# Clinical Cases: Fungi

## Case 1: Cryptococcal Meningitis in HIV

### Presentation
A 38-year-old man with HIV (not on antiretroviral therapy, last CD4 count 45 cells/μL) presents with 2 weeks of progressive headache that has become severe over the past 3 days. He also reports neck stiffness, low-grade fever, and mild confusion. He has no photophobia or focal neurologic deficits. Lumbar puncture shows an opening pressure of 42 cm H2O, CSF with 35 WBC/μL (95% lymphocytes), protein 85 mg/dL, and glucose 28 mg/dL. India ink preparation reveals encapsulated yeast organisms. Serum and CSF cryptococcal antigen are both strongly positive at titers >1:1024.

### Clinical Image
![India ink preparation showing Cryptococcus](image_01.png)
*India ink preparation of cerebrospinal fluid demonstrating encapsulated yeast cells of Cryptococcus neoformans. The capsule appears as a clear halo around the organism against the dark ink background.*

**Image Source**: Lecture image - Cryptococcus diagnosis

### Questions

1. **What is the diagnosis, and why is this patient at particular risk?**

2. **What is the significance of the markedly elevated opening pressure?**

3. **What is the recommended treatment approach for cryptococcal meningitis?**

4. **What complications should be anticipated during treatment?**

### Answers

1. **Diagnosis and risk factors**: This is **cryptococcal meningitis** caused by **Cryptococcus neoformans**. This patient is at high risk because of **AIDS with CD4 count <100 cells/μL**. Cryptococcal meningitis is an AIDS-defining illness and occurs almost exclusively in severely immunocompromised patients. C. neoformans is found in soil contaminated with pigeon droppings and is acquired through inhalation. Its polysaccharide capsule is the major virulence factor, inhibiting phagocytosis and allowing CNS invasion.

2. **Significance of elevated opening pressure**: The markedly elevated opening pressure (normal <20 cm H2O) is **critical for both morbidity and mortality**. Elevated intracranial pressure (ICP) is the primary cause of early death in cryptococcal meningitis. The organism's polysaccharide capsule and inflammatory response obstruct CSF outflow. Management requires:
   - **Therapeutic lumbar puncture**: Remove enough CSF to reduce pressure by 50% or to normalize
   - **Daily LPs** may be needed until pressure normalizes
   - Ventriculoperitoneal shunt for refractory cases
   - This is often overlooked but is as important as antifungal therapy

3. **Treatment approach**: Treatment follows a three-phase strategy:
   - **Induction (at least 2 weeks)**: Liposomal amphotericin B + flucytosine (5-FC) - this combination has demonstrated superior fungicidal activity
   - **Consolidation (8 weeks)**: Fluconazole 400-800 mg daily
   - **Maintenance (indefinite until immune reconstitution)**: Fluconazole 200 mg daily
   - **ART initiation**: Delay 4-6 weeks after starting antifungal therapy to reduce IRIS risk
   - Maintenance can be discontinued after CD4 >100 cells/μL for >3 months on suppressive ART with undetectable viral load

4. **Anticipated complications**:
   - **Elevated ICP** causing herniation (monitor and treat aggressively)
   - **Drug toxicities**: Nephrotoxicity and electrolyte abnormalities (amphotericin B), bone marrow suppression (flucytosine), hepatotoxicity (fluconazole)
   - **Immune reconstitution inflammatory syndrome (IRIS)**: Paradoxical worsening after ART initiation as immune system mounts inflammatory response; may present with worsening headache, fever, lymphadenopathy, or new neurologic findings; managed with corticosteroids while continuing both antifungal and ART
   - **Relapse**: High without maintenance therapy

---

## Case 2: Invasive Aspergillosis in Neutropenic Patient

### Presentation
A 55-year-old man undergoing induction chemotherapy for acute myeloid leukemia has been neutropenic (ANC <100 cells/μL) for 18 days. He has been on broad-spectrum antibiotics for persistent fever without a clear source. He now develops pleuritic chest pain, cough, and hemoptysis. CT chest shows a 3 cm nodule in the right upper lobe surrounded by ground-glass attenuation (halo sign). Serum galactomannan index is elevated at 2.4 (positive >0.5). Bronchoscopy with bronchoalveolar lavage is performed; galactomannan of BAL fluid is markedly elevated.

### Clinical Image
![CT chest showing halo sign](image_02.png)
*CT scan of the chest demonstrating a pulmonary nodule with surrounding ground-glass opacity (halo sign), representing hemorrhage around the invasive fungal focus - characteristic of invasive aspergillosis in neutropenic patients.*

**Image Source**: Lecture image - invasive aspergillosis imaging

### Questions

1. **What is the most likely diagnosis, and what features support this diagnosis?**

2. **Explain the pathophysiology of the halo sign and hemoptysis.**

3. **What is the appropriate treatment, and what determines prognosis?**

4. **What preventive strategies exist for high-risk patients?**

### Answers

1. **Diagnosis and supporting features**: This is **invasive pulmonary aspergillosis (IPA)**, most likely caused by Aspergillus fumigatus. Supporting features include:
   - **Prolonged neutropenia** (>10 days) - the major risk factor
   - **Fever unresponsive to broad-spectrum antibiotics**
   - **Characteristic imaging**: Pulmonary nodule with halo sign
   - **Elevated serum galactomannan**: A cell wall component detected as a biomarker
   - **Hemoptysis**: Suggests angioinvasion

   The combination of host risk factors, clinical presentation, imaging, and biomarker positivity establishes the diagnosis with high probability.

