Multisystem Processes & Disorders

Endemic mycoses: histo, blasto, cocci

Clinical Overview and When to Suspect Endemic Mycoses

— Histoplasma capsulatum: Ohio and Mississippi River valleys; bird/bat guano, caves, chicken coops, demolition/excavation

— Blastomyces dermatitidis: overlapping Midwest/Southeast US, Great Lakes, St. Lawrence River; rotting wood, beaver dams, riverbanks

— Coccidioides immitis/posadasii: arid Southwest US (Arizona, California's San Joaquin Valley), northern Mexico; "Valley fever," dust storms, earthquakes, archaeology digs

— Subacute pneumonia not responding to standard antibiotics

— Cavitary or nodular lung disease mimicking TB or malignancy

— Mediastinal lymphadenopathy with calcifications (histo)

— Skin ulcers/verrucous lesions in a Midwest patient (blasto)

— Erythema nodosum + arthralgias + pneumonia in a Southwest resident (cocci — "desert rheumatism")

— Disseminated disease in HIV (CD4 <150), organ transplant, TNF-α inhibitor users, or pregnant women

Endemic mycoses are dimorphic fungi that cause disease in immunocompetent and immunocompromised hosts after inhalation of conidia from environmental reservoirs

When to suspect on Step 3:

Exposure history is the single highest-yield clue — always ask about travel, occupation (construction, spelunking, farming, military training), and hobbies

Board pearl: A patient with HIV and CD4 <150 who develops pancytopenia, hepatosplenomegaly, and fever in Indianapolis has disseminated histoplasmosis until proven otherwise — start liposomal amphotericin B empirically while awaiting urine Histoplasma antigen

Key distinction: All three are dimorphic (mold in soil at 25°C, yeast/spherule in tissue at 37°C) — but only Coccidioides forms spherules with endospores, histo forms small intracellular yeast in macrophages, and blasto forms broad-based budding yeast

Most acute infections in immunocompetent hosts are self-limited and require only observation; the Step 3 task is recognizing who needs treatment, who needs hospitalization, and who needs lifelong suppression

Presentation Patterns and Key History

— Acute pulmonary: flu-like illness 1–3 weeks post-exposure, dry cough, fever, headache, retrosternal chest pain; often after spelunking, demolishing old buildings, or cleaning bird droppings

— Chronic cavitary pulmonary: middle-aged smokers with underlying COPD; upper-lobe cavities mimicking reactivation TB

— Mediastinal lymphadenitis/granuloma/fibrosis: mass effect on SVC, esophagus, bronchi — years after initial infection

— Progressive disseminated: AIDS, infants, elderly — fever, weight loss, hepatosplenomegaly, oral ulcers, pancytopenia, adrenal insufficiency, HLH-like picture

— Pulmonary: acute pneumonia, chronic mass-like consolidation, or ARDS in severe cases

— Cutaneous (most common extrapulmonary): verrucous, crusted, heaped-up lesions with microabscesses, often misdiagnosed as squamous cell carcinoma

— Osteoarticular: vertebral or long-bone lytic lesions

— GU: prostatitis, epididymo-orchitis

— CNS: abscess or meningitis, especially in immunocompromised

— 60% asymptomatic; symptomatic cases: fever, cough, fatigue, night sweats lasting weeks

— Triad: erythema nodosum/multiforme + arthralgias + pulmonary infiltrate

— Eosinophilia is a classic clue

— Dissemination risk highest in Filipinos, African Americans, pregnant women (3rd trimester), and immunosuppressed — to skin, bone, joints, and meninges (lifelong fluconazole)

Histoplasmosis — protean manifestations driven by inoculum size and host immunity

Blastomycosis — "the great pretender," mimics malignancy and TB

Coccidioidomycosis — "Valley fever"

Board pearl: New oral/laryngeal ulcer + Ohio Valley travel + HIV = think disseminated histoplasmosis, not aphthous ulcers or SCC — biopsy and culture

Key distinction: Erythema nodosum in cocci reflects a robust Th1 response and predicts a good prognosis — paradoxically protective against dissemination

Physical Exam Findings (and Hemodynamic Assessment)

— Fever with hepatosplenomegaly + diffuse lymphadenopathy → disseminated histo (especially HIV/AIDS)

— Hypotension + hyperpigmentation + hyponatremia → adrenal insufficiency from histoplasma adrenalitis

— Bilateral hilar/mediastinal fullness on percussion or stridor → fibrosing mediastinitis

— Often surprisingly mild relative to imaging; crackles, occasional consolidation

— Severe cocci or blasto can present in ARDS with bilateral crackles, hypoxia, and septic-shock physiology — assess MAP, lactate, urine output, mottling

— Blastomycosis: verrucous plaques with violaceous heaped borders and central microabscesses/ulceration, often on face or extremities; may drain pus

— Histoplasmosis: painless oral/tongue/laryngeal ulcers with rolled edges (mimic SCC); molluscum-like papules in AIDS

— Coccidioidomycosis: erythema nodosum on shins (immune reaction, not infection); chronic dissemination causes subcutaneous abscesses and draining sinuses

— Cocci: migratory polyarthralgias ("desert rheumatism"), monoarticular knee/ankle effusions

