only full-text manuscripts, published in an English 
language peer-reviewed journal were included. Manuscript selection procedure and 
numbers are given in Fig. 2. Briefly, the database search with the following 
terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR 
"Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results 
from inception to April 2020. The selection is restricted to the past 5 years 
and only limited numbers of earlier key references were selected, and this 
algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") 
resulted in 115 publications of which 47 studies, together with four sections of 
an online book were used in the final review. No statistical method was used. 
HLH is triggered by genetic conditions, infections, malignancies, 
autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, 
secondary HLH and cytokine storm may be responsible for unexplained progressive 
fever, cytopenia, ARDS, neurological and renal impairment. Differentiation 
between the primary and secondary forms of HLH is utterly important, since 
primary form of HLH requires complicated treatments such as hematopoietic stem 
cell transplantation. Further studies addressing the performance of HScore and 
other recommendations in the classification of these patients is necessary.