Visceral Leishmaniasis with HIV Coinfection: Critical Care Perspectives and Therapeutic Challenges

Dr Neeraj Manikath , claude.ai

Abstract

Background: The intersection of visceral leishmaniasis (VL) and HIV coinfection presents formidable challenges in critical care settings, particularly in endemic regions. This dual pathogen burden creates a synergistic immunosuppressive state that significantly complicates diagnosis, treatment, and prognosis.

Objective: To provide critical care physicians with evidence-based insights into the pathophysiology, diagnostic challenges, and therapeutic management of VL-HIV coinfection in intensive care units.

Methods: Comprehensive review of recent literature (2018-2024) focusing on critical care aspects of VL-HIV coinfection, including pathophysiology, diagnostic modalities, therapeutic interventions, and outcome predictors.

Results: VL-HIV coinfection demonstrates accelerated disease progression, atypical presentations, increased drug resistance, and higher mortality rates. Modern diagnostic approaches combining molecular techniques with clinical scoring systems show promise. Therapeutic strategies require careful consideration of drug interactions, immune reconstitution inflammatory syndrome (IRIS), and multiorgan support.

Conclusion: Successful management requires early recognition, prompt initiation of anti-leishmanial therapy alongside optimal HIV care, and anticipatory management of complications in the ICU setting.

Keywords: Visceral leishmaniasis, HIV coinfection, critical care, IRIS, amphotericin B, miltefosine

Introduction

Visceral leishmaniasis (VL), caused by Leishmania donovani and L. infantum, represents one of the most lethal parasitic diseases globally, with an estimated 50,000-90,000 new cases annually (1). The convergence of VL and HIV epidemics, particularly in the Mediterranean basin, East Africa, and the Indian subcontinent, has created a complex clinical syndrome that challenges even experienced critical care practitioners.

The bidirectional relationship between these pathogens creates a "perfect storm" of immunosuppression: HIV depletes CD4+ T cells essential for anti-leishmanial immunity, while Leishmania parasites accelerate HIV replication and disease progression (2). This synergy results in atypical presentations, diagnostic challenges, therapeutic complications, and significantly increased mortality rates, particularly when patients require intensive care support.

Epidemiology and Risk Stratification

Global Distribution and Emerging Patterns

VL-HIV coinfection prevalence varies geographically, with rates of 2-15% in endemic areas rising to 25-70% in specific high-risk populations (3). The epidemiological shift from rural to urban settings, driven by HIV prevalence in cities, has important implications for critical care services.

🔹 Clinical Pearl: In HIV-positive patients from endemic areas presenting with unexplained fever, pancytopenia, or hepatosplenomegaly, maintain high suspicion for VL even in non-traditional geographical locations due to increased travel and migration patterns.

ICU Risk Factors

Patients requiring ICU admission typically present with:

Severe pancytopenia (platelets <50,000/μL, hemoglobin <7 g/dL)
Secondary bacterial infections or sepsis
Acute renal failure
Respiratory failure
Cardiovascular collapse
Altered mental status

Risk stratification score (proposed):

CD4+ count <200 cells/μL (2 points)
Hemoglobin <7 g/dL (2 points)
Platelet count <50,000/μL (2 points)
Secondary infection present (3 points)
Duration of symptoms >4 weeks (1 point)

Score ≥6: High risk for ICU requirement and mortality

Pathophysiology: The Immunological Catastrophe

Synergistic Immunosuppression

The pathophysiological interaction between HIV and Leishmania creates a devastating cycle:

HIV-mediated immune dysfunction depletes CD4+ T cells, essential for Th1-mediated anti-leishmanial responses
Leishmania-induced immune exhaustion occurs through:
- Upregulation of inhibitory receptors (PD-1, CTLA-4)
- Increased IL-10 and TGF-β production
- Macrophage deactivation and apoptosis
Accelerated HIV replication within infected macrophages increases viral load
Chronic inflammation leads to multi-organ dysfunction

Molecular Mechanisms in Critical Illness

Recent research highlights key molecular pathways:

mTOR pathway dysregulation affecting cellular metabolism and immune function (4)
Complement system activation contributing to tissue damage
Coagulation cascade disruption leading to bleeding complications
Endothelial dysfunction precipitating vascular complications

🔹 Mechanistic Insight: The paradoxical increase in inflammatory markers (ferritin, LDH, CRP) despite profound immunosuppression reflects dysregulated innate immunity rather than effective pathogen control.

