The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS)

Abstract

Objective: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS.

Methods: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.

Results: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.

Conclusion: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.

Figure 1.

Summary of the approach to early or suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). When HLH/MAS is suspected, providers should (in parallel and as clinically appropriate) assess for the key features of HLH/MAS, investigate suspected contributors and treat with supportive care, with empiric and prophylactic antimicrobials, with other prophylaxis regimens, and possibly with empiric immunomodulation. Ongoing monitoring and reassessment should prompt re-evaluation of treatments being given. Patients should transition to context-specific treatment immediately on identification of a confirmed aetiology. *Addressed in separate guidance documents, see www.histiocytesociety.org/HLH-consensus. α-IFNγ = interferon-γ neutralising antibody; CBC+diff = complete blood cell count with leucocyte differential; CMV = cytomegalovirus; CRP = C-reactive protein; CSF = cerebrospinal fluid; DIC = disseminated intravascular coagulopathy; DVT = deep vein thrombosis; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; GC = glucocorticoid; GGT = γ-glutamyl transferase; HLH94 = HLH-94 treatment protocol 1 or current standard of care; IVIg = intravenous immunoglobulin; LDH = lactate dehydrogenase; LFTs = liver function tests; PT/PTT = prothrombin time/partial thromboplastin time; TG = triglycerides; ruxo = ruxolitinib; ritux = rituximab.