Fungal Infections

Grouped by mechanism of acquisition

• Opportunistic endogenous flora: Candida species colonize gut, skin, and vagina; disease requires a breach (mucosal injury from chemotherapy, indwelling catheter, gut translocation) plus loss of competing bacterial flora after broad-spectrum antibiotics
• Inhaled environmental molds: Aspergillus conidia are ubiquitous; disease occurs only when neutrophils or macrophages fail to clear them. Mucorales (Rhizopus) require iron availability and acidosis for hyphal growth
• Inhaled dimorphic (endemic) fungi: Histoplasma (bird/bat guano, caves, Ohio–Mississippi valleys), Blastomyces (rotting wood, waterways), Coccidioides (arthroconidia in Southwest desert soil, released by dust storms, construction, archaeologic digs). These infect immunocompetent hosts; immunosuppression determines dissemination, not acquisition
• **Keratinophilic dermatophytes and *Malassezia***: require only moisture, occlusion, and skin barrier disruption

Non-modifiable risk factors examiners plant

• Neutropenia and defective oxidative burst: prolonged ANC <500 and chronic granulomatous disease predispose specifically to invasive aspergillosis; CGD also causes Aspergillus nidulans infection
• T-cell defects: advanced HIV (CD4 <200 for PCP, <100 for disseminated endemic mycoses, <100 for cryptococcosis), solid organ and allogeneic stem cell transplant, GVHD
• Host genetics/physiology: African, Filipino, and Hispanic ancestry and third-trimester pregnancy markedly increase coccidioidal dissemination risk; extremes of age

Modifiable risk factors

• Iatrogenic: central venous catheters and total parenteral nutrition (candidemia), broad-spectrum antibiotics, corticosteroids, TNF-α inhibitors (histoplasmosis reactivation — an FDA boxed warning), gastric acid suppression
• Metabolic: poorly controlled diabetes and diabetic ketoacidosis — acidosis frees iron from transferrin and impairs neutrophil chemotaxis, the classic setup for rhinocerebral mucormycosis; deferoxamine therapy and iron overload do the same
• Behavioral/structural: injection drug use, occupational soil and dust exposure, smoking and pre-existing cavitary lung disease (aspergilloma, chronic pulmonary histoplasmosis)

• Fungal cell wall composition: Fungi possess a unique cell wall composed of chitin and β-glucans (not present in mammalian cells), allowing selective targeting by antifungal drugs such as echinocandins; this contrasts with bacterial peptidoglycan and mammalian cell membranes
• Ergosterol-dependent membrane function: Fungal cell membranes rely on ergosterol rather than cholesterol; azole and polyene antifungals disrupt ergosterol synthesis or bind ergosterol directly, creating osmotic instability and cell death
• Dimorphism and temperature-dependent morphogenesis: Dimorphic fungi (Histoplasma, Blastomyces, Coccidioides) transition from environmental mold forms (at 25°C) to parasitic yeast forms (at 37°C body temperature), facilitating intracellular survival and evasion of immune recognition
• Immune evasion mechanisms: Fungi produce melanin-containing cell walls (Cryptococcus), polysaccharide capsules (Cryptococcus neoformans), and phenolic compounds that reduce phagocytosis, inhibit complement activation, and promote intracellular survival within macrophages
• Th1 vs. Th2 response dysfunction: Impaired cell-mediated immunity (T-cell and macrophage function) is the primary determinant of susceptibility; defects in IL-12/IFN-γ signaling pathways and CD4+ T-cell depletion (CD4 <50 in HIV) dramatically increase risk for opportunistic mycoses
• Tissue invasion and dissemination: Fungal proteases and phospholipases damage host tissue barriers; angioinvasion by Aspergillus and Mucor causes thrombosis, infarction, and tissue necrosis; thermotolerance of dimorphic fungi allows bloodstream dissemination and hematogenous seeding