— Blasto: vertebral osteomyelitis with paraspinal abscess

— Meningismus, cranial neuropathies, hydrocephalus → coccidioidal meningitis (the most feared cocci complication)

— Focal deficits → blasto brain abscess

— Septic shock physiology in disseminated cocci/blasto/histo warrants early lactate, central access, vasopressors, and ICU

— Suspect adrenal crisis with refractory hypotension despite fluids — give stress-dose hydrocortisone empirically while awaiting cortisol

General exam clues that should redirect your differential

Pulmonary findings

Skin and mucous membrane exam — the highest-yield extrapulmonary clue

Musculoskeletal

Neurologic

Hemodynamic assessment in severe disease

CCS pearl: In a hypotensive AIDS patient from Indianapolis with pancytopenia, order: CBC, CMP, LDH, ferritin, urine and serum Histoplasma antigen, blood cultures (fungal), random cortisol/ACTH stim, CT chest/abdomen, and start liposomal amphotericin B plus stress-dose steroids before confirmation

Diagnostic Workup — Initial Labs and Imaging

— CBC: pancytopenia suggests bone marrow involvement (disseminated histo); eosinophilia is classic for cocci

— CMP: transaminitis and elevated alk phos in hepatic involvement; hyponatremia (adrenal or SIADH)

— LDH and ferritin: markedly elevated in disseminated histo (HLH-like)

— Lactate if septic

— HIV test in every patient with suspected endemic mycosis — drives both diagnosis and treatment intensity

— Pregnancy test in women of reproductive age (azoles are teratogenic)

— CXR first, then CT chest if abnormal or persistent symptoms

— Histo: hilar/mediastinal LAD, scattered nodules, "buckshot" calcifications, upper-lobe cavities in chronic disease

— Blasto: mass-like consolidation, miliary pattern, ARDS

— Cocci: thin-walled cavities ("grape-skin"), pulmonary nodules (must distinguish from malignancy), hilar LAD

— Histoplasma urine antigen: most sensitive (>90%) in disseminated disease and AIDS; serum antigen complementary; cross-reacts with blasto

— Blastomyces urine antigen: sensitive but cross-reacts with histo

— Coccidioides serology: EIA IgM/IgG, then confirm with immunodiffusion and complement fixation (CF) titer; CF titer ≥1:16 suggests dissemination and prompts CSF evaluation

— Induced sputum or BAL for fungal stain, culture, and antigen — particularly when imaging suggests cavitary or diffuse disease

Initial laboratory evaluation

Chest imaging

Antigen and antibody testing — the workhorse of diagnosis

Sputum and bronchoscopy

Board pearl: A CF titer ≥1:16 in coccidioidomycosis is the trigger to perform LP to rule out meningitis, even without neurologic symptoms — meningitis mandates lifelong fluconazole

Step 3 management: In suspected disseminated histo in AIDS, send urine + serum Histoplasma antigen simultaneously — combined sensitivity approaches 100%; do not wait for culture (takes weeks)

Tuberculin skin test and IGRA may be needed to exclude TB given overlapping imaging

Diagnostic Workup — Advanced and Confirmatory Studies

— Sabouraud agar at 25°C: mold phase grows in 2–6 weeks

— Notify the lab when blasto or cocci is suspected — Coccidioides arthroconidia are a BSL-3 biohazard and have caused laboratory-acquired infections

— Histoplasma: 2–4 μm narrow-based budding intracellular yeast within macrophages on GMS or PAS stain; bone marrow biopsy high-yield in disseminated disease

— Blastomyces: broad-based budding yeast, 8–15 μm, thick "doubly refractile" wall; KOH prep of skin lesions or pus is rapid and high-yield

— Coccidioides: spherules (30–60 μm) packed with endospores on GMS — pathognomonic

— PCR available at reference labs; useful when antigen/serology equivocal

— Beta-D-glucan: positive in histo and cocci, negative in blasto; nonspecific

— LP for cocci meningitis: CSF eosinophilia, lymphocytic pleocytosis, low glucose, elevated protein; CSF CF antibody is diagnostic

— MRI brain with contrast for focal deficits (blasto abscess, basilar meningitis with hydrocephalus in cocci)

— CT abdomen for splenic/adrenal involvement in disseminated histo (bilateral adrenal enlargement = consider adrenal insufficiency)

— MRI spine for blasto vertebral osteomyelitis

— Echocardiogram if pericardial involvement (histo pericarditis from adjacent LAD)

Fungal culture — the gold standard but slow

Histopathology

Molecular diagnostics

CNS evaluation

Specialized imaging

HIV staging and CD4 count drive treatment duration and need for chronic suppression

Key distinction: Narrow-based budding intracellular yeast = histo; broad-based budding extracellular yeast = blasto; spherules with endospores = cocci — memorize these three histologic signatures

Board pearl: Never order a coccidioides skin test as a diagnostic — it indicates prior exposure only and is not used clinically in the US currently

Risk Stratification and First-Line Management Logic

— Mild, acute, immunocompetent pulmonary disease (symptoms <1 month, no hypoxia): often observation only for histo and cocci; reassess in 4–6 weeks

— All blastomycosis is treated — spontaneous resolution is uncommon and dissemination risk is high

— All immunocompromised patients are treated regardless of severity

— Persistent symptoms >1 month, hypoxia, weight loss, extrapulmonary involvement, or progression → treat

— Mild–moderate: oral azole (itraconazole for histo/blasto; fluconazole for cocci)

— Moderate–severe / disseminated / CNS / pregnant: liposomal amphotericin B induction, then step-down to azole

— HIV with CD4 <150

— Solid organ or stem cell transplant

— TNF-α inhibitor or high-dose corticosteroid use

— Pregnancy (especially 3rd trimester for cocci)

— Extremes of age

— Diabetes (blasto risk)

Decision framework: who needs antifungal therapy?

