Hemophagocytic Lymphohistiocytosis (HLH) – Early Recognition in the ICU: A Critical Review for Postgraduate Physicians

Dr Neeraj Manikath, Claude.ai

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that poses significant diagnostic and therapeutic challenges in the intensive care unit (ICU). This hyperactivation of macrophages and cytotoxic T cells creates a cytokine storm that can rapidly progress to multi-organ failure and death if unrecognized. The clinical presentation frequently mimics sepsis, making early recognition crucial for favorable outcomes. This review provides a comprehensive update on diagnostic approaches, differential diagnosis, and management strategies specifically tailored for critical care physicians managing postgraduate medical education.

Keywords: Hemophagocytic lymphohistiocytosis, HLH, critical care, diagnostic criteria, immunosuppression, ferritin

Introduction

HLH represents one of the most challenging diagnostic entities in critical care medicine, with mortality rates approaching 50-70% in ICU populations despite treatment. The syndrome results from uncontrolled immune activation, leading to excessive cytokine production and macrophage activation. Early recognition and prompt initiation of immunosuppressive therapy are paramount, as delayed treatment significantly worsens outcomes.

Pathophysiology: The Cytokine Storm

HLH occurs when the normal mechanisms of immune regulation fail, leading to persistent activation of macrophages and cytotoxic T lymphocytes. This results in:

Excessive production of inflammatory cytokines (TNF-α, IL-1β, IL-6, interferon-γ)
Macrophage infiltration into organs
Hemophagocytosis (destruction of blood cells by activated macrophages)
Coagulopathy and multi-organ dysfunction

The syndrome can be classified as primary (genetic defects in cytotoxic function) or secondary (triggered by infections, malignancies, or autoimmune diseases).

Clinical Presentation: The Great Mimicker

HLH presents with nonspecific symptoms that overlap significantly with sepsis and other critical care conditions:

Core Clinical Features

Fever (often persistent and high-grade)
Splenomegaly (present in 90% of cases)
Hepatomegaly (variable presentation)
Lymphadenopathy (may be subtle)
Rash (variable, often maculopapular)

Laboratory Hallmarks

Cytopenias (affecting ≥2 cell lines)
Hyperferritinemia (often >500 ng/mL, frequently >5000 ng/mL)
Elevated triglycerides (>265 mg/dL)
Hypofibrinogenemia (<150 mg/dL)
Elevated LDH and liver enzymes

Diagnostic Criteria: Evolution and Current Standards

HLH-2004 Criteria (Historical Standard)

The diagnosis requires 5 of 8 criteria:

Fever ≥38.5°C
Splenomegaly
Cytopenia (≥2 lineages): Hemoglobin <9 g/dL, Platelets <100,000/μL, Neutrophils <1000/μL
Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
Hemophagocytosis in bone marrow, spleen, or lymph nodes
Low or absent NK cell activity
Ferritin ≥500 ng/mL
Elevated soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL

HLH-2024 Criteria (Updated)

Recent updates have refined diagnostic approaches with improved sensitivity and specificity. The new criteria emphasize:

Modified ferritin thresholds
Enhanced cytokine profiling
Improved genetic testing algorithms

The "Three Fs" Rule

A practical ICU approach emphasizes looking for:

Fever (persistent, high-grade)
Falling blood counts (progressive cytopenias)
Ferritin (markedly elevated, often >5000 ng/mL)

Differential Diagnosis: Separating HLH from Mimics

Primary Differentials

Sepsis/Septic Shock

Similarities: Fever, cytopenias, organ dysfunction
Distinguishing features: HLH typically shows higher ferritin levels, splenomegaly, and lack of response to antimicrobials

Malignancy-Associated Complications

Lymphomas (especially T-cell and NK-cell)
Leukemias with hyperleukocytosis
Tumor lysis syndrome

Autoimmune Conditions

Systemic lupus erythematosus
Adult-onset Still's disease
Macrophage activation syndrome (MAS)

Drug-Induced Hypersensitivity

DRESS syndrome
Drug-induced liver injury with systemic features

Diagnostic Pearls

Ferritin >5000 ng/mL has high specificity for HLH
Progressive cytopenias despite supportive care should raise suspicion
Splenomegaly in the absence of portal hypertension
Lack of response to antimicrobials in suspected sepsis