Clinical Presentation: Recognizing the Atypical

Classical vs. Coinfection Presentation

Feature	VL Alone	VL-HIV Coinfection
Fever pattern	Continuous/intermittent	Often absent/atypical
Splenomegaly	Marked	Variable/absent
Lymphadenopathy	Uncommon	Frequent
Skin lesions	Rare	Up to 60% of cases
Parasitemia	Low	High
Disease progression	Weeks to months	Days to weeks

ICU Presentation Patterns

Primary presentations requiring ICU care:

Septic shock syndrome (40% of ICU admissions)
Pancytopenia-related complications (bleeding, severe anemia)
Respiratory failure (ARDS, pneumonia)
Acute kidney injury (drug-induced, volume depletion)
Neurological complications (encephalitis, seizures)

🔹 Diagnostic Hack: In HIV patients with "sepsis of unknown origin," unexplained pancytopenia, or hepatosplenomegaly, obtain bone marrow aspirate and Leishmania PCR even if initial blood cultures are positive for bacteria – dual pathology is common.

Diagnostic Challenges in Critical Care

Traditional vs. Modern Approaches

Limitations of conventional diagnostics in ICU:

Serology may be negative or delayed in severe immunosuppression
Bone marrow biopsy carries bleeding risks in pancytopenic patients
Splenic aspirate contraindicated in unstable patients

Advanced Diagnostic Strategies

1. Molecular Diagnostics:

Real-time PCR on blood: Sensitivity 95-100%, specificity >95% (5)
Point-of-care PCR platforms reducing time to diagnosis
Quantitative PCR for monitoring treatment response

2. Rapid Diagnostic Tests (RDTs):

rK39-based tests: Limited utility in HIV coinfection (sensitivity 60-80%)
Novel biomarkers: KMP-11, A2 proteins showing promise

3. Advanced Imaging:

18F-FDG PET-CT: Identifies extranodal involvement
Contrast-enhanced ultrasound: Assessment of splenic involvement

🔹 Laboratory Pearl: Elevated ferritin (>2000 ng/mL) with low transferrin saturation in the setting of pancytopenia should trigger Leishmania evaluation, as this pattern is highly suggestive of VL-HIV coinfection.

Diagnostic Algorithm for ICU

HIV+ patient with fever + pancytopenia + organomegaly
                        ↓
    Immediate: Blood PCR + Bone marrow PCR (if feasible)
                        ↓
    Positive ←→ Negative but high suspicion
                        ↓
    Start treatment → Repeat testing in 48-72 hours
                        ↓
                Consider alternative diagnoses

Therapeutic Management: The Critical Care Perspective

First-Line Therapy Selection

Liposomal Amphotericin B (L-AmB) remains the gold standard:

Dosing in ICU: 3-5 mg/kg/day for 5-10 days
Advantages: Rapid parasite clearance, reduced toxicity vs. conventional AmB
Monitoring: Daily creatinine, electrolytes, liver function

Alternative agents:

Miltefosine: 2.5 mg/kg/day (max 150 mg) × 28 days
- Contraindicated in pregnancy
- Monitor for GI toxicity, elevated transaminases
Paromomycin: Limited efficacy in HIV coinfection
Pentavalent antimonials: Contraindicated due to high toxicity

ICU-Specific Considerations

1. Drug Interactions:

L-AmB + HIV protease inhibitors: Monitor for nephrotoxicity
Miltefosine + efavirenz: Potential hepatotoxicity
Consider therapeutic drug monitoring when available

2. Supportive Care:

Fluid management: Balance between adequate perfusion and avoiding pulmonary edema
Electrolyte monitoring: Particularly potassium and magnesium with L-AmB
Transfusion strategy: Liberal approach given severe anemia and bleeding risk

🔹 Therapeutic Hack: Pre-loading with 500-1000 mL normal saline before L-AmB reduces nephrotoxicity without increasing fluid overload risk in most ICU patients.