Severity stratification drives drug choice

Special high-risk populations who always get treated

CNS, bone, or disseminated disease requires prolonged induction (≥2 weeks liposomal amphotericin) then long azole consolidation (≥12 months, often lifelong for cocci meningitis)

Step 3 management: For a previously healthy patient with mild acute pulmonary histoplasmosis after spelunking, the correct answer is usually observation and symptomatic care, not antifungals — overtreatment is a common distractor

CCS pearl: In severe disease, order liposomal amphotericin B (not deoxycholate) to minimize nephrotoxicity; monitor BMP, magnesium, potassium daily, and replace electrolytes aggressively

Key distinction: Cocci pneumonia in low-risk hosts is often observed; cocci meningitis is treated with lifelong fluconazole — relapse after stopping approaches 80%

Pharmacotherapy — First-Line Drug Regimens

— Mild–moderate pulmonary: itraconazole 200 mg TID × 3 days, then BID × 6–12 weeks

— Moderate–severe pulmonary or disseminated: liposomal amphotericin B 3 mg/kg/day × 1–2 weeks, then itraconazole 200 mg BID × ≥12 months

— CNS histo: liposomal ampho 5 mg/kg/day × 4–6 weeks, then itraconazole ≥12 months and until CSF abnormalities resolve

— AIDS: lifelong itraconazole suppression if CD4 <150 until immune reconstitution (CD4 >150 × 6 months on ART, ≥1 year therapy, negative antigen)

— Mild–moderate pulmonary or cutaneous: itraconazole 200 mg TID × 3 days, then BID × 6–12 months

— Moderate–severe, disseminated, or CNS: liposomal ampho B 3–5 mg/kg/day × 1–2 weeks (CNS: 4–6 weeks), then itraconazole or voriconazole/fluconazole for CNS × ≥12 months

— Mild–moderate pulmonary in low-risk host: observation OR fluconazole 400 mg/day if high risk (diabetes, African American, Filipino, pregnant, immunosuppressed)

— Diffuse pulmonary or disseminated nonmeningeal: fluconazole or itraconazole 400 mg/day × ≥12 months; severe → liposomal ampho induction

— Meningitis: fluconazole 400–1200 mg/day LIFELONG (intrathecal ampho if refractory)

— Take with acidic food/cola; capsules need acid (avoid PPIs); solution preferred for AIDS

— Check trough levels at 2 weeks (target 1–2 μg/mL)

— Monitor LFTs, watch for negative inotropy/CHF and QT prolongation

Histoplasmosis

Blastomycosis

Coccidioidomycosis

Itraconazole pearls

Drug interactions (azoles inhibit CYP3A4): warfarin, statins (especially simvastatin/lovastatin — avoid), tacrolimus, DOACs, methadone

Board pearl: Echinocandins (caspofungin) have no activity against endemic dimorphic fungi — a classic wrong-answer trap

Step 3 management: Stop interacting statins or switch to pravastatin/rosuvastatin when starting azole therapy

Expanded Pharmacology and Treatment Monitoring

— Dose 3–5 mg/kg/day IV; premedicate with acetaminophen ± diphenhydramine for infusion reactions

— Monitor daily BMP, Mg, K; expect renal tubular wasting requiring K and Mg repletion

— Hold or reduce for creatinine doubling; switch to azole as early as clinically appropriate

— Liposomal preferred over conventional deoxycholate: less nephrotoxicity, fewer infusion reactions — though more expensive

— Salvage therapy for refractory blasto or histo

— Voriconazole for CNS blastomycosis (good CSF penetration)

— Monitor troughs, visual disturbances, photosensitivity, periostitis, hepatotoxicity, QT

— Alternative for refractory disease; no QT prolongation (actually shortens QT)

— Useful when drug interactions or QT preclude other azoles

— Histoplasma urine antigen trended monthly — declining levels indicate response; rising levels suggest relapse

— Cocci CF titer trended every 3 months — should decline by ≥2 dilutions

— Repeat imaging at 3 and 6 months

— LFTs every 1–3 months on azoles

— Histo pulmonary: 6–12 weeks (mild) to ≥12 months (severe/dissem)

— Blasto: ≥6–12 months all forms

— Cocci pulmonary: 3–6 months minimum; disseminated ≥12 months; meningitis lifelong

— Corticosteroids (methylprednisolone 0.5–1 mg/kg) controversial but considered in severe histo or cocci pneumonia with respiratory failure (1–2 weeks)

— Surgical debridement for blasto abscesses, fibrosing mediastinitis (rarely effective), or cocci empyema

