Pathogenesis, Diagnosis, andTreatment of Fungal Infections¶

Chapter 217 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Fungal · Chapter 217

Key Clinical Points¶

CARD9 deficiency is the only known primary immunodeficiency to feature fungus-specific infection susceptibility without predisposition to other infections, autoimmunity, allergy, or cancer.
Inherited CARD9 deficiency causes severe mucocutaneous and invasive fungal disease (e.g., chronic mucocutaneous candidiasis due to defective IL-17 responses, CNS infections by Candida/Aspergillus, and deep dermatophytosis).
IL-17-producing lymphoid cells are critical for protection; they drive epithelial cell production of antimicrobial peptides that restrict mucosal Candida invasion.
Neutrophils are essential for controlling invasive infections caused by Aspergillus and Candida; inherited deficiency in neutrophil superoxide generation (CGD) carries a ~40% lifetime risk for invasive aspergillosis.
Amphotericin B (AmB) is the broadest-spectrum antifungal agent but has significant toxicity (renal, infusion-related); lipid formulations (liposomal AmB, AmB lipid complex) are preferred over deoxycholate in resource-rich settings.
Fluconazole is the preferred agent for coccidioidal meningitis and mucosal candidiasis; it has no activity against molds or most endemic dimorphic fungi, and is less active against C. glabrata and C. krusei.
Voriconazole is the preferred agent for aspergillosis but requires monitoring of drug levels due to CYP2C19 variability (associated with hepatotoxicity, visual disturbances, and skin rashes).
Posaconazole has broader activity than voriconazole, including activity against Mucorales, and is approved for antifungal prophylaxis in neutropenic leukemic patients and allogeneic HSCT recipients.
Histopathological hallmarks include sclerotic bodies (pathognomonic for chromoblastomycosis), ribbon-like aseptate hyphae (mucormycosis), and steering-wheel budding (paracoccidioidomycosis).
Diagnostic accuracy relies on a combination of histopathology, culture, and biomarkers (Galactomannan, β-glucan, Cryptococcus antigen).

1. DEFINITION & OVERVIEW¶

Fungal infections have increased globally due to the AIDS pandemic, antibiotic overuse, immunosuppressive therapies (e.g., biologics), and transplant medicine.

Classification Systems:

• Anatomic location: Mucocutaneous vs. deep organ infections.

• Epidemiology: Endemic (non-commensal fungi acquired environmentally) vs. opportunistic (commensal fungi causing disease in immunosuppressed hosts).

• Morphology: Yeast (e.g., Candida, Cryptococcus), Mold (e.g., Aspergillus, Mucor), and Dimorphic (yeast at 37°C, hyphae at room temperature; e.g., Histoplasma, Blastomyces).

1.1 Classification Summary¶

• Anatomic: Mucocutaneous (lesser mortality) vs. Deep organ (high mortality).

• Epidemiology: Endemic mycoses (e.g., histoplasmosis, coccidioidomycosis) vs. Opportunistic mycoses (e.g., candidiasis, aspergillosis).

• Morphological: Yeast, Mold, and Dimorphic fungi.

2. EPIDEMIOLOGY¶

Drivers of Global Increase:

• AIDS pandemic.

• Broad-spectrum antibiotic use.

• Cytotoxic and biologic therapies for autoimmune/neoplastic diseases.

• Solid organ and hematopoietic stem cell transplantation (HSCT).

Emerging Threats:

• Drug-resistant species: azole-echinocandin-resistant Candida glabrata/C. auris, and azole-resistant Aspergillus fumigatus.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

Host Defense Mechanisms:

• CLR/SYK/CARD9 signaling pathway: Mediates fungal polysaccharide recognition → proinflammatory mediator production, leukocyte recruitment, inflam1somme activation, and Th17 cell differentiation.

• IL-17 pathway: Critical for epithelial cell production of antimicrobial peptides (AMPs) to restrict mucosal Candida invasion. Defects lead to chronic mucocutaneous candidiasis.

