Mucorales/Mucormycosis

Mucormycosis is an angioinvasive fungal infection caused by multiple fungi within the order, Mucorales. The fungi are ubiquitous in the environment, but mucormycosis is very rare and almost always occurs in patients who are immunocompromised. Inhalation of fungal spores can cause rhinocerebral or pulmonary mucormycosis, direct inoculation can cause cutaneous mucormycosis, and ingestion can cause gastrointestinal mucormycosis. The clinical presentation results from fungal hyphae invading the blood vessels, causing thrombosis and tissue necrosis. Diagnosis is confirmed with the identification of the organism on histopathology of biopsy specimens. Patients must be treated aggressively with antifungals and surgical resection of infected tissues.

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General Characteristics

Basic features of Mucorales

Taxonomy:

  • Order: Mucorales
  • Genera most commonly associated with human infection: 
    • Rhizopus
    • Rhizomucor
    • Mucor
    • Cunninghamella
    • Lichtheimia (formerly Absidia)
    • Apophysomyces
    • Saksenaea

Morphology:

  • Colonies:
    • Fast growing
    • Cottony
    • White-to-yellow color → becomes gray 
  • Microscopic features:
    • Wide hyphae 
    • Lack or rare septations
    • Branching at right angles
    • Sporangiophores:
      • Upright hyphae
      • Support sac-like sporangia filled with asexual sporangiospores
Microscopic view of the biopsy specimen mucormycosis

A microscopic view of the biopsy specimen shows several short, folded hyphae with nonseptate, broad and right-angle buddings, which are characteristic of mucormycosis.

Image: “Histopathological findings” by Baezzat SR et al. License: CC BY 2.5

Associated diseases

Mucormycosis is caused by many species within the Mucorales order, which can be classified based on the site of infection:

  • Rhinocerebral mucormycosis (most common) 
  • Pulmonary mucormycosis
  • Cutaneous mucormycosis
  • Gastrointestinal mucormycosis

Epidemiology

  • Very rare infection; the true incidence is unknown.
  • Approximately 500 annual cases in the United States
  • Incidence is increasing due to a rising number of immunocompromised patients.
  • No gender predilection
  • No racial predilection
  • No age predilection
  • Mortality rate: 50%–85%

Pathogenesis

Reservoir

Mucorales are common in the environment and are found on:

  • Decaying vegetation
  • Soil

Transmission

  • Inhalation of spores (primary method)
  • Ingestion of contaminated food 
  • Skin inoculation

Host risk factors

Almost all infections occur in the presence of an underlying condition:

  • Diabetes (especially diabetic ketoacidosis)
  • Hematological malignancies
  • Solid-organ cancer
  • Organ transplant
  • Stem-cell transplant
  • Immunosuppressive therapy 
  • Chronic corticosteroid use
  • HIV/AIDS
  • Neutropenia (neutrophils are the key host defense against the fungi)
  • Iron-overload conditions (e.g., hemochromatosis and deferoxamine therapy)
  • Skin injury due to surgery, burns, or trauma
  • Use of injection drug
  • Malnutrition

Pathophysiology

  • Most spores enter through the respiratory tract → adhere to mucus
  • Healthy individuals:
    • Usually clear by coughing, sneezing, or swallowing
    • Neutrophils phagocytize → destroy the fungus
  • Susceptible patients:
    • Spores transform into the hyphal form in nasal turbinates or alveoli.
    • Hyphae invade blood vessels → tissue infarction and thrombosis
    • Leads to rhinocerebral or pulmonary disease
  • Other routes of infection → disease at those sites:
    • Traumatic inoculation or contamination → cutaneous disease
    • Ingestion → gastrointestinal disease

Clinical Presentation

Rhinocerebral disease

Patients start with symptoms of acute sinusitis. Symptoms progress due to the spread of the infection to contiguous structures.

  • Fever
  • Nasal congestion (may have black discharge)
  • Unilateral retro-orbital headache
  • Facial pain
  • Numbness
  • Hyposmia
  • Orbital swelling with proptosis and chemosis
  • Facial cellulitis
  • Eschar formation can occur on:
    • Nasal mucosa
    • Palate
    • Overlying skin
Swelling of upper and lower lid mucormycosis

Swelling of the upper and lower lid in a patient with orbital involvement from mucormycosis

Image: “Swelling of upper and lower lid in the patient with mucormycosis” by Badiee P et al. License: CC BY 2.0

Pulmonary disease

Patients with pulmonary disease develop rapidly progressive pneumonia (often bilateral).