Liposomal amphotericin B administration

Voriconazole and posaconazole — when to use

Isavuconazonium

Treatment response monitoring

Duration summary

Adjunctive therapies

CCS pearl: When transitioning from amphotericin to oral itraconazole, overlap 24–48 hours and confirm tolerability before discharge; order pharmacy review of all home meds for CYP interactions

Board pearl: Voriconazole is the preferred azole for CNS blastomycosis because itraconazole has poor CNS penetration

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher risk of severe and disseminated disease due to immunosenescence and comorbidities (COPD, diabetes, malignancy)

— Atypical presentations: failure to thrive, weight loss, unexplained pancytopenia — endemic mycoses are often missed

— Polypharmacy increases azole drug-interaction risk — review all meds, especially warfarin, DOACs, statins, calcium-channel blockers, sulfonylureas

— Higher baseline QT — obtain baseline ECG before initiating fluconazole or itraconazole and recheck after 1 week

— Amphotericin B: nephrotoxic — use liposomal formulation, avoid concomitant nephrotoxins (aminoglycosides, IV contrast, NSAIDs, tenofovir DF)

— Expect K and Mg wasting; replete aggressively

— Fluconazole: renally cleared — reduce dose by 50% if CrCl <50 mL/min

— Itraconazole oral solution: contains cyclodextrin vehicle that accumulates in renal failure — avoid IV itraconazole and oral solution if CrCl <30; capsules acceptable

— Voriconazole IV: also has cyclodextrin vehicle — avoid IV if CrCl <50; oral voriconazole is safe in renal impairment

— All azoles are hepatotoxic — obtain baseline LFTs and recheck at 2 weeks, then monthly

— Stop azole if ALT/AST >3× ULN with symptoms or >5× ULN asymptomatic

— In Child-Pugh B: reduce voriconazole maintenance dose by 50%; itraconazole and fluconazole — use cautiously, monitor closely

— Avoid concurrent acetaminophen >2 g/day and alcohol

— Fluconazole is dialyzable: give after hemodialysis sessions, typically 400 mg post-HD

— Itraconazole and voriconazole minimally dialyzed

Elderly patients

Renal impairment

Hepatic impairment

Dialysis considerations

Step 3 management: Before starting fluconazole in an elderly diabetic on sulfonylurea, anticipate hypoglycemia from azole-induced CYP2C9 inhibition increasing glyburide levels — counsel on glucose monitoring and consider switching agents

Board pearl: Liposomal amphotericin still causes K/Mg wasting; daily electrolytes and proactive repletion prevent torsades when combined with QT-prolonging azoles

Special Populations — Pregnancy and Pediatrics

— Azoles are teratogenic (fluconazole, itraconazole, voriconazole, posaconazole) — category D/X; cause craniofacial, skeletal, and cardiac defects, especially first trimester

— Liposomal amphotericin B is the treatment of choice for all endemic mycoses in pregnancy regardless of severity

— Cocci dissemination risk is markedly elevated in 3rd trimester and postpartum, especially in Filipino and African American women — treat all symptomatic cocci in pregnancy

— Postpartum: may transition to oral azole once delivered; avoid breastfeeding on azoles (limited safety data; voriconazole contraindicated)

— Counsel on contraception during and 6 months after voriconazole

— Vertical transmission of cocci possible — evaluate newborn with serology and exam

— Congenital blastomycosis rare but described

— Histoplasmosis is the most common endemic mycosis in children in endemic areas; presentation similar to adults

— Infants with disseminated histo: failure to thrive, hepatosplenomegaly, pancytopenia — often misdiagnosed as leukemia or HLH

— Drug dosing weight-based; itraconazole pharmacokinetics variable in children — check troughs

— Fluconazole dosing higher per kg in children due to faster clearance (6–12 mg/kg/day)

— TNF-α inhibitor users (infliximab, adalimumab, etanercept): screen for endemic mycoses before starting; hold biologic during acute infection; histoplasmosis is a black-box warning for TNF inhibitors

— Solid organ transplant: consider prophylactic itraconazole in high-endemic regions for histo-seropositive recipients; treat any active infection aggressively

— HIV/AIDS: lifelong suppression considerations as noted; resume ART carefully to avoid IRIS

Pregnancy

Neonatal considerations

Pediatrics

Immunocompromised subgroups

Board pearl: A pregnant woman in Arizona with new pneumonia and erythema nodosum gets fluconazole-free management — use liposomal amphotericin B during pregnancy

Key distinction: Children with disseminated histo often look like hematologic malignancy — bone marrow biopsy with fungal stain is diagnostic; do not delay urine antigen

Complications and Adverse Outcomes

— Fibrosing mediastinitis: late, immune-mediated; constrictive scarring causes SVC syndrome, pulmonary vein/artery stenosis, dysphagia, recurrent hemoptysis — antifungals do NOT help; stenting and surgery have limited benefit

— Mediastinal granuloma: necrotic LAD compressing airway/esophagus

— Broncholithiasis: calcified nodes erode into bronchi → hemoptysis

— Pericarditis from adjacent LAD; treat with NSAIDs, not antifungals

— Adrenal insufficiency from bilateral adrenalitis

— Hemophagocytic lymphohistiocytosis (HLH) in disseminated disease

— ARDS with high mortality (>50%)