• Neutrophil defense: Essential for control of Aspergillus and Candida; NADPH oxidase assembly is required for superoxide generation.

• Macrophage defense: IFN-γ/IL-12 axis critical for intracellular pathogens (e.g., Cryptococcus, Pneumocystis).

3.1 Immunodeficiencies¶

• CARD9 deficiency: - Severe mucocutaneous and invasive fungal disease. - Chronic mucocutaneous candidiasis (defective IL-17). - CNS infections by Candida/Aspergillus. - Deep dermatophytosis.

• APECED syndrome: - Autoantibodies to IL-17A/F, IL-22 → disrupted oral epithelial barrier. - Remission achievable with JAK inhibition.

• Chronic granulomatous disease (CGD): - NADPH oxidase deficiency. - ≈40% lifetime risk of invasive aspergillosis. - Rarely leads to invasive candidiasis (<5%).

• TLR pathway polymorphisms: - Do not cause spontaneous fungal disease; may increase risk in critically ill/immunosuppressed patients.

4. CLINICAL FEATURES¶

Clinical Manifestations by Type:

• Mucocutaneous infections: Chronic mucocutaneous candidiasis (nail dystrophy, angular cheilitis), dermatophytosis.

• Deep organ infections: - Pulmonary: Aspergillus pneumonia (hemoptysis, fever), Pneumocystis pneumonia (hypoxia, diffuse infiltrates). - CNS: Cryptococcus meningitis (headache, confusion), Candida meningitis (fever, focal neurological deficits). - Disseminated: Mucormycosis (rhinocerebral necrosis), histoplasmosis (fibrosing mediastinitis).

4.1 Clinical Presentation Summary¶

• Mucocutaneous: Chronic mucocutaneous candidiasis, dermatophytosis.

• Deep Organ: Pulmonary (Aspergillus, Pneumocystis), CNS (Cryptococcus, Candida), Disseminated (Mucormycosis, Histoplasmosis).

5. DIFFERENTIAL DIAGNOSIS¶

Systematic Differentiation:

• Morphology: - Aspergillus: Acute-angle septate hyphae. - Mucor: Ribbon-like aseptate hyphae. - Blastomyces: Yeast with broad-based budding.

• Histologic Features: - Histoplasmosis: Granuloma formation. - Mucormycosis: Angioinvasion. - Fusariosis: Necrosis.

• Biomarkers: Galactomannan (Aspergillus), β-glucan (Candida), Cryptococcus antigen.

6. INVESTIGATIONS & DIAGNOSIS¶

Definitive diagnosis requires histopathologic identification of fungi with parallel culture.

Diagnostic Modalities:

Stains: PAS/GMS for fungal morphology; India ink for Cryptococcus.
Culture: Blood/BAL cultures (Candida, Aspergillus); tissue cultures (dimorphic fungi).
Biomarkers: Galactomannan (GM), β-glucan (BDG), Cryptococcal antigen.
Molecular: PCR for rapid detection (e.g., T2 magnetic resonance for Candida in blood).
Imaging: CT for pulmonary aspergillosis; MRI for CNS cryptococcosis.

Table 217-1: Major Fungal Infections, Risk Factors, and Diagnostic Tests¶

• Aspergillosis (A. fumigatus, A. terreus): - Clinical: Pneumonia/disseminated infection; ABPA; keratitis. - Risks: Neutropenia, glucocorticoids, HSCT, post-influenza/COVID-19, BTK inhibition; atopic individuals. - Tests: Culture of BAL (low sensitivity); Histology (acute-angle septate hyphae); GM (BAL > serum), BDG (nonspecific).

• Mucormycosis (Rhizopus spp.): - Clinical: Sinopulmonary/rhinocerebral infection; necrotizing skin infection. - Risks: Neutropenia, HSCT; diabetic ketoacidosis; direct inoculation. - Tests: Culture of sinus tissue (very low sensitivity); Histology (ribbon-like aseptate hyphae); Biomarkers (GM may be positive, BDG nonspecific).

