245.1 🎓 醫學生版

245.1.0.1 📌 一頁重點

245.1.0.1.1 Microbiology

• Histoplasma capsulatum — dimorphic fungus
• Mold phase at room temp (environmental)
• Yeast phase at 37°C (tissue, intracellular in macrophages)
• 2 varieties: capsulatum (worldwide) + duboisii (African, larger yeasts)

245.1.0.1.2 Geography

• Endemic: Ohio + Mississippi River valleys (USA), Central + South America, Caribbean, parts of Africa + Asia + Australia
• Hot spots: chicken coops, caves (bat guano), old buildings demolition, bird roosts

245.1.0.1.3 Transmission

• Inhalation of microconidia (spores)
• Bat + bird droppings in soil
• Cave exploration, construction, gardening, demolition
• NOT person-to-person
• NOT zoonotic (despite animal association)

245.1.0.1.4 Clinical Spectrum

245.1.0.1.4.1 Asymptomatic (90%+)

• Most acquired infections subclinical
• Latent infection lifelong
• Reactivation in immunocompromise possible

245.1.0.1.4.2 Acute Pulmonary Histoplasmosis

• 1-3 wk post-exposure
• Influenza-like illness (fever, headache, cough, myalgia, fatigue)
• Mostly self-limited (weeks)
• Heavy exposure → severe with hypoxia + ARDS
• CXR: mediastinal LAP, infiltrates, sometimes nodules

245.1.0.1.4.3 Chronic Pulmonary Histoplasmosis

• Older men with pre-existing COPD/emphysema typically
• Cavitary disease (mimics TB)
• Months-years course
• Cough, weight loss, fatigue, fever

245.1.0.1.4.4 Disseminated Histoplasmosis

• HIV CD4 < 100 classic; also transplant + anti-TNF + immunocompromise
• Multi-organ: bone marrow + liver + spleen + adrenal + skin + CNS
• Pancytopenia + hepatosplenomegaly + LAP + oral ulcers + adrenal insufficiency
• Mortality high without treatment
• HIV: AIDS-defining illness

245.1.0.1.4.5 Mediastinal Histoplasmosis

• Fibrosing mediastinitis — rare severe complication of past infection; vascular + airway compression; pulmonary HTN

245.1.0.1.4.6 Other Forms

• Acute pericarditis (post-infection)
• Histoplasmoma (chronic granuloma, often calcified)
• Sclerosing mediastinitis (rare)
• Adrenal insufficiency (disseminated)
• Cutaneous + ocular + CNS in disseminated

245.1.0.1.5 Diagnosis

245.1.0.1.5.1 Urinary Histoplasma Antigen

• Rapid + sensitive (90% in disseminated; lower in chronic pulmonary)
• ELISA
• Used for diagnosis + monitoring response

245.1.0.1.5.2 Serum Histoplasma Antigen

• Complementary
• Sometimes positive when urinary negative

245.1.0.1.5.3 Antibody Tests

• Complement fixation, immunodiffusion
• Help in chronic / mild disease where antigen less sensitive
• May be negative in severe immunocompromise

245.1.0.1.5.4 Culture

• Slow (2-6 wk)
• Sputum, BAL, blood, bone marrow, tissue
• Gold standard but slow

245.1.0.1.5.5 Histology

• Small intracellular yeast in macrophages (Giemsa, GMS stain)
• Often with negative birefringent halo on H&E (capsule artifact)

245.1.0.1.5.6 Imaging

• CXR / CT chest
• CT abdomen / MRI brain for disseminated

245.1.0.1.6 Treatment

245.1.0.1.6.1 Mild-Moderate (Pulmonary, Disseminated)

• Itraconazole 200 mg PO bid × 6-12 weeks (acute pulmonary) or longer (chronic pulmonary 12-24 months)
• TDM essential (variable absorption)

245.1.0.1.6.2 Severe / Disseminated

• Liposomal Amphotericin B 3-5 mg/kg/d × 1-2 weeks induction
• Then itraconazole 200 mg PO bid × 12+ months consolidation
• HIV: maintenance until CD4 > 150 for 6+ months on ART

245.1.0.1.6.3 Mediastinal Forms

• Fibrosing mediastinitis: minimal benefit of antifungal; mostly supportive
• Mediastinal LAP / pericarditis: NSAID + observation; steroids for severe; antifungal for confirmed active