— Disseminated skin, bone, GU, CNS disease

— CNS abscess or meningitis

— Chronic pulmonary fibrosis and cavities

— Meningitis: most feared; hydrocephalus, vasculitis, stroke, lifelong therapy required

— Osteomyelitis and septic arthritis: vertebral, ankle, knee — often requires surgical debridement

— Cutaneous abscesses and draining sinuses

— Pulmonary cavity rupture → pyopneumothorax

— Cocci nodule mistaken for lung cancer → unnecessary resection

— Amphotericin: nephrotoxicity, K/Mg wasting, anemia, infusion reactions

— Azoles: hepatotoxicity, QT prolongation, photosensitivity (voriconazole — SCC risk with long-term use), peripheral neuropathy, alopecia (fluconazole), CHF (itraconazole)

— IRIS in HIV patients starting ART within 2 weeks of antifungal initiation

— Cocci meningitis: cognitive impairment, hydrocephalus requiring VP shunt

— Histo fibrosing mediastinitis: chronic dyspnea, pulmonary hypertension

— Blasto: scarring, fibrosis, recurrent infection

Histoplasmosis complications

Blastomycosis complications

Coccidioidomycosis complications

Treatment-related complications

Long-term morbidity

Board pearl: Fibrosing mediastinitis represents an exuberant fibrotic host response, not active infection — antifungals are ineffective; this is one of the few times you do NOT treat with antifungals despite Histoplasma association

Step 3 management: Suspect adrenal insufficiency in any disseminated histo patient with hypotension, hyponatremia, or hyperkalemia — check cosyntropin stim and give stress-dose steroids

When to Escalate Care — ICU, Consult, Inpatient Triage

— Respiratory failure requiring mechanical ventilation (ARDS in blasto, severe cocci or histo pneumonia)

— Septic shock physiology

— Refractory hypotension suggesting adrenal crisis

— Acute meningitis with altered mental status or hydrocephalus

— Massive hemoptysis from broncholithiasis or cavitary disease

— Need for IV amphotericin induction

— Hypoxia (SpO₂ <92%) or moderate respiratory distress

— Inability to tolerate oral azoles

— Disseminated disease without shock

— New diagnosis in immunocompromised host

— Significant electrolyte abnormalities requiring repletion

— Diagnostic uncertainty requiring bronchoscopy or biopsy

— Mild–moderate pulmonary disease in immunocompetent adult

— Cutaneous blastomycosis without systemic features

— Stable cocci pneumonia in low-risk host

— Adequate oral intake, normal vitals, reliable follow-up

— Infectious disease: essentially all confirmed cases — drug selection, duration, monitoring

— Pulmonology: cavitary lesions, fibrosing mediastinitis, suspected malignancy

— Neurosurgery: hydrocephalus from cocci meningitis (VP shunt), brain abscess

— Orthopedic surgery: osteomyelitis requiring debridement

— Dermatology: biopsy of skin lesions

— OB: pregnant patients

— Transplant/Rheum: review of immunosuppression; consider holding TNF inhibitors

Admit to ICU

Admit to floor

Outpatient management appropriate when

Consultations to obtain

CCS pearl: On a CCS case, admit hypoxic blasto pneumonia patient → order ABG, CXR, CT chest, BAL with fungal stain/culture, HIV test, liposomal ampho B, daily BMP/Mg, ID consult, advance to ICU if PaO₂/FiO₂ <200

Step 3 management: Any cocci patient with CF titer ≥1:16, new headache, or unexplained fever after treatment initiation → LP to rule out meningitis before deciding on disposition

Public health: notify state health department in reportable jurisdictions (cocci is reportable in AZ, CA, others)

Key Differentials — Same-Category Causes

— Geographic exposure is the strongest discriminator — always anchor on travel/residence history

— Antigen and serology assays cross-react (especially histo and blasto urine antigens) — confirm with culture or histopathology

— Paracoccidioidomycosis (Paracoccidioides brasiliensis): Central/South America, especially Brazil; rural agricultural workers; mucocutaneous lesions (mulberry-like oral ulcers), cervical LAD, "mariner's wheel" yeast on histopathology; treat with itraconazole or sulfonamides

— Talaromycosis (Penicilliosis) (Talaromyces marneffei): Southeast Asia (Thailand, Vietnam, southern China); AIDS patients with CD4 <100; umbilicated skin papules mimicking molluscum, fever, anemia, hepatosplenomegaly; sausage-shaped yeast with central septum; treat with liposomal ampho then itraconazole

— Sporotrichosis (Sporothrix schenckii): rose gardeners, sphagnum moss; lymphocutaneous nodular lymphangitis; treat with itraconazole

— Emergomycosis: newly described dimorphic fungi causing disseminated disease in HIV

— Aspergillosis: invasive in neutropenics or after influenza/COVID; halo and air-crescent signs; galactomannan positive; treat with voriconazole

— Cryptococcosis: AIDS or transplant; meningitis with elevated ICP; CrAg positive; fluconazole + flucytosine + ampho for severe

— Pneumocystis jirovecii (PCP): AIDS CD4 <200; diffuse bilateral infiltrates, elevated LDH; TMP-SMX

— Mucormycosis: diabetic ketoacidosis, neutropenia; rhinocerebral or pulmonary; broad ribbon-like nonseptate hyphae; ampho + surgical debridement

