Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by persistent, dysregulated immune activation that leads to unremitting fevers, hyperferritinemia, cytopenias, multiorgan dysfunction, and death. Although primary HLH (pHLH) is associated with well-characterized genetic defects, the pathogenesis of secondary HLH (sHLH) is complex and multifactorial. This is complicated further in the intensive care unit (ICU), where the clinical phenotype of HLH overlaps substantially with sepsis syndromes and carries an exceptionally high mortality.

Despite its high mortality, prompt recognition and appropriate management with optimized pharmacotherapy can significantly improve survival. This is complicated by the diverse underlying triggers spanning multiple specialties that can contribute to the development of HLH. Therefore, successful management of HLH necessitates fundamental overarching principles to be followed:

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  Due to the variety of contributing factors and multi-organ involvement in HLH, a cross-specialty, multidisciplinary collaboration is essential and can improve mortality.

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  Understanding the fundamentals of the immunopathogenesis of HLH is vital as newer targeted therapies acting on the IFNγ-IL18 axis can also markedly improve outcomes.

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  When HLH is suspected–less toxic treatment approaches can often be pursued initially while evaluation for the underlying trigger is ongoing. ^,

This article aims to provide a comprehensive overview of the recognition, evaluation, and management of patients with possible HLH. It focuses on several key considerations specific to the ICU, such as distinguishing HLH from sepsis including the promise of new biomarkers, as well as emphasizing the importance of a broad diagnostic evaluation in all-comers, due to the myriad of underlying drivers that contribute to the development of HLH. Finally, it will highlight optimal initial treatment approaches with an emphasis on supportive care and suppressing the cytokine storm while identifying and treating all potential disease triggers.

HLH is the pathologic description of the characteristic findings from early reports of these cases. “Hemophagocytosis” is the engulfment of red blood cells by macrophages, although any cell can be consumed by macrophages during this process. While “lymphohistiocytosis” refers to the infiltration and proliferation of both lymphocytes and histiocytes (also known as monocytes/macrophages) within primarily the liver, spleen, and bone marrow, although any organ can be involved. When patients with similar findings were later described in the setting of rheumatic diseases, they were termed macrophage activation syndrome (MAS)—which is not a unique syndrome from HLH, but simply the same hyperinflammatory process occurring in the setting of an underlying autoimmune disease.

The hallmark of sepsis pathophysiology is an overwhelming host response to infection, typically characterized by prominent innate immune activation, hypotension, and end-organ damage. ^, In fulminant HLH, the cytokine profile demonstrates more prominent adaptive immune activation, primarily characterized by increases in the most important pathogenic drive of HLH, interferon-γ (IFNγ) . The overlapping clinical features between the 2 hyperinflammatory syndromes are significant, however, due to the specificity IFNγ production with HLH pathogenesis; demonstration of an IFNγ-driven cytokine profile with markers like C-X-C motif ligand-9 (CXCL9), ^,, a reliable surrogate marker of IFNγ-driven inflammation, are now being used in clinical settings to identify this unique patient population that may respond to IFNγ-targeting therapies such as ruxolitinib (Janus kinase inhibitor) and emapalumab (monoclonal antibody directly targeting IFNγ).

Available data suggest HLH may occur in up to approximately 4% to 5% of patients with sepsis. For context, sepsis affects an estimated 1.7 million adults annually in the United States and ∼50 million adults worldwide. ^, A UK population-based study estimates 1 to 2 HLH cases per 1,000,000 person-years (UK HLH registry). While macrophage hemophagocytic activity in sepsis could be part of their regulatory function, the evidence of hemophagocytosis in 2/3 of sepsis non-survivors raises concern that undiagnosed HLH may contribute to sepsis-related mortality. ^,, It also suggests that the true frequency in septic patients may be higher than recognized.

Increasing recognition has led to earlier therapeutic interventions, which leads to better outcome.

Since HLH is a systemic hyperinflammatory condition, any organ system can be involved. Typical features include.

Multiple consensus articles and criteria exist to aid in earlier identification of these high-risk patients. A summary of commonly used approaches include.

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  HiHASC : The “3 F’s”– Fever , rising Ferritin , and Falling blood counts.

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  EULAR/ACR Points to Consider: Persistent fever; elevated/rising ferritin, CRP, LDH, liver enzymes; inappropriately low or declining cell counts; coagulopathy; splenomegaly; CNS dysfunction.

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  Hines 2022 consensus : Critically ill patient with unexplained or disproportionate inflammation (fever, cytopenias, hyperferritinemia, hepatosplenomegaly, coagulopathy) or rapidly evolving MODS and poor response to appropriate empirical therapy/escalating support should be evaluated for HLH.

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  HLH-2004 : Developed in familial HLH; widely used across ages but less sensitive for early secondary disease ( Table 1 ).

