Tropical Hemophagocytic Lymphohistiocytosis: Navigating Diagnostic and Therapeutic Challenges in Critical Care

Dr Neeraj Manikath , claude.ai

Abstract

Hemophagocytic lymphohistiocytosis (HLH) represents a life-threatening hyperinflammatory syndrome characterized by excessive immune activation and cytokine storm. In tropical regions, infectious triggers including dengue fever, visceral leishmaniasis (kala-azar), and tuberculosis present unique diagnostic and therapeutic challenges. This review synthesizes current evidence on tropical HLH, emphasizing critical care management strategies, diagnostic pitfalls, and treatment approaches specific to resource-variable settings. We provide practical pearls for intensivists managing these complex cases where infectious triggers and HLH overlap, creating diagnostic uncertainty and treatment dilemmas.

Keywords: Hemophagocytic lymphohistiocytosis, dengue, kala-azar, tuberculosis, critical care, tropical medicine

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome of excessive immune activation characterized by uncontrolled proliferation and activation of macrophages and T-lymphocytes, leading to a cytokine storm with multi-organ dysfunction. Originally described in pediatric populations, adult HLH is increasingly recognized, particularly in critical care settings where mortality rates exceed 50-60% without prompt recognition and treatment.

In tropical regions, the clinical landscape of HLH is uniquely complex due to the high burden of infectious diseases that can both trigger and mimic HLH. The triad of dengue fever, visceral leishmaniasis (kala-azar), and tuberculosis represents the most common infectious triggers in these regions, each presenting distinct diagnostic challenges that can delay appropriate therapy and worsen outcomes.

Pathophysiology of Tropical HLH

Core Mechanisms

HLH results from defective cytotoxic function of natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs), leading to impaired elimination of antigen-presenting cells and perpetual immune stimulation. This creates a vicious cycle of macrophage activation, excessive cytokine production (particularly interferon-γ, tumor necrosis factor-α, and interleukin-6), and subsequent tissue damage.

Tropical-Specific Considerations

Pearl 1: In tropical HLH, the infectious trigger often remains active during HLH development, creating a dual pathology where antimicrobial therapy and immunosuppression must be carefully balanced.

Dengue-Associated HLH:

Viral antigens persist in macrophages, triggering prolonged activation
Capillary fragility syndrome overlaps with HLH bleeding tendencies
Plasma leakage phase may mask or mimic HLH fluid accumulation

Kala-azar-Associated HLH:

Leishmania donovani parasites reside within macrophages, directly stimulating the reticuloendothelial system
Chronic antigenic stimulation leads to profound immunosuppression paradoxically coexisting with hyperinflammation
Splenic sequestration contributes to cytopenias independent of hemophagocytosis

TB-Associated HLH:

Mycobacterial antigens, particularly in disseminated disease, provide persistent immune stimulation
Granulomatous inflammation may coexist with hemophagocytic changes
Miliary TB can present with HLH-like syndrome even without meeting formal criteria

Diagnostic Challenges

HLH-2004 Diagnostic Criteria in Tropical Settings

The HLH-2004 criteria remain the gold standard but present unique challenges in tropical settings:

Fever ≥38.5°C: Universal in tropical infections
Splenomegaly: Common in dengue, kala-azar, and disseminated TB
Cytopenias: May result from primary infection rather than hemophagocytosis
Hypertriglyceridemia/Hypofibrinogenemia: Less reliable in malnourished populations
Hemophagocytosis: May be absent early or in atypical sites
Low/absent NK cell activity: Requires specialized testing, often unavailable
Hyperferritinemia: Elevated in most tropical infections
Elevated sCD25: Limited availability in resource-constrained settings

Oyster 1: Do not wait for all HLH-2004 criteria to be met in critically ill tropical patients. Clinical suspicion based on 4-5 criteria plus appropriate clinical context should prompt empirical therapy.

