Invasive Fungal Diseases

Introduction

Invasive fungal diseases (IFDs) are life-threatening infections where fungi invade body tissues (deep-seated infections) or are recovered from normally sterile body fluids. While historically rare, the incidence of IFDs has risen significantly due to the increased survival of critically ill neonates, children with malignancies, and transplant recipients. Unlike superficial mycoses, IFDs are associated with high morbidity and mortality, necessitating early recognition and aggressive management.

Classification and Etiology

Fungi causing invasive disease are generally classified based on their morphology and epidemiology.

1. Yeasts

• Candida species: The most common cause of IFD in children.
  • C. albicans remains the most frequent isolate, but non-albicans species (C. parapsilosis, C. tropicalis, C. krusei, C. glabrata) are increasing.
  • C. auris is an emerging multidrug-resistant pathogen.
• Cryptococcus: C. neoformans (associated with HIV/immunocompromise) and C. gattii (can infect immunocompetent hosts).
• Trichosporon and Malassezia (associated with lipid emulsions).

2. Molds (Filamentous Fungi)

• Aspergillus species: A. fumigatus (most common), A. flavus, A. terreus. They cause angioinvasive disease.
• Mucorales (Zygomycetes): Genera include Rhizopus, Mucor, and Lichtheimia. Previously called zygomycosis, now mucormycosis. Characterized by broad, aseptate hyphae.
• Hyalohyphomycetes (others): Fusarium spp., Scedosporium spp.
• Phaeohemomycetes (Dematiaceous): Dark-pigmented fungi (e.g., Cladophialophora, Bipolaris).

3. Dimorphic Fungi (Endemic Mycoses)

These exist as molds in the environment and yeasts in tissue.

• Histoplasma capsulatum.
• Coccidioides immitis/posadasii.
• Blastomyces dermatitidis.

4. Pneumocystis

• Pneumocystis jirovecii: Atypical fungus previously classified as a protozoan.

Risk Factors

IFDs are predominantly opportunistic. Risk factors can be categorized by host immunity and iatrogenic interventions.

1. Host Factors

• Prematurity: Very low birth weight (VLBW) infants due to immature skin barriers and immune systems.
• Malignancy: Particularly Acute Myeloid Leukemia (AML) and relapsed Acute Lymphoblastic Leukemia (ALL).
• Neutropenia: Profound (<500 cells/mm³) and prolonged (>7–10 days) neutropenia is the single most significant risk factor for mold infections like Aspergillosis and Fusariosis.
• Primary Immunodeficiencies:
  • Chronic Granulomatous Disease (CGD): High risk for Aspergillus and Nocardia.
  • Severe Combined Immunodeficiency (SCID), DiGeorge syndrome.
  • STAT1 gain-of-function mutations (Chronic Mucocutaneous Candidiasis).
• Acquired Immunodeficiency: HIV/AIDS (low CD4 counts predispose to Cryptococcus, Pneumocystis, Histoplasma).
• Metabolic Disorders: Diabetic Ketoacidosis (DKA) and iron overload states are specific risk factors for Mucormycosis.

2. Iatrogenic/Nosocomial Factors

• Central Venous Catheters (CVC): Major risk for Candida and Malassezia.
• Broad-spectrum Antibiotics: Alter microbiome allowing fungal overgrowth.
• Total Parenteral Nutrition (TPN): Lipid emulsions support fungal growth (e.g., Malassezia).
• Corticosteroids and Chemotherapy: Impair macrophage and neutrophil function.
• Transplantation: Hematopoietic Stem Cell Transplant (HSCT) and Solid Organ Transplant (SOT) recipients.

Clinical Features

Clinical presentation varies by the organism and the host's immune status.

1. Invasive Candidiasis

• Candidemia: Fever unresponsive to antibiotics, sepsis-like syndrome (shock, hypotension).
• Neonates: Lethargy, apnea, temperature instability, thrombocytopenia, hyperglycemia.
• Chronic Disseminated Candidiasis (Hepatosplenic): Persistent fever in neutropenic patients recovering counts, with abdominal pain and elevated alkaline phosphatase.
• Endophthalmitis: Retinal lesions (cotton wool spots); requires dilated eye exam.
• Cutaneous: Congenital cutaneous candidiasis in neonates (diffuse burn-like rash).

