Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.

Keywords: hematology; hemophagocytic lymphohistiocytosis; immunology.

FIGURE 1

Categorizing HLH Note. The HLH syndrome includes all conditions meeting consensus diagnostic criteria. This syndrome includes conditions that would benefit from HLH-directed immunosuppressive therapies, which are termed “HLH disease,” and those conditions that would not benefit from such therapy or require entirely different treatments, termed as “HLH disease mimics.” HLH disease includes recognizable subgroups: familial HLH with clear genetic etiology, HLH associated with malignancy, HLH associated with rheumatologic conditions (also called MAS), HLH observed after immune activating therapies (iatrogenic HLH, also called cytokine release syndrome), HLH associated with immune compromise (either primary immune deficiency or treatment-related immune suppression), and HLH not associated with other specific conditions. Recognition of these subcategories is valuable as this may alter treatment, though some categories overlap with each other or have indistinct borders (as indicated above), and may include examples of both HLH disease and HLH disease mimics. Use of these category-specific terms is preferred over the historical terms of “primary” and “secondary” because the older concepts are ambiguous due to increasing understanding of genetic complexity, involvement of infection in triggering multiple distinct variations of HLH, and varied application. Incomplete, forme fruste episodes of HLH (similar but not completely fulfilling diagnostic criteria) are also well recognized in patients with familial HLH and may occur in others, such as “mild MAS” in patients with soJIA.

FIGURE 2

Algorithm for diagnostic workup of HLH Note. Suggested assessment for patients suspected of having HLH. See Tables 1 and 2 for further explanation/context and Figure S1 for standard treatment roadmap with monitoring strategy.