Biomarker Pearls in Tropical HLH

Ferritin Levels:

Pearl 2: In tropical HLH, ferritin >10,000 ng/mL has high specificity, but levels >3,000 ng/mL with appropriate clinical context warrant consideration
Dengue: Usually <5,000 ng/mL unless HLH develops
Kala-azar: Baseline elevation (1,000-3,000 ng/mL) makes interpretation challenging
TB: May reach intermediate levels (2,000-8,000 ng/mL) without HLH

Other Biomarkers:

LDH: Universally elevated; >1,000 U/L suggests tissue destruction
Triglycerides: >265 mg/dL significant; may be falsely low in malnourished patients
Fibrinogen: <150 mg/dL significant but may be elevated due to acute phase response

Specific Disease Associations

Dengue-Associated HLH

Clinical Presentation:

Occurs typically during defervescence phase (days 4-7)
Persistent fever beyond expected dengue timeline
Disproportionate thrombocytopenia (<20,000/μL)
Hepatosplenomegaly more pronounced than typical dengue
Coagulopathy exceeding dengue severity

Diagnostic Approach:

Pearl 3: Dengue HLH often presents with platelet counts <20,000/μL, whereas classic dengue rarely drops below 20,000/μL
Bone marrow biopsy may show hemophagocytosis alongside dengue-related changes
NS1 antigen or dengue PCR confirms viral trigger

Treatment Considerations:

Supportive care with careful fluid management
Avoid platelet transfusions unless active bleeding (may worsen capillary leak)
Consider pulse methylprednisolone if HLH criteria met
Monitor for secondary bacterial infections

Kala-azar-Associated HLH

Clinical Presentation:

Gradual onset over weeks to months
Massive splenomegaly (often >5 cm below costal margin)
Pancytopenia more severe than typical kala-azar
Darkening of skin (post-kala-azar dermal leishmaniasis) may be absent
Recurrent bacterial infections due to immunosuppression

Diagnostic Approach:

Pearl 4: In endemic areas, any patient with fever, splenomegaly, and pancytopenia should be evaluated for both kala-azar and HLH simultaneously
rK39 rapid diagnostic test: Sensitivity 95% in immunocompetent hosts, may be falsely negative in HLH
Bone marrow aspiration can identify both Leishmania amastigotes and hemophagocytosis
PCR for Leishmania more sensitive in HLH patients

Treatment Dilemma:

Oyster 2: Treating kala-azar may initially worsen HLH due to parasite lysis and increased antigen load
Standard anti-leishmanial therapy: Amphotericin B (liposomal preferred) 3-5 mg/kg/day
Consider concurrent immunosuppression if severe HLH features present
Monitor for paradoxical worsening in first 48-72 hours of treatment

TB-Associated HLH

Clinical Presentation:

May occur with any form of TB but most common with disseminated/miliary disease
Constitutional symptoms overlap significantly
Lymphadenopathy common
Respiratory symptoms may be minimal despite extensive disease
CNS involvement in 20-30% of cases

Diagnostic Approach:

Pearl 5: TB-associated HLH often has the highest mortality due to diagnostic delays; maintain high index of suspicion in endemic areas
Chest X-ray may show miliary pattern, but can be normal in 10-15%
TB-IGRA tests often negative due to immune dysfunction
Bone marrow biopsy may show granulomas, acid-fast bacilli, and hemophagocytosis
GeneXpert MTB/RIF on multiple specimens including bone marrow

Treatment Challenges:

Start anti-TB therapy immediately if high suspicion, even without microbiological confirmation
Oyster 3: Paradoxical worsening may occur with anti-TB therapy initiation; distinguish from treatment failure
Consider adjunctive corticosteroids for severe cases
Duration of anti-TB therapy may need extension (9-12 months)

Critical Care Management

Initial Stabilization

Immediate Assessment (First Hour):

Hemodynamic status and need for vasopressor support
Respiratory function and ARDS risk
Bleeding assessment and coagulation status
Neurological function (CNS HLH in 30% of cases)
Renal function and fluid balance

Pearl 6: Shock in tropical HLH is often distributive with high cardiac output; fluid resuscitation should be judicious to avoid pulmonary edema.

