Can we truly diagnose adult secondary hemophagocytic lymphohistiocytosis (HLH)? A critical review of current paradigms

Abstract

The HLH-2004 criteria were initially conceived as inclusion criteria for a clinical trial investigating therapy for (largely primary) pediatric hemophagocytic lymphohistiocytosis (HLH). These criteria have since been extrapolated to diagnose adult secondary HLH despite their questionable generalizability. It remains unclear whether these diagnostic criteria are truly applicable among adult secondary cases, and rigorous evidence for their use among such patients is lacking. This review critically examines the utility of the HLH-2004 criteria for the diagnosis of adult secondary HLH. It is framed as a reappraisal of each of the criteria's individual components, with an assessment of the relevance of, and/or evidence regarding, each. There are clear limitations to these criteria as they apply to adult secondary HLH, however they may help guide our understanding of the disease to some extent. Some new paradigms are emerging for the diagnosis of adult secondary HLH, however these too are limited by the difficulties inherent in formulating specific criteria for a very non-specific syndrome, which lacks any single gold-standard diagnostic test.

Keywords: Adult HLH; Diagnosis; HLH-2004 criteria; Hemophagocytic lymphohistiocytosis (HLH); Secondary HLH; Specificity.