Cutaneous and Superficial Infections

• Dermatophyte infections (tinea pedis, tinea corporis, onychomycosis): Pruritic, scaly patches with erythematous borders ("ringworm" appearance); onychomycosis presents with nail discoloration, thickening, and crumbling—may take months to resolve even with treatment due to slow nail growth
• Candida intertrigo: Bright erythema with satellite pustules in skin fold areas (axillae, groin, inframammary); associated with maceration, moisture, and obesity; oral thrush presents as white pseudomembranes on tongue/palate
• Pityriasis versicolor: Hypo- or hyperpigmented patches caused by Malassezia; classically on chest and back; may recur after treatment

Respiratory Infections

• Histoplasmosis: Ranges from asymptomatic to acute pneumonia (fever, cough, dyspnea, chest pain); chronic form mimics tuberculosis with cavitary disease; disseminated disease presents with hepatosplenomegaly, lymphadenopathy, and potentially CNS involvement
• Coccidioidomycosis ("Valley Fever"): Initial influenza-like illness or pneumonia; erythema nodosum or erythema multiforme may appear (more common in women); disseminated disease affects skin, bone, joints, and meninges
• Blastomycosis: Subacute to chronic pneumonia with nodular or mass-like infiltrates; extrapulmonary dissemination common (skin, bone, prostate, CNS); skin lesions are verrucous or ulcerated
• Aspergillosis: Allergic bronchopulmonary aspergillosis (ABPA) presents with asthma exacerbations, hemoptysis, pulmonary infiltrates, and elevated IgE; chronic pulmonary aspergillosis in cavitary lung disease; invasive aspergillosis in severe immunosuppression presents with fever, hemoptysis, and rapid respiratory decline
• Pneumocystis jirovecii pneumonia (PCP): Subacute dyspnea, nonproductive cough, fever, and chest discomfort; elevated LDH and hypoxemia out of proportion to physical exam findings; classic "ground-glass" opacities on imaging

CNS Infections

• Cryptococcal meningitis: Subacute meningitis with minimal meningeal signs; fever, headache, altered mental status develop insidiously over weeks; elevated opening pressure on lumbar puncture common; India ink stain shows yeast with clear halos; cryptococcal antigen positive in >90%
• Coccidioidal meningitis: Chronic meningitis with basilar enhancement; hydrocephalus common; CSF with elevated protein, low glucose, and lymphocytic pleocytosis

Disseminated/Systemic Infections

• Candidemia: Line-associated or from translocation through damaged mucosa; fever, hemodynamic instability; retinal cotton-wool spots and Candida endophthalmitis indicate hematogenous dissemination
• Endemic mycoses dissemination: Hepatosplenomegaly, lymphadenopathy, skin lesions, osteomyelitis; dissemination risk increases dramatically with CD4 <100 in HIV patients
• Mucormycosis (Zygomycosis): Rapidly progressive infection presenting with necrotic tissue (black eschar on palate, nasal bridge); angioinvasion causes rapid progression to CNS, with rhinocerebral form most common; highly aggressive in diabetic ketoacidosis and hematologic malignancy

Important Clinical Pearls

• Fungal infections often present with nonspecific symptoms mimicking bacterial or viral infections, delaying diagnosis
• Geographic exposure history is critical: Histoplasma and Blastomyces endemic to Ohio/Mississippi River valleys; Coccidioides to Southwest US; Paracoccidioides to Latin America
• Immunosuppression severity determines presentation: superficial in mild immunosuppression, disseminated in severe (CD4 <50)
• Fungal infections rarely present with purulent drainage or neutrophilic response early in severe immunosuppression

Microscopy and Staining

• KOH (potassium hydroxide) preparation: Gold standard for dermatophytes; dissolves cellular material to reveal fungal elements; shows pseudohyphae and budding yeast in Candida
• Gram stain: Poorly visualizes most fungi; Cryptococcus may appear as round structures; not sensitive and not recommended for diagnosis
• India ink stain: Highlights Cryptococcus neoformans by showing clear halo around organism due to polysaccharide capsule; sensitivity ~50-60% (less sensitive than antigen)
• GMS stain (Gomori methenamine silver): Best staining method for Pneumocystis jirovecii in bronchoalveolar lavage; also useful for molds and dimorphic fungi in tissue