245.1.0.1.6.4 Asymptomatic / Mild Acute (Immunocompetent)

• No treatment; self-limited
• Symptomatic acute / progressive: itraconazole

245.1.0.1.7 Prophylaxis

• Itraconazole 200 mg/d for HIV CD4 < 150 in endemic area (not universal)
• Pre-immunosuppression considerations for high-risk

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245.1.0.2 1️⃣ Microbiology + Life Cycle

245.1.0.2.1 Dimorphism

• Mold phase at environmental temperature (25-30°C): hyphal form
• Yeast phase at body temperature (37°C): intracellular, small (2-4 µm)
• Conidia + microconidia spores in environment

245.1.0.2.2 Life Cycle

1. Microconidia inhaled
2. Reach alveoli
3. Phagocytosed by alveolar macrophages
4. Transform to yeast in macrophages (intracellular)
5. Multiply in macrophages → cell rupture
6. Disseminate via lymph + blood to reticuloendothelial system
7. Cell-mediated immunity activates → granulomas form
8. Most controlled at granuloma stage → asymptomatic + latent
9. Reactivation in immunocompromise

245.1.0.2.3 Granuloma Formation

• Similar to TB
• Caseating + non-caseating granulomas
• Calcified scars seen in radiographs of past infection

245.1.0.2.4 Reactivation

• Immunocompromise → disrupted granulomas → reactivation
• Similar pattern to TB latent reactivation
• Can occur years-decades after primary infection

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245.1.0.3 2️⃣ Geography + Exposure

245.1.0.3.1 USA Endemic

• Ohio + Mississippi River valleys classic
• Includes parts of: Ohio, Indiana, Kentucky, Tennessee, Missouri, Illinois, Arkansas, Mississippi
• Spreading northward + westward
• ~ 80% population in endemic areas serologically positive (past exposure)

245.1.0.3.2 Worldwide

• Central + South America (Brazil, Argentina, Venezuela, Colombia)
• Caribbean
• Parts of Africa
• SE Asia + India
• Australia (north + east)
• Climate change effects on distribution

245.1.0.3.3 High-Risk Exposures

• Caves (bat guano — guano increased fungal growth)
• Chicken coops + bird roosts
• Old buildings demolition (renovation, construction)
• Gardening (especially with bird-frequented areas)
• Cleaning bat / bird droppings
• Speleologists, construction workers, agricultural

245.1.0.3.4 Outbreaks

• Cave / cave dwellings
• Demolition projects (urban renewal)
• HVAC work in old buildings
• Aboveground exposure during dust storms

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245.1.0.4 3️⃣ Clinical Forms

245.1.0.4.1 Asymptomatic (90%+)

• Subclinical primary infection
• Skin test conversion
• Calcified pulmonary nodules + lymphadenopathy on retrospective imaging
• Lifelong latent reservoir
• Reactivation potential

245.1.0.4.2 Acute Pulmonary Histoplasmosis

245.1.0.4.2.1 Mild

• Flu-like syndrome 1-3 weeks post-exposure
• Fever, headache, fatigue, cough, myalgia, chest pain
• 1-3 wk self-limited

245.1.0.4.2.2 Heavy Exposure (Severe Acute)

• Hypoxia, dyspnea
• ARDS possible
• Mediastinal lymphadenopathy
• Systemic illness

245.1.0.4.2.3 Imaging

• Diffuse small nodules (“buckshot pattern”)
• Mediastinal + hilar LAP
• Patchy infiltrates
• Sometimes calcifications later

245.1.0.4.3 Chronic Pulmonary Histoplasmosis

• Pre-existing COPD/emphysema typically (older men > 50)
• Months-years onset
• Productive cough, hemoptysis, fatigue, weight loss, low-grade fever
• Apical cavitary disease (mimics TB)
• Progressive destruction without treatment

245.1.0.4.4 Disseminated Histoplasmosis

245.1.0.4.4.1 Risk

• HIV CD4 < 100 (especially < 50)
• Solid organ transplant
• Anti-TNF therapy
• Severe immunocompromise
• Steroids
• Hematologic malignancy