  Table 1

  Early clinical laboratory findings and diagnostic criteria for recognizing HLH in the ICU

  Parameter	Early/Evolving HLH	Sepsis	HLH-2004	HScore	MAS-sJIA
  Patient subset	All	Any	Validated in children	Adults with any underlying cause	Children with systemic JIA
  Fever (°C)	Yes, despite antibiotic therapy	Yes	>38.5	<38.4: 0 38.4–39.4:33 >39.4: 49	Any
  Ferritin (ng/mL)	Elevated or rising ferritin	Mild- Up to 2000	>500	<2000: 0 2000–6000: 35 >6000: 50	>684
  Cytopenias	Low or dropping Blood cell counts (Falling blood counts)	Uncommon	Affecting more than 2 of 3 lineages: hemoglobin <90 g/L, platelets <100 × 10 9/L, neutrophils <1·0 × 10 9/L)	1 lineage: 0 2 lineages: 24 3 lineages: 34	Laboratory Criteria: Platelet count ≤ 181 × 109/L
  Fibrinogen	Low or dropping fibrinogen, even if not below criteria threshold	Uncommon	Low fibrinogenemia ≤1·5 g/L Or High trigylceride≥ 3·0 mmol/L, or both	Fibrinogen>2·5 g/L: 0 ≤2·5 g/L: 30	Fibrinogen ≤ 360 mg/dL (≤3.60 g/L)
  Triglyceride	High or increasing triglyceride, even if not above criteria threshold	Normal		<1·5 mmol/L: 0 1·5–4 mmol/L:44 >4 mmol/L:64	Triglycerides > 156 mg/dL (>1.76 mmol/L)
  Liver dysfunction	High or increasing AST, ALT, or Bilirubin	Shock Liver	No	Serum aspartate aminotransferase <30 IU/L: 0 or ≥30 IU/L:19	Serum aspartate aminotransferase >48 U/L
  Hepatomegaly/Splenomegaly or Lymphadenopathy	Either	Uncommon	Splenomegaly	No organomegaly: 0 Hepatomegaly or Splenomegaly: 23 Both hepatomegaly and splenomegaly: 38	N/A
  Hemophagocytosis in bone marrow, spleen, or lymph node	Yes	Literature showing evidence of hemophagocytosis, but it is unclear if these findings are evidence of undiagnosed HLH	Yes	Hemophagocytosis features on bone marrow aspirate No: 0 or Yes:35	N/A
  Low or no natural killer cell activity	Unreliable	Low NK count, but normal NK Cell Activity	Yes	No	N/A
  High soluble CD25 (≥2400 U/mL)	Sometimes	No	Yes	N/A	N/A
  CNS Dysfunction	Yes	Sometimes	N/A	N/A	N/A
  Minimum Required Score for Diagnosis	NA	NA	Four out of eight criteria	likelihood of 99% for score of 169 or above	Fever, Ferritin, and at least two of the Laboratory Criteria

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  HScore : Established in adults with sHLH; often performs well in ICU, including early recognition.

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  2016 MAS criteria : Designed for MAS in systemic JIA; sometimes extrapolated beyond original scope.

Historically, HLH has been classified as primary (genetic) versus secondary (reactive). Emerging data showing enrichment of heterozygous, protein-altering variants in HLH-associated genes among sHLH cohorts have begun to blur these boundaries. ^,, Genetic effect modifiers and/or haploinsufficiency may be more common than previously appreciated in adult sHLH. Moreover, malignancy and autoimmune-associated HLH frequently co-exist with acute/subacute infections. Clinically, sHLH is best approached as a multifactorial threshold syndrome that involves accumulation of immunologic and genetic risk factors that converge along the IFNγ-IL18 axis driving a life-threatening hyperinflammatory syndrome.

Upon presentation to the ICU, patients not only require acute stabilization and supportive care, but also a comprehensive clinical assessment for acute infectious triggers as well as immunologically predisposing diseases including hematologic malignancies, autoimmune conditions, lymphoproliferative diseases, and even genetic evaluation for immune dysregulation disorders. All individuals require broad CT imaging to screen for underlying malignancies, occult infections, and organ-specific involvement. Biopsies, including bone marrow biopsies, should be aggressively pursued to identify the underlying driver of the HLH, and not specifically to search for hemophagocytosis, which has a poor sensitivity and specificity for diagnosing HLH. ^, Additional key clinical considerations are detailed later ( Tables 2 and 3 ).

Infections are the most common acute triggers, however traumatic injuries, surgeries, and recent vaccinations can also precipitate episodes. ^, Every ICU patient with hyperinflammation warrants a broad evaluation for infection. Mechanistically, infections can contribute to HLH in multiple ways.

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  Direct IFN-γ induction (eg, Epstein-Barr virus [EBV], histoplasmosis, ehrlichiosis, anaplasmosis, mycobacteria, and other intracellular pathogens)

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  Acute trigger in a predisposed host (eg, influenza infection in Still’s disease)

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  Hyperinflammatory exacerbation despite partial treatment or underlying susceptibility (eg, bacteremia or herpes virus reactivation after initial improvement on immunosuppression)