• Fusariosis (F. solani, F. oxysporum): - Clinical: Pneumonia/disseminated infection; keratitis. - Risks: Neutropenia; direct inoculation. - Tests: Culture of tissue or blood (one of the few molds recovered from blood); Histology (acute-angle septate hyphae).

• Phaeohyphomycosis: - Clinical: Sinopulmonary, CNS, or disseminated infection; skin infection; allergic sinusitis. - Risks: HSCT, neutropenia, glucocorticoids, healthy individuals (CNS), TNF-α inhibition. - Tests: Histology (H&E: dark brown/gold; Fontana-Masson for melanin).

• Eumycetoma: - Clinical: Skin and subcutaneous infections. - Risks: Healthy individuals. - Tests: Culture and macroscopic/histologic examination of grains.

• Invasive Candidiasis (C. albicans, C. glabrata, C. auris): - Clinical: Candidemia; disseminated infection (spleen, liver, kidney, eye, heart, CNS). - Risks: Critical illness (ICU), Neutropenia, glucocorticoids. - Tests: Blood culture (low sensitivity); Histology (yeast/pseudohyphae); BDG; T2 magnetic resonance in whole blood.

• Trichosporonosis: - Clinical: Superficial skin infection; disseminated infection. - Risks: Healthy individuals, Neutropenia, glucocorticoids, HSCT, SOT. - Tests: Culture of tissue/blood; Histology (yeasts, hyphae, and arthroconidia).

• Blastomycosis (B. dermatitidis): - Clinical: Pneumonia; disseminated infection (skin, bone, mucosal surfaces). - Risks: Healthy individuals, AIDS, glucocorticoids, TNF-α inhibition. - Tests: Culture of BAL/tissue (low sensitivity); Histology (broad-based budding yeast); Serology (CF, ID) low sensitivity; Blastomyces Ag test cross-reacts.

• Paracoccidioidomycosis (P. brasiliensis): - Clinical: Pneumonia; disseminated infection (skin, bone, mucosal surfaces). - Risks: Healthy individuals, AIDS, glucocorticoids. - Tests: Culture of tissue; Histology (KOH/tissue: yeast with budding in steering-wheel pattern); Serology (ID, CF); Paracoccidioides Ag test.

7. MANAGEMENT & TREATMENT¶

Treatment principles:

Early Intervention: Prompt initiation of antifungal therapy is critical.
Source Control:
Remove central venous catheter in candidemia.
Drain abscesses.
Debride mucormycosis tissue.
Immune Reconstitution: Neutrophil recovery, glucocorticoid tapering, ART initiation in AIDS.

Pharmacotherapy:

• Amphotericin B (AmB): - Mechanism: Forms extramembranous aggregates that extract ergosterol from fungal membranes. - Indications: Mucormycosis/fusariosis; cryptococcal meningitis; disseminated dimorphic infections. - Toxicity: Renal (requires dose adjustment), infusion-related reactions (fever, chills). - Formulations: Liposomal AmB and AmB lipid complex (preferred in resource-rich settings); Deoxycholate used in developing countries due to cost.

• Azoles: - Mechanism: Inhibit lanosterol 14α-demethylase → inhibit ergosterol synthesis. - Fluconazole: - Use: Mucosal candidiasis, coccidioidal meningitis. - Note: Long half-life (70-80 hours); no activity against molds or most dimorphic fungi; less active against C. glabrata and C. krusei. - Voriconazole: - Use: First-line for aspergillosis. - Monitoring: Required due to CYP2C19 variability (hepatotoxicity, visual disturbances, skin rashes). - Posaconazole: - Use: Broadest spectrum (including Mucorales). - Prophylaxis: Approved for HSCT/neutropenic patients.