2. **Pathophysiology of halo sign and hemoptysis**: Aspergillus demonstrates **angioinvasive** behavior in neutropenic patients - the fungal hyphae invade blood vessel walls. This causes:
   - **Thrombosis** of invaded vessels
   - **Hemorrhage** around the infected focus (produces the halo sign = ground-glass surrounding nodule)
   - **Tissue infarction** from vascular occlusion
   - **Hemoptysis** from erosion into airways
   - Later, as neutropenia resolves, the **air-crescent sign** appears as necrotic tissue separates

3. **Treatment and prognosis**:
   - **First-line therapy**: **Voriconazole** (IV then oral) - superior to amphotericin B
   - **Alternative**: Isavuconazole (similar efficacy, fewer drug interactions, better tolerated)
   - **Salvage therapy**: Liposomal amphotericin B
   - **Combination therapy**: Sometimes used for refractory cases

   **Prognosis depends on**:
   - **Immune reconstitution** - most critical factor; mortality drops significantly when neutropenia resolves
   - Early diagnosis and treatment
   - Extent of infection
   - Underlying disease status

   Overall mortality ranges from 30-80% depending on these factors.

4. **Prevention strategies**:
   - **Antifungal prophylaxis**: Posaconazole for high-risk patients (prolonged neutropenia, HSCT with GVHD)
   - **HEPA-filtered rooms** to reduce airborne spore exposure
   - **Galactomannan monitoring**: Twice-weekly testing enables early preemptive therapy
   - **Avoid high-risk exposures**: Construction sites, gardening, areas with decaying vegetation
   - **Prompt empiric therapy** for suspected fungal infection in high-risk neutropenic patients

---

## Case 3: Coccidioidomycosis (Valley Fever)

### Presentation
A 42-year-old previously healthy man presents with 3 weeks of cough, low-grade fever, fatigue, and chest pain. He recently returned from Arizona where he was working on a construction project in the desert. He also reports painful red nodules on his shins and joint aches. Chest radiograph shows right hilar lymphadenopathy and a right lower lobe infiltrate. Examination reveals tender erythematous nodules on the anterior shins bilaterally. CBC shows eosinophilia (12%). Coccidioides IgM antibodies are positive.

### Clinical Image
![Erythema nodosum and Coccidioides spherule](image_03.png)
*Left: Erythema nodosum - tender erythematous nodules on the shins, a reactive phenomenon in acute coccidioidomycosis associated with good prognosis. Right: Histopathology showing a Coccidioides spherule filled with endospores.*

**Image Source**: Lecture image - coccidioidomycosis clinical and pathologic findings

### Questions

1. **What is the diagnosis, and what exposure history is significant?**

2. **What is the significance of the skin findings and eosinophilia?**

3. **Does this patient require antifungal treatment?**

4. **What complications should be monitored for, and who is at high risk?**

### Answers

1. **Diagnosis and exposure**: This is **acute pulmonary coccidioidomycosis** (Valley fever) caused by Coccidioides species, acquired through inhalation of arthroconidia during construction work in the endemic desert southwest (Arizona). The organism is found in arid soils, and infection risk increases with soil disruption (construction, dust storms, earthquakes). Approximately 60% of infections are asymptomatic; symptomatic cases present 1-3 weeks after exposure with flu-like illness and pneumonia.

2. **Significance of skin findings and eosinophilia**:
   - **Erythema nodosum** (and erythema multiforme, arthralgias) represent **immune-mediated reactive phenomena** called "desert rheumatism" or "Valley fever arthritis"
   - **Paradoxically, these are good prognostic signs** indicating a robust cell-mediated immune response that will likely control the infection
   - **Eosinophilia** is common in coccidioidomycosis and can suggest fungal infection in the appropriate clinical context
   - Erythema nodosum is NOT due to fungal skin involvement - skin lesions in disseminated disease appear different (papules, nodules, plaques, draining sinuses)

3. **Treatment decision**: For uncomplicated acute pulmonary coccidioidomycosis in healthy patients with good immune response (as suggested by erythema nodosum):
   - **Observation without antifungal therapy** may be appropriate - most cases are self-limited
   - However, treatment with **fluconazole or itraconazole** for 3-6 months is often given to reduce symptom duration and prevent complications

   Treatment is **definitely indicated** for:
   - Severe disease (extensive infiltrates, respiratory failure)
   - Prolonged symptoms (>6-8 weeks)
   - High-risk patients (immunocompromised, pregnant, diabetes, Filipino or African American ancestry)
   - Disseminated disease
   - High complement fixation titers (>1:16)

4. **Complications and high-risk groups**:
   **Complications**:
   - **Chronic pulmonary disease**: Cavitary lesions that may cause hemoptysis or pneumothorax
   - **Dissemination** (<1% of cases in healthy hosts): Skin, bones/joints, meninges
   - **Coccidioidal meningitis**: Most serious complication; requires lifelong fluconazole; high mortality

   **High-risk groups for severe/disseminated disease**:
   - HIV/AIDS (especially CD4 <250)
   - Organ transplant recipients
   - Patients on TNF-alpha inhibitors
   - **Pregnancy** (especially third trimester)
   - **Filipino and African American ancestry** (genetic susceptibility)
   - Diabetes mellitus