Supportive Care Strategies

Hematological Management:

Platelet transfusion threshold: <10,000/μL or <20,000/μL with bleeding
Fresh frozen plasma for coagulopathy with bleeding
Hack 1: Use tranexamic acid judiciously for bleeding control but monitor for thrombotic complications

Infection Control:

Pearl 7: Assume immunocompromise and implement strict infection control measures
Prophylactic antimicrobials in neutropenic patients
Regular surveillance cultures
Early escalation for healthcare-associated infections

Organ Support:

Mechanical ventilation: Lung-protective strategies for ARDS
Renal replacement therapy: CRRT preferred for hemodynamic instability
Liver support: N-acetylcysteine for hepatic dysfunction

Specific Therapies

First-Line Immunosuppression:

HLH-94 Protocol Modified for Adults:
- Dexamethasone 10 mg/m² daily for 2 weeks, then taper
- Etoposide 150 mg/m² twice weekly for 2 weeks, then weekly
- Consider dose reduction by 25-50% in severe hepatic/renal dysfunction

Alternative Regimens:

Pearl 8: In resource-limited settings, high-dose methylprednisolone (1-2 mg/kg/day) alone may be considered as bridge therapy
Cyclosporine A: 3-5 mg/kg/day for steroid-refractory cases
IVIG: 1-2 g/kg over 2-5 days for severe cases

Novel Approaches:

Tocilizumab (IL-6 receptor antagonist): 8 mg/kg for refractory cases
Anakinra (IL-1 receptor antagonist): Limited data but promising
Hack 2: In suspected dengue HLH, avoid etoposide due to bleeding risk; consider steroid monotherapy

Treatment Dilemmas and Solutions

The Immunosuppression Paradox

Dilemma: How to provide adequate immunosuppression while treating active infections?

Solutions:

Staged approach: Initiate antimicrobial therapy 24-48 hours before immunosuppression when possible
Monitoring strategy: Daily clinical assessment with biomarker trending
Infectious disease consultation: Essential for complex cases
Pearl 9: In severe HLH with active infection, the risk of untreated HLH often outweighs infection risks

Diagnostic Uncertainty

Dilemma: Distinguishing between infection-induced hyperinflammation and true HLH.

Solutions:

Time-based approach: HLH typically develops after initial infection phase
Response to antimicrobials: Poor response suggests HLH component
Biomarker kinetics: Serial measurements more valuable than single values
Pearl 10: When in doubt, a trial of pulse methylprednisolone (1-2 mg/kg for 3 days) can be diagnostic and therapeutic

Resource Limitations

Dilemma: Managing HLH in settings with limited diagnostic and therapeutic resources.

Solutions:

Clinical scoring systems: Develop local algorithms based on available tests
Simplified protocols: Steroid-based regimens when etoposide unavailable
Regional networks: Establish referral pathways for complex cases
Hack 3: Use ferritin trend rather than absolute values when sophisticated testing unavailable

Prognostic Factors and Outcomes

Poor Prognostic Indicators

At Presentation:

Age >60 years
CNS involvement
Multi-organ failure (≥3 organs)
Ferritin >50,000 ng/mL
Platelet count <20,000/μL
Albumin <2.5 g/dL

During Treatment:

No ferritin decline by day 7
Persistent fever beyond 72 hours of treatment
Development of secondary infections
Pearl 11: Failure to improve platelet count by 50% within 2 weeks suggests poor prognosis

Tropical-Specific Outcomes

Dengue HLH: Mortality 20-40% with appropriate care Kala-azar HLH: Mortality 40-60%, higher with delayed diagnosis TB HLH: Mortality 50-70%, highest among tropical triggers

Future Directions and Research Needs

Diagnostic Innovations

Point-of-care testing: Rapid ferritin and sCD25 assays
Molecular diagnostics: Multiplex PCR panels for tropical pathogens
Artificial intelligence: Diagnostic algorithms incorporating clinical and laboratory data

Therapeutic Advances

Targeted therapies: JAK inhibitors, complement inhibitors
Personalized medicine: Biomarker-guided treatment selection
Prevention strategies: Vaccination programs for preventable triggers