7.1 Drug Specifics¶

• Amphotericin B: - Mechanism: Extramembranous aggregates → ergosterol extraction. - Formulations: Liposomal/Lipid complex (preferred) vs. Deoxycholate (cost-effective).

• Azoles: - Mechanism: Lanosterol 14α-demethylase inhibition. - Fluconazole: Long half-life; no mold activity. - Voriconazole: Aspergillosis first-line; CYP2C19 monitoring required. - Posaconazole: Broadest spectrum (Mucorales); used for prophylaxis.

8. PROGNOSIS & COMPLICATIONS¶

Prognosis depends on:

• Timely Intervention: Early diagnosis and treatment initiation.

• Source Control: Debridement of necrotic tissue, removal of catheters.

• Immune Recovery: Rapid neutrophil recovery and steroid tapering.

Complications include:

• Systemic Spread: Disseminated disease with multi-organ involvement.

• Neurological: CNS complications (cryptococcal meningitis, aspergillus brain abscesses).

• Resistance: Drug resistance (e.g., azole-resistant Aspergillus, echinocandin-resistant Candida glabrata).

9. SPECIAL CONSIDERATIONS¶

• Drug Interactions: Azoles interact with CYP450 substrates (e.g., warfarin, statins).

• Toxicity Monitoring: - Amphotericin B: Renal function, electrolytes. - Voriconazole: Liver enzymes, visual acuity. - Posaconazole: Drug levels in HSCT patients.

• Prophylaxis: - Fluconazole: ICU patients at risk for candidemia. - Posaconazole: Neutropenic HSCT recipients.

9.1 Monitoring Summary¶

• AmB: Renal/Electrolytes.

• Voriconazole: Liver/Vision.

• Posaconazole: Serum levels.

10. KEY PEARLS & CLINICAL TRAPS¶

• CARD9: Only primary immunodeficiency with fungus-specific susceptibility without other immune defects.

• IL-17 Pathway: Defects cause mucosal but not invasive candidiasis (e.g., APECED).

• Neutrophils/CGD: Critical for Aspergillus; CGD patients have a ≈40% risk of invasive aspergillosis.

• Amphotericin B: Broadest spectrum but high toxicity; lipid formulations preferred in resource-rich settings.

• Fluconazole Limitations: No activity against molds or dimorphic fungi (e.g., histoplasmosis, blastomycosis); less active against C. glabrata and C. krusei.

11. WHAT TO LOOK FOR — DIAGNOSTIC CLUES¶

• Mucocutaneous candidiasis: Persistent oral/nail infections despite normal immune function.

• Cryptococcus: Encapsulated yeast on India ink/GMS; positive cryptococcal antigen in CSF.

• Aspergillus: Acute-angle septate hyphae on histology; galactomannan positivity in BAL fluid.

• Mucormycosis: Ribbon-like aseptate hyphae; rhinocerebral necrosis in diabetic ketoacidosis.

• Chromoblastomycosis: Sclerotic bodies on KOH/GMS stain (pathognomonic).

• Paracoccidioidomycosis: Steering-wheel pattern of budding yeast.

Reference Tables¶

TABLE 217-1 Major Fungal Infections, Associated At-Risk Patient Populations, and Diagnostic Tests¶

