Best of 2023: EULAR/ACR Guidance on Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Save

Editor's note: this article originally appeared July 26, 2023, and is being shared again as a Best of 2023. Enjoy!

A EULAR/American College of Rheumatology task force has established evidence based, up-to-date guidance, and expert opinion on the evaluation, management and monitoring of patients with Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), with the primary intent to halt disease progression and prevent life-threatening complications from HLH/MAS.

HLH and MAS are life-threatening systemic hyperinflammatory syndromes that can develop in many inflammatory contexts but have been prominently seen in Still's disease and COVID-19. Their rapid progression and potential for organ failure and mortality escalate the need for such guidance from a multinational, multidisciplinary task force of adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents. The task force formulated relevant research questions and conducted a systematic literature review (SLR) and a Delphi process to promulgate this guidance.

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.

Importantly, the nosology of overlapping terms are discussed including HLH, MAS, ‘cytokine storm syndrome’, ‘hyperinflammation’, cancer immunotherapy–related ‘cytokine release syndrome (CRS)’, ‘hyperferritinemic sepsis–induced multiorgan dysfunction’ or SARS-CoV2–associated ‘multisystem inflammatory syndrome of children or adults.  The TF use the term HLH/MAS, defined systemic hyperinflammation as a state of excessive immune activation at risk of progression to HLH/MAS.

Additionally, the TF identified three categories of contributors to the development of HLH/MAS: genetic causes of HLH/MAS, predisposing conditions (e.g., sJIA, lymphoma, certain metabolic conditions) that increase susceptibility and acute triggers (e.g., infections, immunotherapies).

Overarching Statements

• Systemic hyperinflammation is an immunopathological continuum; the characteristic clinical and laboratory findings are individually non-specific, but when viewed collectively and longitudinally are recognisable and warrant prompt diagnostic evaluation. Therapeutic intervention may be warranted even when not satisfying specific classification/diagnostic criteria for HLH/MAS.

• Systemic hyperinflammation can be associated with hyperferritinemia and can progress to life-threatening HLH/MAS.

• Systemic hyperinflammation and HLH/MAS can occur in nearly any inflammatory state, but certain predisposing conditions and/or inflammatory triggers warrant a high index of suspicion.

• Investigating and treating modifiable contributors to systemic hyperinflammation and HLH/MAS are essential in the management of every patient.

• HLH/MAS should be treated with an urgency based on both the degree of inflammation and extent of organ dysfunction; the goals of therapy are to prevent/limit immunopathology, preserve integrity of the ongoing diagnostic workup and minimise toxicity.

• The evaluation and management of patients with systemic hyperinflammation suspected of having or progressing to HLH/MAS may benefit from consultation with experts in these disorders.

Points to Consider

1. Recognition, screening and early diagnosis is paramount. These unexplained or unusually severe clinical and laboratory features, particularly if co-occurring, may represent a systemic hyperinflammatory syndrome and should prompt consideration of HLH/MAS in appropriate clinical contexts:

   • Persistent fever, Elevated and/or rising ferritin or other markers of inflammation/damage (CRP, LDH), Inappropriately low or declining haemoglobin, platelet counts or white blood cells (neutrophils and lymphocytes), Hepatic dysfunction (increased ALT, AST, bilirubin), Coagulopathy (low fibrinogen, increased PT/INR, increased d-dimers), Splenomegaly, CNS dysfunction.

   • Patients with features of a systemic hyperinflammatory syndrome that could represent or progress to HLH/MAS should have a ferritin level checked

   • Patients with a normal ferritin but ongoing clinical suspicion for HLH/MAS should have serial ferritin testing

   • In addition to ferritin, clinicians should obtain the following routine laboratory evaluations: CBC with differential, liver panel, fibrinogen, d-dimer, LDH and CRP

   • Following initial laboratory evaluations, assessment of specialised biomarkers of inflammation (e.g., IL-2Rα [CD25], CD163, IL-18, CXCL9, neopterin, if available) may further aid in the diagnosis of HLH/MAS. These tests should be interpreted in consultation with a specialist with expertise in HLH/MAS

2. Criteria: Existing classification or diagnostic criteria perform well in specific settings, but no single set of criteria is sufficient to diagnose a syndrome of HLH/MAS across all contexts.

3. Evaluating contributors and associations:

   • Certain underlying infections, rheumatic diseases, malignancies, metabolic diseases and genetic inborn errors of immunity are frequently associated with HLH/MAS and clinicians should consider evaluations for these in appropriate contexts.

   • Genetic testing in patients with probable HLH/MAS can dramatically affect diagnosis and management and should be considered early.

   • Decision-making about genetic testing in patients with probable HLH/MAS is complex, should integrate age, clinical features and laboratory/functional test results, and should involve specialists with expertise in HLH/MAS

   • In patients for whom genetic testing is indicated, next-generation sequencing (e.g., targeted gene panel, whole exome or whole genome sequencing) to screen for pathogenic variants, rather than single gene Sanger sequencing, is recommended.

   • Genetic counselling to assist with consenting and interpretation of results should be offered to patients being considered for genetic testing.

4. Prognostic factors and CNS involvement

   • Underlying malignancy, CNS involvement, liver failure, multiple organ dysfunction and prolonged active disease are associated with a poor prognosis in patients with probable HLH/MAS; these should prompt urgency in establishing the diagnosis of HLH/MAS, identifying triggering conditions and initiating appropriate treatment.

   • All individuals with probable HLH/MAS should undergo a complete neurological examination. Patients with any of the following should be assessed for CNS involvement: age <1 year, known genetic HLH disorder, encephalopathy, seizures, altered mental status, irritability, meningism, headache, vision changes or focal deficits.

   • Assessment for CNS involvement should include brain MRI and evaluation of cerebrospinal fluid glucose, protein and cell count with differential (with pathological review of cytology) when safe to do so.

   • In patients with probable HLH/MAS, assessment for CNS involvement should not delay initiation of systemic immunomodulatory therapy.4C9.7 ± 0.7

5. Treatment

   • For patients with probable HLH/MAS and persistent, severe or worsening inflammation or organ dysfunction, initiation of immunomodulatory treatment should be considered while diagnostic testing is ongoing.

   • Choice of initial immunomodulatory treatment is complex and requires balancing an assessment of urgent risk due to rapid HLH/MAS progression with potential for obscuring diagnosis of malignancy or worsening active infection.

   • Initial empiric immunomodulatory therapy in patients with rapidly progressive HLH/MAS could include high-dose glucocorticoids, anakinra and/or IVIg based on local access.

   • In addition to supportive care and immunomodulatory HLH/MAS treatment, patients should receive appropriate antimicrobial and antiviral therapies and treatment of any underlying triggers or disorders. 

   • In patients for whom prolonged immunomodulatory regimens are anticipated, consideration should be given to the use of antimicrobial and/or antiviral prophylaxis in consultation with an infectious disease expert.

6. Monitoring

   • In patients with probable HLH/MAS, worsening or lack of improvement in laboratory parameters of systemic inflammation (particularly ferritin), DIC, hepatitis or cytopenias may indicate disease progression and a need to re-assess diagnosis and/or treatment.

   • Patients with systemic hyperinflammation suspected of having or progressing to HLH/MAS require continuous clinical monitoring and frequent reassessment of organ dysfunction, which may necessitate ICU care.

   • Clinicians should monitor initial response to treatment by assessing clinical and laboratory markers of organ involvement at least daily and markers of systemic inflammation at least twice weekly.

7. Multidisciplinary teams: a multidisciplinary approach is preferred and can optimise the diagnostic workup and management of patients with systemic hyperinflammation and HLH/MAS.