HIV Management During Acute VL

Antiretroviral therapy (ART) considerations:

Continue ART if already established (interruption worsens outcomes)
Delay ART initiation if treatment-naïve (risk of IRIS)
Optimal timing: Start ART 2-4 weeks after VL treatment initiation
Preferred regimens: Integrase inhibitor-based to minimize drug interactions

Complications and Their Management

Immune Reconstitution Inflammatory Syndrome (IRIS)

Epidemiology: Occurs in 25-40% of patients starting/restarting ART during VL treatment (6)

Clinical manifestations:

Paradoxical worsening of fever, lymphadenopathy, hepatosplenomegaly
New onset symptoms 2-12 weeks after ART initiation
Laboratory findings: Rising inflammatory markers despite parasite clearance

Management approach:

Confirm parasitological response to VL therapy
Continue both ART and anti-leishmanial therapy
Corticosteroids: Prednisolone 1 mg/kg/day × 2-4 weeks for severe cases
Supportive care: Manage organ-specific complications

🔹 IRIS Pearl: Distinguished from VL treatment failure by: continued parasite clearance on PCR, temporal relationship with ART, and response to steroids while continuing anti-leishmanial therapy.

Secondary Infections

Common bacterial co-pathogens:

Staphylococcus aureus, Streptococcus pneumoniae (skin, pneumonia)
Salmonella species (enteric fever)
Mycobacterium tuberculosis (pulmonary/extrapulmonary)

Management strategy:

Empirical broad-spectrum antibiotics in septic patients
Anti-tuberculosis therapy if clinical/radiological suspicion
Prophylaxis: Consider cotrimoxazole for PCP prevention

Organ-Specific Complications

1. Acute Kidney Injury:

Causes: Drug toxicity (L-AmB), volume depletion, sepsis
Management: Fluid optimization, electrolyte correction, consider RRT

2. Respiratory Failure:

Etiologies: Secondary pneumonia, ARDS, fluid overload
Approach: Early intubation, lung-protective ventilation

3. Cardiovascular Collapse:

Mechanisms: Septic shock, drug-induced cardiotoxicity
Treatment: Vasopressors, careful fluid management

Monitoring and Prognostication

Treatment Response Assessment

Clinical parameters:

Defervescence (usually within 5-7 days)
Reduction in organomegaly
Improvement in blood counts

Laboratory monitoring:

Quantitative PCR: >2-log reduction at 1 month indicates good response
Biomarkers: Declining ferritin, rising albumin
HIV markers: Stable/improving CD4 count, controlled viral load

Prognostic Indicators

Poor prognosis factors:

Age >50 years
CD4+ count <50 cells/μL
Severe anemia (Hb <5 g/dL)
Acute kidney injury
Secondary bacterial infections
Delayed diagnosis (>4 weeks symptoms)

ICU-specific mortality predictors:

APACHE II score >20
Need for mechanical ventilation
Vasopressor requirement
Multi-organ failure

🔹 Prognostic Pearl: Early clinical improvement (fever reduction within 72 hours) strongly predicts survival, while persistent fever beyond 7 days suggests treatment failure or complications.

Secondary Prevention and Long-term Management

Relapse Prevention

Risk factors for relapse:

CD4+ count persistently <200 cells/μL
Incomplete primary treatment
Drug resistance
Non-adherence to ART

Secondary prophylaxis indications:

CD4+ count <200 cells/μL after initial treatment
≥2 previous VL episodes
Poor treatment adherence
High endemic exposure

Prophylactic regimens:

Amphotericin B: 3 mg/kg every 3-4 weeks
Pentamidine: 4 mg/kg every 2-4 weeks
Miltefosine: 50-100 mg daily

Long-term Monitoring

Follow-up schedule:

Months 1, 3, 6, 12, then every 6 months
Monitor: Clinical status, blood counts, HIV parameters, VL PCR