2. Invasive Aspergillosis (IA)

• Pulmonary: Fever, pleuritic chest pain, cough, hemoptysis.
• Sinusitis: Facial pain, nasal discharge, eschar.
• Disseminated: CNS abscesses, cutaneous nodules, osteomyelitis.
• Allergic: Allergic Bronchopulmonary Aspergillosis (ABPA) in asthma/CF patients (wheezing, eosinophilia).

3. Mucormycosis

• Rapidly progressive and destructive.
• Rhinocerebral: Facial pain, black eschar on palate/nose, proptosis, ophthalmoplegia, cavernous sinus thrombosis.
• Pulmonary: Mimics aspergillosis but may have rapid necrosis.
• Gastrointestinal: Necrotizing enterocolitis-like picture in premature neonates.

4. Cryptococcosis

• Meningitis: Headache, fever, vomiting, altered sensorium. Indolent course. Elevated intracranial pressure is common.
• Pulmonary: Cough, nodules.

5. Pneumocystis jirovecii Pneumonia (PCP)

• Hypoxia out of proportion to radiological findings, tachypnea, dry cough, dyspnea.
• In non-HIV immunocompromised children, onset is fulminant.

Diagnostic Investigations

Diagnosis is challenging; a combination of methods is often required.

1. Microscopy and Histopathology

• Direct Wet Mount/KOH: For skin/mucosal lesions.
• Stains:
  • Gomori Methenamine Silver (GMS) / PAS: Fungal elements turn black/red.
  • India Ink: For Cryptococcus in CSF (encapsulated yeast).
• Morphology in Tissue:
  • Aspergillus: Narrow, septate hyphae with acute-angle (45°) branching.
  • Mucorales: Broad, aseptate (ribbon-like) hyphae with right-angle (90°) branching.
  • Candida: Yeast cells and pseudohyphae.

2. Culture

• Blood Culture: Gold standard for candidemia but only ~50% sensitive. Poor sensitivity for molds (Aspergillus/Mucor rarely grow from blood).
• Automated Systems: Detect Candida in 2-3 days.
• Lysis Centrifugation: Improves yield for intracellular fungi like Histoplasma.

3. Non-Culture Based Biomarkers (Serology/Antigen Detection)

• Galactomannan (GM) Antigen: Detects cell wall component of Aspergillus.
  • Sample: Serum or BAL fluid.
  • Useful in neutropenic patients; false positives occur with certain antibiotics (e.g., Piperacillin-Tazobactam in older assays).
• Beta-D-Glucan (BDG): Pan-fungal marker (cell wall component).
  • Positive in: Candida, Aspergillus, Pneumocystis.
  • Negative in: Mucorales (they lack BDG), Cryptococcus.
• Cryptococcal Antigen (CrAg): Lateral flow assay or latex agglutination in serum/CSF. Highly sensitive and specific (>95%).
• Histoplasma Antigen: Detected in urine/serum.

4. Imaging

• CT Chest:
  • Aspergillus: Halo sign (nodule with ground-glass opacity, represents hemorrhage) is classic in neutropenic adults but less common in children. Air-crescent sign seen during recovery.
  • Mucormycosis: Reverse halo sign, multiple nodules (>10), pleural effusion.
• Ultrasound/MRI: For hepatosplenic candidiasis (bull's eye lesions) and brain abscesses.

Management

Management involves three pillars: Antifungal therapy, Source control, and Reversal of immunosuppression.

1. Systemic Antifungal Agents (Pediatric Considerations)

A. Polyenes

• Amphotericin B Deoxycholate: Broad spectrum (Yeasts, Molds, Dimorphic). High nephrotoxicity.
• Lipid Formulations (L-AmB): Preferred due to reduced nephrotoxicity.
  • Drug of Choice for: Mucormycosis, Cryptococcal meningitis (induction), Severe Histoplasmosis.
  • Dose: 3–5 mg/kg/day (up to 10 mg/kg for CNS Mucor).

