zygomycosis

**Terminology:** "Zygomycosis" is the older umbrella term for infections by the former phylum Zygomycota. Taxonomy has since been revised. Infections by the order Mucorales are now called **mucormycosis**. Entomophthorales cause a separate, indolent subcutaneous/rhinofacial disease called entomophthoramycosis (basidiobolomycosis and conidiobolomycosis), usually in immunocompetent hosts in tropical regions. On boards the terms zygomycosis and mucormycosis are used interchangeably.

**Organisms:** Rhizopus (most common), Mucor, Lichtheimia (Absidia), Cunninghamella. They are ubiquitous in soil, decaying organic matter, and bread mold. Infection follows inhalation of spores, ingestion, or traumatic inoculation.

**Risk factors (high-yield):** - Diabetic ketoacidosis (classic). Acidosis impairs neutrophil function and releases free iron from transferrin. Hyperglycemia up-regulates the host GRP78 receptor, which promotes fungal invasion. Rhizopus also has ketone reductase, so it thrives in ketoacidosis. - Neutropenia and hematologic malignancy - Hematopoietic stem cell or solid organ transplant - Corticosteroids - Iron overload, and deferoxamine therapy (the fungus uses the siderophore for iron) - Burns and trauma - COVID-19 with diabetes and steroid use (the "COVID-associated mucormycosis" surge in India)

**Clinical forms:** - **Rhinocerebral (most common, especially in DKA):** Sinusitis, facial pain and swelling, and nasal congestion progress to **black necrotic eschar** on the nasal turbinates or palate. The infection spreads through the orbit and the cribriform plate to the brain, causing proptosis, ophthalmoplegia, vision loss, and cranial nerve palsies. It can invade the cavernous sinus, causing cavernous sinus thrombosis and internal carotid artery involvement. - **Pulmonary:** Seen in neutropenic and transplant patients. Fever, cough, and hemoptysis, with nodules, cavities, or the reverse halo sign on CT. - **Cutaneous:** After trauma or burns, or from contaminated dressings. - **Gastrointestinal:** Seen in malnourished patients and preterm neonates. - **Disseminated:** Seen in severe immunosuppression.

**Pathophysiology:** The fungus is **angioinvasive**. It invades blood vessels, causing thrombosis, infarction, and tissue necrosis. This produces the black eschar and the poor antifungal penetration into necrotic tissue.

**Diagnosis:** - Tissue biopsy is the key test. H&E, GMS, or PAS stains show **broad (5–15 μm), ribbon-like, pauciseptate or nonseptate hyphae with irregular, right-angle (~90°) branching**. - Culture is often negative because the fungus is fragile. - Imaging (CT or MRI of sinuses, brain, and chest) shows the extent of disease. - **Serum β-D-glucan and galactomannan are typically negative.**

**Contrast with Aspergillus:** Aspergillus has narrow, **septate** hyphae with **acute-angle (45°) branching**. It causes invasive sinopulmonary disease, and galactomannan is positive.

**Treatment:** 1. Reverse the underlying cause (correct DKA and acidosis, stop or reduce steroids, restore neutrophils, stop deferoxamine). 2. **Early, aggressive surgical debridement** of necrotic tissue. This is essential, and the debridement may be extensive (for example, orbital exenteration). 3. **Liposomal amphotericin B** is first-line. 4. Isavuconazole or posaconazole are used as step-down or salvage therapy. - **Voriconazole is not active** against Mucorales, and echinocandins are ineffective. Voriconazole exposure is a risk factor for breakthrough mucormycosis.

**Prognosis:** Mortality is high (about 50% or more, and approaching 100% if disseminated or if treatment is delayed). Early recognition is critical.

**Board pearl:** A diabetic patient in DKA with sinus pain, facial swelling, and black nasal discharge or eschar should prompt a diagnosis of rhinocerebral mucormycosis. The next steps are emergent ENT or surgical consultation with biopsy, and starting amphotericin B.