Harrison's 22e, p.1688

INFECTION (MOST COMMON FUNGAL GENERA AND SPECIES)	CLINICAL SYNDROME(S)	RISK FACTOR(S)	DIAGNOSTIC TEST(S)
Mold (Filamentous) Fungi
Aspergillosis (Aspergillus fumigatus, A. terreus, A. flavus, A. niger, A. nidulansa)	Pneumonia or disseminated infection ABPA Keratitis	Neutropenia, glucocorticoids, HSCT, post-influenza or COVID-19, BTK inhibition Atopic individuals Direct inoculation	Culture of BAL fluid: low sensitivity, nonspecific (colonization, contamination) Histologic examination of tissueb: acute-angle septate hyphae Biomarkers: GM (BAL > serum); serum BDG (nonspecific)
	Sinopulmonary infection Rhinocerebral infection Necrotizing skin infection	Neutropenia, HSCT Diabetic ketoacidosis Direct inoculation (e.g., tornado victims)
Fusariosis (Fusarium solani, F. oxysporum)	Pneumonia or disseminated infection Keratitis	Neutropenia Direct inoculation	Culture of tissue or blood: one of the few molds recovered from blood Histologic examination of tissue: acute-angle septate hyphae Biomarkers: GM can be positive; BDG (nonspecific)
	Pneumonia or disseminated infection	Neutropenia, glucocorticoids, HSCT
Phaeohyphomycosis (Cladophialophora, Alternaria, Phialophora, Rhinocladiella, Exophiala, and Exserohilum spp.)	Sinopulmonary, CNS, or disseminated infection Skin infection Allergic sinusitis	HSCT, neutropenia, glucocorticoids, healthy individuals (for CNS), TNF-α inhibition Direct inoculation Atopic individuals	Culture of ordinarily sterile site Histologic examination of tissue: cell walls may appear dark brown or golden on H&E; Fontana-Masson may stain fungal melanin
	Skin and nail infections	Healthy individuals
Eumycetoma (Madurella mycetomatis)	Skin and subcutaneous infections	Healthy individuals	Culture and macroscopic and histologic examination of grains harvested from biopsy or aspiration
Yeast Fungi
	Oropharyngeal or esophageal candidiasis Vulvovaginal candidiasis	AIDS, glucocorticoids Antibiotic use
Invasive candidiasisc (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. auris)	Candidemia Disseminated infection (spleen, liver, kidney, eye, heart, CNS)	Critical illness (ICU) Neutropenia, glucocorticoids	Culture of blood: low sensitivity Histologic examination of tissue: yeast and/or pseudohyphae Biomarkers/other tests: BDG (nonspecific); T2 magnetic resonance in whole blood
	Pneumonia Osteomyelitis Meningoencephalitis	AIDS, glucocorticoids Sarcoidosis AIDS, AAbs to IFN-γ or GM-CSF, BTK or JAK inhibition
Trichosporonosisd (Trichosporon asahii, T. mucoides, T. asteroides)	Superficial skin infection (white piedra) Disseminated infection (skin, eye)	Healthy individuals Neutropenia, glucocorticoids, HSCT, SOT	Culture of tissue or blood Histologic examination of tissue: yeasts, hyphae, and arthroconidia Biomarkers: BDG can be positive
Endemic Dimorphic Fungi
	Self-limited pneumonia Disseminated infection (liver, bone, bone marrow) Fibrosing mediastinitis	Healthy individuals AIDS, SOT, glucocorticoids, AAbs to IFN-γ, JAK or TNF-α inhibition
Blastomycosis (Blastomyces dermatitidis, B. gilchristii)	Pneumonia Disseminated infection (skin, bone, mucosal surfaces, genitourinary tract)	Healthy individuals AIDS, glucocorticoids, TNF-α inhibition	Culture of BAL or tissue: low sensitivity; weeks needed for growth Histologic examination of tissue: yeast with broad-based budding Other tests: serology (CF, ID) has low sensitivity; Blastomyces Ag test cross-reacts with other endemic fungi; GM can be positive
	Self-limited pneumonia Disseminated infection (CNS, bone)	Healthy individuals AIDS, glucocorticoids, TNF-α inhibition
Paracoccidioidomycosis (Paracoccidioides brasiliensis, P. lutzii)	Pneumonia Disseminated infection (skin, bone, mucosal surfaces)	Healthy individuals AIDS, glucocorticoids	Culture of tissue: active disease; several weeks needed for growth Histologic examination of KOH preparations or tissue: yeast with budding in steering-wheel pattern Other tests: serology (ID, CF); Paracoccidioides Ag test