Mucorales/Mucormycosis

Mucormycosis is an angioinvasive fungal infection caused by multiple fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview within the order, Mucorales. The fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin inoculation

Host risk factors

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

  • Diabetes (especially diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises)
  • Hematological malignancies
  • Solid-organ cancer
  • Organ transplant
  • Stem-cell transplant
  • Immunosuppressive therapy 
  • Chronic corticosteroid use
  • HIV/AIDS
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (neutrophils are the key host defense against the fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview)
  • Iron-overload conditions (e.g., hemochromatosis and deferoxamine therapy)
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin injury due to surgery, burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, or trauma
  • Use of injection drug
  • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries

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 Sinusitis Sinusitis refers to inflammation of the mucosal lining of the paranasal sinuses. The condition usually occurs concurrently with inflammation of the nasal mucosa (rhinitis), a condition known as rhinosinusitis. Acute sinusitis is due to an upper respiratory infection caused by a viral, bacterial, or fungal agent. Sinusitis. Symptoms progress due to the spread of the infection to contiguous structures.

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Nasal congestion (may have black discharge)
  • Unilateral retro-orbital headache
  • Facial pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Numbness
  • Hyposmia
  • Orbital swelling with proptosis and chemosis
  • Facial cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis
  • Eschar formation can occur on:
    • Nasal mucosa
    • Palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: 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 Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (often bilateral).

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Cough
  • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises).
  • 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
Organism Mucorales Aspergillus
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
Clinical Mucormycosis:
  • Rhinocerebral disease
  • Pulmonary disease
  • Gastrointestinal disease
  • Cutaneous disease
  • ABPA
  • Sinusitis
  • Aspergilloma
  • Chronic pulmonary aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis
  • Invasive aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis
  • Cutaneous aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/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 Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis

Differential Diagnosis

  • Bacterial orbital cellulitis Orbital cellulitis Orbital and preseptal cellulitis are infections differentiated by the anatomic sites affected in the orbit. Infection posterior to the septum is orbital cellulitis. Inoculation with the pathogen can occur through trauma or surgery. Cellulitis also occurs via extension from a nearby structure (such as from sinus infection or sinusitis). Orbital and Preseptal 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: infection of the lung parenchyma most often caused by a bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview or virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview. 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.

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