245.1.0.4.4.2 Clinical

• Multi-organ disease (reticuloendothelial system):
  • Bone marrow suppression (pancytopenia)
  • Hepatosplenomegaly
  • Lymphadenopathy
  • Oral ulcers + tongue lesions (especially HIV)
  • Adrenal insufficiency (bilateral adrenal involvement)
  • CNS (meningitis, focal lesions)
  • Cutaneous (papules, ulcers, mucosal)
  • GI (ulcers + bleeding)
• AIDS-defining illness when HIV + disseminated

245.1.0.4.4.3 Severe Outcomes

• Mortality 50%+ untreated
• Improved with timely Tx

245.1.0.4.5 Other Forms

245.1.0.4.5.1 Acute Pericarditis

• Post-acute pulmonary infection
• Fever + chest pain
• Pericardial friction rub
• Treat with NSAID + observation; antifungal not always

245.1.0.4.5.2 Histoplasmoma

• Single solitary nodule in lung
• Calcified often
• Sometimes mistaken for malignancy
• Stable; biopsy if uncertain

245.1.0.4.5.3 Mediastinal Lymphadenopathy

• Symmetric mediastinal + hilar LAP
• Often asymptomatic
• Resolves over months
• Sometimes calcifies

245.1.0.4.5.4 Mediastinal Granuloma

• Coalescent lymph nodes with caseation
• Sometimes airway / vascular compression
• Surgery if symptomatic

245.1.0.4.5.5 Fibrosing Mediastinitis

• Rare severe complication
• Late after past infection
• Excessive fibrosis encasing mediastinal structures
• Vascular (SVC syndrome, pulmonary HTN)
• Airway (compression, post-obstructive pneumonia)
• Esophageal (rarely)
• Treatment: surgery + supportive; antifungal minimal benefit

245.1.0.4.5.6 Sclerosing Mediastinitis

• Even rarer
• Similar to fibrosing
• Diffuse fibrosis

245.1.0.4.5.7 Adrenal Insufficiency

• Disseminated involves adrenals frequently
• Bilateral adrenal masses on imaging
• Need acute Tx
• Steroid replacement

245.1.0.4.5.8 Eye Disease (POHS — Presumed Ocular Histoplasmosis Syndrome)

• Choroidal lesions
• Often without active infection
• Eye complication of past histoplasmosis

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245.1.0.5 4️⃣ Diagnosis

245.1.0.5.1 Urinary Histoplasma Antigen

• Most useful for disseminated (90% sens)
• ELISA-based
• Quantitative — useful for monitoring response
• Rapid (within days)
• Cross-reactivity: blastomycosis, paracoccidioidomycosis, talaromycosis (mild)

245.1.0.5.2 Serum Histoplasma Antigen

• Complementary to urinary
• Sometimes positive when urinary negative
• Particularly for severe disseminated

245.1.0.5.3 Antibody Tests

• Complement fixation (CF) — measures Histoplasma antibodies
  • Titer > 1:32 supportive
  • Rises 2-6 weeks post-exposure
• Immunodiffusion for specific bands (M, H bands)
• May be negative in:
  • Severe immunocompromise
  • Acute primary infection
  • Chronic stable disease
• Useful for past infection / chronic / mild acute

245.1.0.5.4 Culture

• Gold standard but slow (2-6 weeks)
• Sputum, BAL, blood (lysis-centrifugation), bone marrow, tissue
• For severe / disseminated diagnosis

245.1.0.5.5 Histology

• Small intracellular yeast in macrophages (2-4 µm)
• GMS or Giemsa stain preferred
• Often with apparent “capsule” (artifact)
• Bone marrow biopsy often diagnostic in disseminated

245.1.0.5.6 Imaging

• CXR / CT:
  • Acute: diffuse small nodules, mediastinal LAP, infiltrates
  • Chronic: apical cavities (mimics TB)
  • Calcifications (past infection)
• CT abdomen: hepatosplenomegaly, adrenal enlargement
• MRI brain: CNS disease

245.1.0.5.7 Lab Findings

• Pancytopenia in disseminated
• Elevated LDH (high in disseminated)
• Elevated ferritin (very high in disseminated; useful adjunctive marker)
• Hypoalbuminemia
• Hyperbilirubinemia (hepatic involvement)
• Adrenal insufficiency labs

