Secondary Hemophagocytic Lymphohistiocytosis (HLH): A Systematic Review of Incidence and Prognostic Outcomes

Introduction:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder caused by immune system dysregulation of natural killer cells, cytotoxic CD8+ T-cells and macrophages, resulting in malignant inflammation and multi-system failure. HLH can be classified into distinct primary and secondary entities; primary HLH presents in childhood due to genetic mutations, while secondary HLH typically presents in adulthood due to triggers inclusive of malignancy, infections, and autoimmune disease. This systematic literature review aimed to assess the characteristics and prognostic indicators of secondary HLH.

Methods:

A systematic review was conducted in adherence to the PRISMA guidelines. A literature search was performed utilizing Medline, Embase, Scopus, Cochrane, and Clinicaltrials.gov databases without restricting to a starting date. MeSH terms included “Secondary HLH,” “Acquired HLH,” “prognosis,” and “outcomes”. The inclusion criteria were defined as retrospective or prospective, randomized, or non-randomized controlled studies published in English that include adult patients over the age of 18 with secondary or acquired HLH and have outcomes of overall survival (OS), HLH-free/relapsed-free survival.

Results:

After meeting the inclusion criteria, 23 studies were included. Among the total 2833 patients with a median age of 48.3 years, 1482 (52%) males were studied. Most articles were published in China (48%), followed by Korea (13%) and the USA (13%). HLH secondary to malignancy (most frequently lymphomas) followed by infections (most frequently EBV) represented the most common etiologies across all the studies. Two studies involved ICU-related secondary HLH diagnoses, whereby sepsis-associated HLH with gram-negative bacteremia, particularly E. coli (30%), was most implicated. OS was a ubiquitously reported outcome, with only two studies (9%) including HLH-free survival/HLH-relapse-free survival. Most frequently reported statistically significant worse prognostic factors in terms of OS included older age 8 (35%), low platelets < 100 in 7 (30%), HLH-secondary to malignancy 7 (30%), with two studies demonstrating worse prognosis in terms of HLH-free survival as well. Other reported worse OS prognostic factors included HLH-secondary to EBV 6 (26%), low fibrinogen 5 (22%), elevated AST 5 (22%), elevated LDH >400 in 4 (17%), high bilirubin 4 (17%), albumin <2.8 g/dL 4 (17%), male sex 3 (13%), ferritin >2000 in 3 (13%), low hemoglobin 3 (13%), prolonged APTT 3 (13%), prolonged PT 3 (13%), elevated creatinine 2 (9%), sCD25 2 (9%) and elevated IL-10 in 2 (9%). The least frequently reported were prolonged INR, fever, low total T3, presence of fever, and elevated beta-2-microglobulin. One study demonstrated that germline HAVCR2 mutation had a better prognosis.

Conclusion:

Older age, thrombocytopenia, and malignancy were the most common, significantly worse prognostic indicators for secondary HLH when indexed to outcomes of OS. Several other prognostic indicators have been reported but require further research across more demographic populations to ascertain their strength of association and possibly direct future screening and management. This review also highlights a potential gap in the global understanding and documentation of secondary HLH, given the notable scarcity of studies from countries outside of China.

No relevant conflicts of interest to declare.