Distinguishing among the three endemic mycoses

Other dimorphic and endemic fungi to consider

Other fungal pneumonias to distinguish

Board pearl: AIDS patient from Thailand with umbilicated skin papules and fever → talaromycosis, not histoplasmosis or molluscum — geography is everything

Key distinction: Sporotrichosis presents as ascending nodular lymphangitis along an extremity after rose-thorn injury — clinically distinct from systemic endemic mycoses

Always reconsider the diagnosis if patient fails to respond to appropriate therapy at 2–4 weeks — repeat imaging, biopsy, reculture

Key Differentials — Other-Category Causes

— Upper-lobe cavitary disease, weight loss, night sweats, hemoptysis

— Calcified hilar LAD overlaps with histo (Ghon complex vs histo calcifications)

— Always obtain sputum AFB and IGRA in any cavitary or chronic granulomatous pulmonary process

— Coinfection is common in HIV

— Bilateral hilar LAD, noncaseating granulomas, hypercalcemia, elevated ACE

— Erythema nodosum overlap with cocci

— Distinguish via biopsy (organisms absent), serology, and exposure history

— Treating with steroids without excluding endemic mycosis can cause dissemination

— Lung cancer: solitary pulmonary nodule from cocci or histo often resected before diagnosis — PET-positive lesions can be inflammatory

— Lymphoma: mediastinal LAD overlaps with histo; B symptoms similar

— Squamous cell carcinoma: blasto skin lesions and histo oral ulcers commonly biopsied as SCC

— Bacterial CAP (Strep pneumoniae, Mycoplasma, Legionella, Chlamydia) — initially indistinguishable; suspect mycosis when no improvement on antibiotics after 5–7 days

— Influenza, RSV, SARS-CoV-2 — viral pneumonias

— Granulomatosis with polyangiitis (GPA): cavitary lung nodules, sinus disease, glomerulonephritis; c-ANCA positive

— Hypersensitivity pneumonitis: exposure-related, ground-glass infiltrates

— Nontuberculous mycobacteria (MAC): cavitary lung disease in elderly women, smokers

— Cocci "desert rheumatism" with EN and arthralgias mimics acute sarcoidosis, Löfgren syndrome, reactive arthritis

Tuberculosis — the single most important mimicker

Sarcoidosis

Malignancy

Community-acquired pneumonia

Other granulomatous diseases

Rheumatologic mimics

Step 3 management: Before initiating immunosuppression (steroids, methotrexate, TNF-α inhibitors, JAK inhibitors) in a patient from an endemic region, screen for and treat latent/active endemic mycosis — especially histoplasmosis with TNF blockers

Board pearl: A solitary lung nodule with central calcification in a patient from Ohio is most likely a histoplasmoma, not malignancy — but if PET-avid or growing, biopsy is warranted

Key distinction: Empirically treating presumed sarcoidosis with steroids in an endemic-region patient without ruling out mycosis is a classic Step 3 error

Secondary Prevention, Discharge Meds, Long-Term Plan

— Oral azole with explicit dose, duration, and food instructions (itraconazole with acidic food; avoid PPIs and H2 blockers)

— Electrolyte repletion if recent amphotericin (K, Mg supplements)

— Stress-dose steroid instructions if adrenal insufficiency

— Updated medication reconciliation removing CYP3A4 substrates with narrow therapeutic indices (avoid simvastatin, ergot alkaloids, quinidine)

— Antiretroviral therapy plan in HIV (coordinate timing to minimize IRIS risk — typically start ART within 2 weeks unless CNS involvement)

— AIDS with prior histoplasmosis: itraconazole 200 mg/day lifelong until CD4 >150 × 6 months on ART + 12 months therapy + negative antigen

— Cocci meningitis: lifelong fluconazole — never stop, relapse rate ~80%

— Transplant recipients in endemic areas: case-by-case prophylaxis

— Pre-TNF inhibitor screening in endemic regions for histo

— Avoid bird/bat-laden environments, caves, demolition sites (histo)

— Avoid wooded riverbanks, beaver lodges, rotting wood (blasto)

— In endemic Southwest: avoid dust exposure, archaeology, gardening without masks; high-risk groups should consider relocating if feasible (cocci)

— Occupational protection: N95 respirators for at-risk workers

— No vaccines exist for endemic mycoses

— Ensure influenza, COVID, pneumococcal vaccines up to date — superinfection risk

— Maintain ART adherence

— CD4 monitoring every 3 months until consistently >200

Discharge medication checklist

Prophylaxis and suppression

Lifestyle and exposure reduction

Vaccinations

HIV-specific

Step 3 management: Document explicit azole stop criteria (negative antigen, adequate CD4, imaging resolution) in discharge summary so the primary care physician knows when to discontinue suppression

Board pearl: Cocci meningitis patients who stop fluconazole have an 80% relapse rate within 1 year — this is one of the few infections requiring true lifelong oral antifungal therapy

Key distinction: Stopping itraconazole suppression in AIDS-related histo is safe only when all three criteria are met (CD4 >150 sustained, ≥12 months therapy, antigen negative)

Follow-Up, Monitoring, Rehab, Counseling

— 2 weeks: symptom check, LFTs, azole trough level (itraconazole, voriconazole), medication adherence