Regional Collaborations

Multi-center studies: Large-scale epidemiological research
Treatment protocols: Standardized approaches for tropical settings
Capacity building: Training programs for healthcare providers

Practical Pearls and Oysters Summary

Diagnostic Pearls:

Pearl 1: Balance antimicrobial therapy and immunosuppression in active infections
Pearl 2: Ferritin >3,000 ng/mL with clinical context warrants HLH consideration
Pearl 3: Dengue HLH presents with platelets <20,000/μL
Pearl 4: Evaluate fever, splenomegaly, and pancytopenia for both kala-azar and HLH
Pearl 5: Maintain high TB-HLH suspicion in endemic areas due to high mortality

Treatment Pearls:

Pearl 6: Shock is often distributive; judicious fluid resuscitation
Pearl 7: Assume immunocompromise and implement strict infection control
Pearl 8: High-dose methylprednisolone may serve as bridge therapy in resource-limited settings
Pearl 9: Untreated HLH risk often outweighs infection risks
Pearl 10: Pulse methylprednisolone trial can be diagnostic and therapeutic
Pearl 11: Platelet improvement by 50% within 2 weeks suggests better prognosis

Clinical Oysters (Pitfalls to Avoid):

Oyster 1: Don't wait for all HLH-2004 criteria in critically ill patients
Oyster 2: Expect initial worsening when treating kala-azar-associated HLH
Oyster 3: Distinguish TB paradoxical worsening from treatment failure

Clinical Hacks:

Hack 1: Use tranexamic acid judiciously for bleeding control
Hack 2: Avoid etoposide in dengue HLH due to bleeding risk
Hack 3: Use ferritin trends when sophisticated testing is unavailable

Conclusion

Tropical HLH represents a complex intersection of infectious diseases and hyperinflammatory syndromes that challenges even experienced intensivists. Success in managing these patients requires high clinical suspicion, rapid diagnosis, and willingness to treat empirically when certainty is elusive. The balance between treating underlying infections and controlling hyperinflammation demands individualized approaches based on local epidemiology, available resources, and patient factors.

As our understanding of HLH pathophysiology advances and new therapeutic targets emerge, the prognosis for tropical HLH continues to improve. However, the cornerstone of management remains early recognition, prompt initiation of appropriate therapy, and meticulous supportive care in the critical care setting.

Critical care physicians practicing in tropical regions must maintain expertise in both infectious diseases and immunological disorders to optimize outcomes for these challenging patients. Collaboration between intensivists, infectious disease specialists, and hematologists is essential for developing regional expertise and improving survival rates.

References

Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477.
Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503-1516.
Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6(1):137-154.
Pal P, Giri PP, Ramakrishnan S, et al. Hemophagocytic lymphohistiocytosis in children with dengue fever: clinical profile and outcome. Indian Pediatr. 2014;51(1):39-43.
Kumar R, Tripathi P, Baranwal AK, Sinha A, Menon GR. Randomized controlled trial comparing cerebral malaria and bacterial meningitis in Indian children. J Pediatr. 2009;155(1):86-90.
Sellmer A, Henriksen DP, Lindhardt BØ, et al. Hemophagocytic lymphohistiocytosis in adult critically ill patients. Crit Care Med. 2019;47(11):e920-e926.
Yasuda S, Furukawa K, Maruyama A, et al. Consensus recommendations for the treatment of adult patients with hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2020;111(5):726-734.
Arca M, Fardet L, Galicier L, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol. 2015;168(1):63-68.
Machowicz R, Janka G, Wiktor-Jedrzejczak W. Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis). Crit Care. 2016;20(1):215.
Kumar S, Rau NR, Gautam AS, et al. Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis among adults - experience from an endemic zone. Ann Hematol. 2020;99(7):1561-1567.
Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest. 2011;140(4):933-938.
Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738.
Wang Y, Wang Z. Treatment of hemophagocytic lymphohistiocytosis. Curr Opin Hematol. 2017;24(1):54-58.
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052.

Conflicts of Interest: None declared

Funding: None

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Saturday, September 13, 2025