B. Azoles

• Fluconazole:
  • Activity: Candida (except C. krusei, some C. glabrata), Cryptococcus, Coccidioides. No activity against molds (Aspergillus/Mucor).
  • Use: Prophylaxis in NICU, step-down therapy for sensitive Candida, Cryptococcal consolidation.
• Voriconazole:
  • Drug of Choice for: Invasive Aspergillosis.
  • Activity: Aspergillus, Scedosporium, Fusarium, Candida. No activity against Mucor.
  • Note: Non-linear pharmacokinetics; requires therapeutic drug monitoring. Side effects include visual disturbances, photosensitivity.
• Posaconazole/Isavuconazole: Extended spectrum azoles. Active against Mucorales and Aspergillus. Used for salvage therapy or prophylaxis in high-risk leukemia.

C. Echinocandins (Caspofungin, Micafungin, Anidulafungin)

• Mechanism: Inhibit Beta-D-glucan synthesis.
• Drug of Choice for: Invasive Candidiasis (especially in hemodynamically unstable or prior azole exposure).
• Activity: Fungicidal for Candida, fungistatic for Aspergillus. No activity against Cryptococcus or Mucor.
• Safety: Excellent safety profile, few drug interactions.

2. Specific Management Strategies

• Invasive Candidiasis:

  • Start Echinocandin or Amphotericin B.
  • Remove central venous catheters (crucial for clearance).
  • Ophthalmology screen for endophthalmitis.
  • Duration: 14 days after first negative culture (if no metastatic foci).

• Invasive Aspergillosis:

  • Voriconazole is first-line. L-AmB is alternative.
  • Duration: Minimum 6–12 weeks, until resolution of imaging and immune recovery.

• Mucormycosis:

  • Medical Emergency.
  • Surgical: Extensive and urgent debridement of necrotic tissue.
  • Medical: High dose Liposomal Amphotericin B (5–10 mg/kg).
  • Control sugar/acidosis in DKA.

• Pneumocystis pneumonia:

  • High dose TMP-SMX + Corticosteroids (if hypoxic).

3. Empiric Therapy in Febrile Neutropenia

• Indicated for high-risk neutropenic patients with persistent fever (>96 hours) despite broad-spectrum antibiotics.
• Caspofungin or Liposomal Amphotericin B are preferred. Voriconazole is avoided if used for prophylaxis.

Prevention and Prophylaxis in High-Risk Populations

1. Neonates (NICU)

• Target: Extremely Low Birth Weight (<1000g).
• Agent: Fluconazole prophylaxis (3–6 mg/kg twice weekly) reduces invasive candidiasis but not mortality. Recommended in units with high fungal rates (>10%).

2. Oncology / HSCT (Neutropenia)

• Target: AML, myelodysplastic syndrome, Graft-vs-Host Disease (GVHD).
• Agent: Posaconazole (preferred for mold coverage) or Voriconazole/Fluconazole (depending on risk).
• Environment: HEPA filtration, positive pressure rooms, avoidance of construction sites and plants/flowers.

3. HIV/AIDS

• Target: CD4 count low (age-dependent thresholds).
• PCP Prophylaxis: TMP-SMX is the gold standard for all infants exposed to HIV until infection is ruled out, and for infected children with severe immunosuppression.
• Cryptococcus: Screening for CrAg in adolescents with CD4 <100; Fluconazole prophylaxis in specific high-risk scenarios.

4. Chronic Granulomatous Disease (CGD)

• Lifelong prophylaxis with Itraconazole or Posaconazole to prevent Aspergillus.

5. Infection Control

• Hand hygiene.
• Protocols for central line insertion and maintenance (CLABSI bundles).
• Gut decontamination (controversial).

Summary Table: Drug of Choice (DOC)