— 1 month: repeat antigen (histo) or CF titer (cocci), CBC, CMP

— 3 months: imaging (CXR or CT), antigen/serology trend, clinical assessment

— 6 months and 12 months: imaging, labs, decision on duration

— More frequently in immunocompromised or severe disease

— LFTs every 1–3 months on azoles; stop if >3× ULN with symptoms

— Itraconazole trough 1–2 μg/mL at 2 weeks

— Voriconazole trough 1–5.5 μg/mL (avoid >5.5 to limit neurotoxicity)

— ECG for QT prolongation in patients on QT-prolonging drugs

— Renal function and electrolytes on amphotericin

— Antigen titers (histo) monthly during treatment, then quarterly

— CF titers (cocci) every 3 months

— Pulmonary rehab for chronic cavitary or fibrotic lung disease

— Physical therapy for prolonged hospitalization and deconditioning

— Cognitive rehab and OT for cocci meningitis survivors

— Adherence to long courses (6–12+ months) is challenging — discuss expectations

— Sun protection on voriconazole (SCC risk with chronic use)

— Pregnancy avoidance on azoles, especially voriconazole (6 months after)

— Recognize relapse signs: new fevers, weight loss, recurrent skin lesions, headaches

— Discuss occupational and recreational exposures

— Mental health screening for chronic illness burden

— ID for ongoing antifungal management

— PCP for comorbidity management and vaccine updates

— HIV provider for ART optimization

— State public health reporting for cocci where mandated

Outpatient follow-up cadence

Monitoring parameters

Rehabilitation considerations

Counseling points

Coordination of care

CCS pearl: When discharging a histoplasmosis patient on itraconazole, schedule 2-week trough level, 1-month antigen, 3-month CT chest, and explicitly counsel against PPI use

Board pearl: Rising antigen titers despite therapy = treatment failure or non-adherence — recheck levels, assess absorption, consider switching agents

Ethical, Legal, and Patient Safety Considerations

— Coccidioidomycosis is reportable in Arizona, California, Nevada, New Mexico, Utah, Washington, and other states — physicians have a mandatory reporting duty

— Histoplasmosis and blastomycosis are reportable in select states

— Outbreak clusters (construction, archaeology, dust storms) require coordinated public health response

— Lifelong fluconazole for cocci meningitis raises adherence, cost, and side-effect counseling needs

— Document shared decision-making for high-risk options (voriconazole + photosensitivity/SCC; amphotericin + nephrotoxicity)

— Pregnancy counseling: discuss teratogenicity of azoles, contraception requirements, and need for liposomal amphotericin during pregnancy

— Inpatient-to-outpatient handoff: ensure azole prescription filled before discharge, drug interactions reviewed by pharmacy, and follow-up appointment scheduled within 2 weeks — gaps lead to relapse and resistance

— Communicate diagnosis clearly to PCP — endemic mycoses are often unfamiliar to general practitioners

— In AIDS patients, coordinate ART initiation timing to balance IRIS risk vs OI prevention

— Workers in construction, archaeology, agriculture, military, and laboratory settings have occupational exposure — document workers' compensation claims; advise N95 respirators

— Laboratory personnel handling cultures: biosafety level 3 for Coccidioides; alert the lab when ordering fungal cultures

— Avoid unnecessary lung biopsy or resection of pulmonary nodules in endemic areas — antigen testing first

— Avoid empiric steroids for presumed sarcoidosis without ruling out mycosis

— Antifungal cost can be prohibitive (especially posaconazole, isavuconazole) — engage social work and patient assistance programs

— Migrant farmworkers in endemic Southwest have elevated cocci risk and limited healthcare access

Public health reporting

Informed consent for off-label or prolonged therapy

Transition-of-care safety

Occupational health

Diagnostic stewardship

Equity and access

Step 3 management: A patient with newly diagnosed cocci pneumonia in Arizona requires immediate public health notification in addition to clinical care — failure to report is a regulatory violation

Board pearl: Always notify the microbiology lab when sending cultures from a patient with suspected coccidioidomycosis — protects technicians from BSL-3 pathogen exposure and is a documented patient-safety practice

High-Yield Associations and Rapid-Fire Clinical Facts

— Ohio/Mississippi River valleys + caves/bats/birds → histoplasmosis

— Great Lakes / Wisconsin / Mississippi + rotting wood/beaver dam → blastomycosis

— Arizona/San Joaquin Valley + dust → coccidioidomycosis

— Brazil + agricultural worker + mulberry oral lesions → paracoccidioidomycosis

— Southeast Asia + AIDS + molluscum-like papules → talaromycosis

— Small intracellular narrow-budding yeast in macrophages → histo

— Broad-based budding yeast with thick wall → blasto

— Spherules with endospores → cocci

— Mulberry/mariner's wheel multipolar budding → paracocci

— Sausage-shaped yeast with central septum → talaromyces

— "Spelunker with flu" → histo

— "Skin lesion mistaken for SCC in Wisconsin hunter" → blasto

— "Desert rheumatism" with EN + arthralgias + pneumonia → cocci

— "Pancytopenia + hepatosplenomegaly in AIDS patient from Indianapolis" → disseminated histo

— "African American or Filipino pregnant woman with severe pneumonia in Arizona" → high-risk cocci