Culture and Isolation

• Sabouraud dextrose agar (SDA): Standard fungal culture medium; requires 1-4 weeks for growth depending on organism; Histoplasma requires special lysis centrifugation blood cultures for recovery from blood in disseminated disease
• Temperature-dependent growth: Dimorphic fungi show mold form at room temperature (25°C) and yeast form at body temperature (37°C)—critical diagnostic feature
• Culture sensitivity: Generally lower than bacterial cultures but specificity is high; fungal cultures of blood have low sensitivity except in disseminated candidiasis and histoplasmosis

Serologic and Antigen Testing

• Cryptococcal antigen (CrAg): Highly sensitive (~95%) and specific

Immediate stabilization

• Source control first: remove or exchange infected central venous catheters in candidemia (IDSA candidiasis guideline) and obtain urgent surgical debridement for mucormycosis — antifungals alone cannot penetrate infarcted, angioinvaded tissue
• Reduce immunosuppression where possible: taper corticosteroids, correct ketoacidosis and hyperglycemia, support neutrophil recovery

First-line therapy by syndrome (IDSA guidelines)

• Candidemia/invasive candidiasis: an echinocandin (e.g., micafungin) empirically, before speciation, because it covers fluconazole-resistant isolates; step down to fluconazole once susceptible C. albicans is confirmed and the patient is stable. All candidemia patients need a dilated ophthalmologic exam and repeat blood cultures to date the clearance
• Invasive aspergillosis: a mold-active triazole — voriconazole (or isavuconazole) is first-line; liposomal amphotericin B is the alternative
• Mucormycosis: liposomal amphotericin B plus aggressive surgical debridement; posaconazole or isavuconazole for step-down/salvage
• Cryptococcal meningitis: induction with liposomal amphotericin B plus flucytosine, then consolidation and maintenance fluconazole; manage raised intracranial pressure with serial therapeutic lumbar punctures
• PCP: TMP-SMX is first-line; add adjunctive corticosteroids when room-air PaO₂ is <70 mmHg or the A–a gradient exceeds 35 mmHg (IDSA/CDC/NIH OI guidelines). Alternatives: pentamidine, atovaquone, clindamycin-primaquine
• Endemic mycoses: itraconazole for mild-to-moderate histoplasmosis, blastomycosis, and non-meningeal coccidioidomycosis; liposomal amphotericin B induction for severe or disseminated disease. Coccidioidal meningitis requires lifelong fluconazole
• Superficial disease: topical azoles or terbinafine; oral terbinafine for onychomycosis; nystatin or clotrimazole troches for thrush

Contraindications and cautions

• Echinocandins: inadequate CNS, vitreous, and urinary concentrations — do not use for meningitis, endophthalmitis, or candiduria
• Voriconazole: no Mucorales activity; breakthrough mold infection on voriconazole should raise suspicion for mucormycosis
• Azoles in pregnancy: high-dose fluconazole and voriconazole are teratogenic; amphotericin B is the preferred agent
• Itraconazole: negative inotrope — avoid in heart failure; strong CYP3A4 interactions with tacrolimus, warfarin, and statins
• C. krusei is intrinsically fluconazole-resistant; C. glabrata is often resistant