Emerging Therapies and Research Directions

Novel Anti-leishmanial Agents

Pipeline drugs:

Fexinidazole: Oral nitroimidazole showing promise in Phase II trials
DNDI-0690: Oxaborole compound with potent anti-leishmanial activity
Combination therapies: L-AmB + miltefosine reducing treatment duration

Immunomodulatory Approaches

Therapeutic targets:

PD-1/PD-L1 inhibitors: Reversing T-cell exhaustion
IL-7 therapy: Enhancing T-cell recovery
Therapeutic vaccines: Boosting anti-leishmanial immunity

Precision Medicine

Pharmacogenomics:

CYP2C19 polymorphisms affecting miltefosine metabolism
MDR1 variants influencing drug efflux
HLA typing for IRIS risk stratification

Clinical Pearls and Oysters

🔹 Diagnostic Pearls

"Sepsis mimic": VL-HIV coinfection can present as bacterial sepsis with positive blood cultures for opportunistic organisms
"The ferritin trap": Extremely high ferritin (>5000 ng/mL) may suggest hemophagocytic lymphohistiocytosis (HLH) secondary to VL
"Skin tells the story": Cutaneous lesions in HIV patients should prompt VL evaluation even without systemic symptoms
"The platelet paradox": Severe thrombocytopenia with minimal bleeding may indicate hypersplenism rather than consumption

🔸 Therapeutic Oysters (Common Pitfalls)

"The ART rush": Starting ART immediately can precipitate severe IRIS – delay 2-4 weeks after VL treatment initiation
"The steroid trap": Avoid empirical steroids for fever in HIV patients without excluding VL – can worsen parasitic load
"The miltefosine mistake": Don't use miltefosine as monotherapy in severe VL-HIV coinfection – L-AmB remains first-line
"The PCR pitfall": Negative initial PCR doesn't exclude VL in severely immunosuppressed patients – repeat testing essential

🔹 ICU Management Hacks

"The volume balance": Use CVP/echo guidance for fluid management in pancytopenic patients with capillary leak
"The transfusion strategy": Maintain Hb >8 g/dL and platelets >20,000/μL in actively treated patients
"The antimicrobial approach": Start broad-spectrum antibiotics empirically but don't delay specific VL therapy
"The family meeting": Early discussion about prognosis and goals of care given high mortality risk

Future Directions and Research Priorities

Critical Research Gaps

Optimal ART timing in treatment-naïve patients
IRIS prediction models and prevention strategies
Point-of-care diagnostics for resource-limited settings
Combination therapy regimens to reduce treatment duration
Biomarkers for early treatment failure detection

Technology Integration

Digital health solutions:

Mobile health platforms for remote monitoring
Artificial intelligence for diagnostic support
Telemedicine for specialist consultation in endemic areas

Conclusion

VL-HIV coinfection represents one of the most challenging infectious disease syndromes encountered in critical care medicine. The complex pathophysiology, atypical presentations, and high mortality rates demand a sophisticated understanding of both conditions and their interactions.

Key principles for ICU management include early recognition through high clinical suspicion, prompt initiation of appropriate anti-leishmanial therapy, careful timing of ART initiation, anticipation and management of complications including IRIS, and comprehensive supportive care addressing multi-organ dysfunction.

As our understanding of the immunological interactions deepens and new therapeutic options emerge, there is cautious optimism for improved outcomes. However, the cornerstone of successful management remains early diagnosis, appropriate treatment selection, and meticulous critical care support.

The complexity of VL-HIV coinfection necessitates multidisciplinary collaboration between critical care physicians, infectious disease specialists, HIV specialists, and parasitologists. Only through such coordinated efforts can we hope to improve outcomes for these critically ill patients.

Acknowledgments

The authors acknowledge the contributions of healthcare workers in endemic regions who continue to provide care for patients with VL-HIV coinfection under challenging circumstances.

References

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Conflicts of Interest: None declared

Funding: None

Ethical Approval: Not applicable (review article)

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Thursday, September 25, 2025