— Cocci meningitis → lifelong fluconazole

— CNS blasto → voriconazole (or liposomal ampho induction)

— Severe/disseminated any endemic mycosis → liposomal amphotericin B

— Mild-moderate histo/blasto → itraconazole

— Histo → fibrosing mediastinitis, adrenal insufficiency, HLH, broncholithiasis

— Blasto → ARDS, CNS abscess, verrucous skin

— Cocci → meningitis with hydrocephalus, osteomyelitis, EN

— Urine antigen most sensitive for disseminated histo and AIDS

— Cocci CF ≥1:16 = LP indication

— Eosinophilia + EN + arthralgias = cocci

— Beta-D-glucan positive in histo/cocci, negative in blasto and crypto

— Black-box warning for histoplasmosis reactivation; screen and counsel before initiation

Geographic anchor points

Histopathology one-liners

Clinical aphorisms

Drug-disease pairings

High-yield complications

Lab pearls

TNF-α inhibitor association

Board pearl: Echinocandins are ineffective against ALL endemic dimorphic fungi — a perennial wrong-answer trap when "broad-spectrum antifungal" is needed

Board Question Stem Patterns

— College student returns from spelunking trip in Kentucky, develops fever, dry cough, retrosternal chest pain, CXR shows hilar LAD with scattered nodules

— Answer: histoplasmosis; if mild and immunocompetent → observation, not antifungals

— Middle-aged man with violaceous heaped-up skin plaque on face, biopsy shows broad-based budding yeast

— Answer: blastomycosis; treat with itraconazole × 6–12 months

— Third trimester, fever, cough, joint pains, erythema nodosum, eosinophilia

— Answer: coccidioidomycosis with dissemination risk; treat with liposomal amphotericin B (avoid azoles in pregnancy)

— Indianapolis resident, CD4 <50, urine antigen positive

— Answer: disseminated histoplasmosis; liposomal ampho × 2 weeks → itraconazole lifelong until immune reconstitution; coordinate ART

— Asymptomatic patient from Ohio, screening CT shows 1-cm nodule with central calcification, PET non-avid

— Answer: histoplasmoma — observe, no biopsy needed

— Patient with cocci pneumonia develops new headache; CF titer 1:32

— Answer: LP to rule out meningitis; if positive → lifelong fluconazole

— Answer: screen for latent histoplasmosis, counsel on exposure avoidance, monitor for reactivation

— Answer: fibrosing mediastinitis — antifungals NOT indicated; refer to interventional pulm/cardiothoracic surgery

— Answer: adrenal insufficiency from histo adrenalitis — give stress-dose hydrocortisone, check cosyntropin stim

— Answer: cocci; report to public health if in mandatory reporting jurisdiction

Stem 1 — Spelunker with flu-like illness

Stem 2 — Verrucous skin lesion in a Wisconsin hunter

Stem 3 — Pregnant Filipino woman in Arizona with pneumonia and EN

Stem 4 — AIDS patient with pancytopenia, hepatosplenomegaly, oral ulcers

Stem 5 — Solitary lung nodule with central calcification

Stem 6 — Headache after cocci diagnosis

Stem 7 — Patient about to start TNF inhibitor for RA in Tennessee

Stem 8 — SVC syndrome years after histo exposure

Stem 9 — Refractory hypotension in disseminated histo

Stem 10 — Worker with rash and pneumonia after construction in Arizona dust

Board pearl: When the vignette emphasizes geographic exposure, occupation, or hobby, the answer is almost always an endemic mycosis — let the exposure drive the diagnosis

One-Line Recap

Endemic mycoses — histoplasmosis, blastomycosis, and coccidioidomycosis — are dimorphic fungal infections defined by geographic exposure, diagnosed primarily by urine antigen/serology plus characteristic histopathology, and treated with itraconazole (or fluconazole for cocci) for mild-moderate disease and liposomal amphotericin B for severe, disseminated, CNS, or pregnant cases — with cocci meningitis requiring lifelong fluconazole and AIDS-associated histoplasmosis requiring suppression until immune reconstitution.

Geography is destiny: Ohio/Mississippi valleys + caves/birds = histo; Great Lakes + rotting wood = blasto; Southwest deserts + dust = cocci — always anchor on exposure history

Histology signatures: narrow-based intracellular budding yeast (histo), broad-based budding yeast (blasto), spherules with endospores (cocci) — these three patterns answer most histopathology questions

Treatment logic: mild + immunocompetent → observe (histo, cocci) or itraconazole (blasto, always treated); moderate-severe or disseminated → liposomal amphotericin induction then azole consolidation; CNS cocci → lifelong fluconazole; pregnancy → amphotericin only (no azoles)

High-stakes pitfalls to avoid: empirical steroids for presumed sarcoidosis without excluding mycosis, starting TNF-α inhibitors without histo screening, using echinocandins (ineffective), stopping fluconazole in cocci meningitis (80% relapse), and missing adrenal insufficiency in disseminated histo presenting as refractory shock

Board pearl: When in doubt on Step 3, the safest decisions are to send urine/serum antigen plus serology, consult infectious disease, screen for HIV, and start liposomal amphotericin B in any severe or disseminated presentation while awaiting confirmation