Disease-related — emergencies flagged

• Raised intracranial pressure in cryptococcal meningitis (EMERGENCY): capsular polysaccharide obstructs arachnoid granulations, blocking CSF resorption. Signal: opening pressure markedly elevated with papilledema, visual loss, or declining mental status despite sterile-appearing CSF chemistries. Treat with serial LPs, not corticosteroids
• Rhinocerebral extension of mucormycosis (EMERGENCY): hyphal angioinvasion produces vascular thrombosis and infarction. Signal: black necrotic eschar on palate or turbinates, cranial neuropathies, proptosis, cavernous sinus thrombosis
• Massive hemoptysis from an aspergilloma (EMERGENCY): the fungus ball erodes bronchial arteries within a pre-existing cavity. Signal: air-crescent sign and a mobile intracavitary mass; management is bronchial artery embolization or resection
• Candida endophthalmitis and chorioretinitis: hematogenous seeding of the choroid; signal is blurred vision or floaters with fluffy white retinal lesions — vision-threatening and mandates a systemic agent with ocular penetration
• Candida endocarditis and deep-seated abscess: persistent candidemia beyond catheter removal; large friable vegetations often require valve surgery
• Fibrosing mediastinitis and broncholithiasis after histoplasmosis: exuberant fibrotic response entraps SVC, pulmonary vessels, and airways; signal is SVC syndrome or lithoptysis
• Chronic cavitary disease and ARDS; disseminated coccidioidomycosis causing osteomyelitis and hydrocephalus (may need shunting)
• IRIS after antiretroviral initiation in cryptococcosis: paradoxical clinical worsening as immune function returns

Treatment-related

• Amphotericin B: infusion reactions with rigors and fever; dose-limiting nephrotoxicity with distal tubular injury producing potassium and magnesium wasting and type 1 RTA — signal is rising creatinine with refractory hypokalemia. Liposomal formulations reduce, not eliminate, this
• Flucytosine: converted to 5-FU by gut flora → bone marrow suppression; signal is cytopenias requiring level monitoring
• Azoles: hepatotoxicity and QT prolongation (isavuconazole shortens QT); voriconazole additionally causes transient visual disturbances/photopsia, phototoxicity with long-term squamous cell carcinoma risk, and periostitis from fluoride accumulation
• CYP3A4 interactions: azoles raise tacrolimus, warfarin, and statin levels — watch for rejection-drug toxicity or rhabdomyolysis

• DKA plus black necrotic eschar on the palate or nasal turbinates is mucormycosis until proven otherwise. The single best next step is urgent surgical debridement with liposomal amphotericin B — not a triazole, and not waiting for culture. Biopsy shows broad, ribbon-like, non-septate hyphae with wide-angle (90°) branching, versus Aspergillus which is septate with acute-angle (45°) branching
• Breakthrough mold infection in a patient on voriconazole prophylaxis points to Mucorales, which voriconazole does not cover — a favorite distractor
• Candidemia: start an echinocandin empirically, remove the line, and order a dilated ophthalmologic exam. Echinocandins fail in the urine, eye, and CNS — for candiduria or Candida endophthalmitis, use fluconazole or amphotericin instead
• Cryptococcal meningitis with a markedly elevated opening pressure: the next step is serial therapeutic lumbar punctures, not corticosteroids, not mannitol, and not immediate shunting. Cryptococcal antigen outperforms India ink
• Aspergilloma with hemoptysis: air-crescent sign in an old TB or sarcoid cavity. Antifungals do little; embolization or resection is definitive. Contrast with ABPA, where the treatment is corticosteroids (± itraconazole), and the stem gives asthma, central bronchiectasis, eosinophilia, and markedly elevated IgE
• Disseminated histoplasmosis in advanced HIV: urine Histoplasma antigen is the highest-yield test; smear shows small intracellular yeasts within macrophages. Reactivation after starting a TNF-α inhibitor is the classic association
• Coccidioidomycosis: spherules packed with endospores; erythema nodosum signals a good immune response, while third-trimester pregnancy and Filipino or African ancestry predict dissemination. Coccidioidal meningitis requires lifelong fluconazole
• PCP: hypoxemia out of proportion to exam with elevated LDH; add corticosteroids when PaO₂ is <70 mmHg on room air or the A–a gradient exceeds 35 mmHg