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245.1.0.6 5️⃣ Treatment

245.1.0.6.1 Asymptomatic / Mild Acute (Immunocompetent)

• No treatment typically
• Self-limited

245.1.0.6.2 Symptomatic Acute Pulmonary (Immunocompetent)

245.1.0.6.2.1 Mild-Moderate

• Itraconazole 200 mg PO bid × 6-12 weeks
• TDM (trough > 1.0 mg/L target)

245.1.0.6.2.2 Severe Acute Pulmonary

• Liposomal Amphotericin B 3-5 mg/kg/d IV × 1-2 weeks
• Then Itraconazole 200 mg PO bid × 12 weeks

245.1.0.6.3 Chronic Pulmonary Histoplasmosis

• Itraconazole 200 mg PO bid × 12-24 months
• Monitor radiographic + clinical response
• Long course often required

245.1.0.6.4 Disseminated Histoplasmosis

245.1.0.6.4.1 Severe / Moderate

• Liposomal Amphotericin B 3-5 mg/kg/d × 1-2 weeks induction → Itraconazole 200 mg PO bid × 12+ months consolidation
• HIV CD4 < 150: maintenance until CD4 > 150 for 6+ months on ART

245.1.0.6.4.2 Mild Disseminated

• Itraconazole 200 mg PO bid × 12 months

245.1.0.6.5 CNS Histoplasmosis

• Liposomal AmB 5 mg/kg/d × 4-6 weeks induction → Itraconazole 200 mg PO tid × 12+ months
• Higher dose AmB for CNS penetration
• Longer course

245.1.0.6.6 Mediastinal Forms

• Fibrosing mediastinitis: minimal benefit of antifungal; mostly supportive (vascular procedures, airway stents)
• Mediastinal LAP / pericarditis: observation; NSAID for pericarditis; antifungal for active confirmed
• Surgery for compressive disease

245.1.0.6.7 Alternative Drugs

• Posaconazole (alternative; some intolerance to itraconazole)
• Voriconazole (less data)
• Isavuconazole (alternative; FDA approved indication)
• Amphotericin B alternative forms

245.1.0.6.8 TDM for Itraconazole

• Variable absorption (especially capsule form; better with solution + food)
• Trough > 1.0 mg/L target (some > 0.5)
• Hepatotoxicity, GI, drug interactions

245.1.0.6.9 Monitoring Response

• Urinary antigen levels — decrease with treatment
• Imaging (resolution + improvement)
• Clinical response
• Serial labs

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245.1.0.7 6️⃣ HIV + Histoplasmosis

245.1.0.7.1 Pre-Emptive in Endemic Areas

• Some guidelines: itraconazole 200 mg/d prophylaxis for HIV CD4 < 150 in heavily endemic areas
• Not universal (cost, drug interactions, alternative ART regimens)
• Antigen screening selectively

245.1.0.7.2 Acute Diagnosis

• HIV + CD4 < 100 + fever + pancytopenia + hepatosplenomegaly + skin / oral lesions → consider disseminated histoplasmosis (especially in / from endemic area)
• Urinary antigen + serum antigen
• Bone marrow biopsy + culture (high yield)
• Multi-organ workup

245.1.0.7.3 Treatment

• Liposomal AmB induction × 1-2 wk → itraconazole 200 mg bid maintenance
• Continue maintenance until CD4 > 150 × 6+ mo on ART
• ART critical for cure

245.1.0.7.4 IRIS

• Paradoxical worsening with immune recovery
• Continue antifungal + ART
• Steroid for severe

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245.1.0.8 7️⃣ Special Forms

245.1.0.8.1 Histoplasma duboisii (African Histoplasmosis)

• West + Central Africa
• Larger yeast (8-15 µm)
• More skin + bone involvement
• Lymphadenopathy
• Treatment similar (itraconazole + AmB)

245.1.0.8.2 Pregnancy

• Avoid azoles 1st trimester
• Amphotericin B preferred if needed
• Severe disease + pregnancy: liposomal AmB

245.1.0.8.3 Pediatric

• Similar regimens, weight-based
• HIV + endemic: prophylaxis considerations

245.1.0.8.4 Reactivation

• In immunocompromise, years after primary infection
• Mimics primary infection presentation
• Treat as primary

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