  • Fever
  • Dyspnea
  • Cough
  • Hemoptysis

Cutaneous disease

  • Cellulitis
  • Dermal necrosis
  • Formation of black eschar

Gastrointestinal disease

The condition causes necrotic ulcers in the gastrointestinal tract, which can lead to perforation. Signs and symptoms include:

  • Abdominal pain
  • Distention
  • Nausea
  • Vomiting
  • Hematochezia
  • Obstruction
  • Peritoneal signs

Rare manifestations

  • Disseminated disease:
    • Can present with nonspecific signs and symptoms
  • CNS mucormycosis:
    • Usually direct spread from a sinus infection
    • Signs and symptoms:
      • Lethargy
      • Headache
      • Focal neurologic deficits

Diagnosis and Management

Diagnosis

A high index of suspicion is required to make the diagnosis.

  • Biopsy specimen:
    • Histopathologic identification of the causative organism establishes the diagnosis.
    • Tissue necrosis can be seen.
  • Fungal cultures (often negative)
  • Imaging (e.g., head or chest CT) to assess the extent of infection and tissue damage
  • 1,3-β-D-glucan is not useful (not a component of the Mucorales cell wall).

Management

  • Treat the underlying condition when possible (e.g., diabetic ketoacidosis).
  • If possible, management should occur in a tertiary care center.
  • Antifungal therapy should be started immediately:
    • Liposomal amphotericin B (1st line)
    • Isavuconazole 
    • Posaconazole
  • Surgical resection of necrotic tissue is indicated to limit further spread:
    • Associated with improved survival
    • Can lead to significant disfigurement

Comparison of Species

Table: Comparison of species
OrganismMucoralesAspergillus
Characteristics
  • Wide hyphae
  • Lack of rare septations
  • Branch at 90-degree angles
  • Septated hyphae
  • Branch at 45-degree angles
Transmission
  • Inhalation
  • Ingestion
  • Inoculation
  • Inhalation
  • Invasion through damaged skin
ClinicalMucormycosis:
  • Rhinocerebral disease
  • Pulmonary disease
  • Gastrointestinal disease
  • Cutaneous disease
  • ABPA
  • Sinusitis
  • Aspergilloma
  • Chronic pulmonary aspergillosis
  • Invasive aspergillosis
  • Cutaneous aspergillosis
Diagnosis
  • Histopathology
  • Histopathology
  • Culture
Management
  • Antifungal therapy
  • Surgical resection for any form
  • Antifungal therapy
  • Surgery for necrotic tissue in invasive disease
ABPA: allergic bronchopulmonary aspergillosis

Differential Diagnosis

  • Bacterial orbital cellulitis: infection of the orbital tissues, which can occur from hematogenous spread, extension from adjacent sinuses, or traumatic inoculation. Patients present with swelling and redness, conjunctival erythema, pain from eye movement, and proptosis. Diagnosis is clinical. The mainstay of treatment is antibiotic therapy and surgery is reserved for severe cases. 
  • Cavernous sinus thrombosis: a rare, life-threatening condition occurring from a facial infection. Cavernous sinus thrombosis is usually bacterial in etiology. Patients present with fever, headache, proptosis, and ophthalmoplegia. Diagnosis is confirmed with CT or MRI. Management includes antibiotics and, occasionally, steroids. Anticoagulation is controversial.
  • Community-acquired pneumonia: infection of the lung parenchyma most often caused by a bacteria or virus. Patients present with fever, dyspnea, and a productive cough. Chest X-ray typically shows lobar consolidation. Management involves empiric antibiotics, which can be tailored if the causative organism is identified. Antivirals are used when a viral cause is suspected.

References

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  12. Vallabhaneni S, Mody RK. (2015). Gastrointestinal mucormycosis in neonates: a review. Current Fungal Infect Rep. 10.1007/s12281-015-0239-9. https://www.researchgate.net/publication/283943193_Gastrointestinal_Mucormycosis_in_Neonates_a_Review
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