Management Strategies: Time-Sensitive Interventions

Immediate Assessment (First 24 Hours)

Comprehensive workup for triggers (infections, malignancies)
Baseline investigations for HLH criteria
Genetic counseling consideration for familial cases
Multidisciplinary consultation (hematology, rheumatology)

Immunosuppressive Therapy

First-Line Treatment: HLH-2004 Protocol

Etoposide 150 mg/m² IV twice weekly
Dexamethasone 10 mg/m² daily (tapering schedule)
Cyclosporine A 3-5 mg/kg/day (in refractory cases)

Steroid Considerations

Methylprednisolone 1-2 mg/kg/day as alternative
Pulse steroids for severe cases
Tapering schedule critical to prevent rebound

Targeted Therapies

Emapalumab (anti-interferon-γ antibody) for refractory cases
Tocilizumab (IL-6 receptor antagonist) in selected cases
JAK inhibitors (ruxolitinib) emerging as rescue therapy

Critical Care Management

Supportive Care

Hemodynamic support with vasopressors as needed
Transfusion support for severe cytopenias
Infection prevention due to immunosuppression
Renal replacement therapy for acute kidney injury

Monitoring Parameters

Daily ferritin levels to assess response
Complete blood counts for cytopenia trends
Liver function tests for hepatotoxicity
Coagulation studies for DIC monitoring

Prognosis and Outcomes

Mortality Rates

ICU mortality: 50-70%
Early treatment (<7 days): Improved survival
Delayed recognition: Significantly worse outcomes

Prognostic Factors

Age (worse in elderly)
Underlying trigger (infection-related better than malignancy-related)
Organ dysfunction severity
Time to treatment initiation

Clinical Pearls and Oysters

Pearls (What to Remember)

Think HLH in any sepsis-like syndrome not responding to antimicrobials
Ferritin >5000 ng/mL should prompt immediate HLH workup
Splenomegaly + cytopenias = HLH until proven otherwise
Early immunosuppression saves lives; don't wait for all criteria
Treat the trigger alongside immunosuppressive therapy

Oysters (Common Mistakes)

Waiting for all 5 criteria before starting treatment
Assuming it's sepsis because the patient looks septic
Delaying hematology consultation for "unstable" patients
Starting steroids alone without etoposide in severe cases
Stopping immunosuppression too early due to infection concerns

Practical ICU Hacks

Rapid Assessment Tool

HLH Suspicion Score (Bedside Assessment):

Fever + Splenomegaly + Cytopenias = 3 points
Ferritin >1000 ng/mL = 2 points
Triglycerides >265 mg/dL = 1 point
Score ≥4: High suspicion, initiate workup

Emergency Management Algorithm

Recognize (Three Fs + clinical suspicion)
Investigate (HLH criteria + trigger workup)
Consult (hematology within 24 hours)
Treat (immunosuppression + supportive care)
Monitor (response markers + toxicity)

Communication Points

Family counseling about diagnosis and prognosis
Multidisciplinary rounds for complex decision-making
Clear handoffs regarding treatment protocols
Documentation of rationale for immunosuppression

Future Directions

Emerging Therapies

CAR-T cell therapy for refractory cases
Novel cytokine inhibitors (IL-18, IL-1β)
Personalized medicine approaches based on genetic profiling

Diagnostic Advances

Biomarker panels for rapid diagnosis
Point-of-care testing for soluble CD25
Artificial intelligence algorithms for early recognition

Conclusion

HLH remains one of the most challenging diagnoses in critical care medicine, requiring high clinical suspicion and prompt action. The key to success lies in early recognition using the "Three Fs" approach, rapid initiation of appropriate workup, and timely immunosuppressive therapy. Critical care physicians must maintain awareness of this condition and work closely with hematology colleagues to optimize patient outcomes.

The evolution of diagnostic criteria and treatment approaches continues to improve outcomes, but the fundamental principle remains unchanged: early recognition and prompt treatment are essential for survival in this devastating condition.

References

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Conflicts of Interest: None declared

Funding: No external funding received

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Tuesday, June 24, 2025