Epidemiology

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Etiology

General Comments

• Most Human Infections are Caused by Members of the Order Mucorales
• These Fungi Live on Decaying Organic Matter and in the Soil
  • Spores are Ubiquitous and Can Become Airborne

Zygomycetes (see Zygomycetes, [[Zygomycetes]])

• Order: Mucorales
  • Absidia
  • Apophysomyces
  • Cunninghamella
  • Cokeromyces
  • Mortierella
  • Mucor (see Mucor, [[Mucor]]): one of the most common genera responsible for human infection
  • Rhizomucor: one of the most common genera responsible for human infection
  • Rhizopus (see Rhizopus, [[Rhizopus]]): one of the most common genera responsible for human infection
  • Saksenaea
  • Syncephalastrum
• Order: Entomophthorales
  • Basidiobolus
  • Conidiobolus

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Physiology

Entry and Infection

• Inhalation of Spores is the Portal of Entry for Rhino-Orbital-Cerebral and Pulmonary Mucormycosis
  • In Normal Patients, Spores Undergo Ciliary Transport to the Gastrointestinal Tract with Excretion in the Stool
• Characteristic Angioinvasion with Thrombosis and Distal Infarction
• Characteristic Perineural Invasion

Unique Features of Rhizopus

• Possesses Ketone Reductase Enzyme: allows this organism to grow in high glucose, acidic conditions (such as diabetic ketoacidosis)

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Diagnosis

Direct Microscopy/Histopathology (Preferably with Optical Brighteners)

Characteristics of Mucorales

• Hyphae are Morphologically Distinctive from Those of Aspergillus: hyphae of Aspergillus are narrower, 2-5 μm in diameter, exhibit regular branching, and have regular septations
• Broad Hyphae: 5-15 μm in diameter
• Irregular Right Angle (90°) Branching
• Irregular Ribbon-Like Appearance
• Rare Hyphal Septations
• No Pseudohyphae or Budding Yeasts
• May Stain Better with Hematoxylin + Eosin (H+E) Stain than Fungal Stains (Calcofluor White, Methenamine Silver)
  • Blankophor and Calcofluor Bind to Chitin and Cellulose and Fluoresce in Ultraviolet Light

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• Direct Microscopy (Preferably Using Optical Brighteners) is Recommended to Diagnose Mucormycosis (Strength of Recommendation A, Quality of Evidence IIu)

Immunohistochemistry

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• Monoclonal Antibodies are Commercially Available and Immunohistochemistry May Be Utilized (Strength of Recommendation C, Quality of Evidence IIu)
  • No Commercial Assay Available

Fungal Culture

• Tissue Handling/Processing
  • Recovery of Mucorales from Tissues May Be Problematic Due to the Fragility of the Organism
    • Negative Culture Appears to Be Related to Aggressive Processing of the Specimen Before Plating
    • Grinding of Specimen Should Be Avoided
• Culture is Often Negative
  • Specimen is Preferably Incubated at 37°C
  • Mucorales Grow Well on Both Non-Selective and Fungus-Selective Media and the Growth Tends to Be Rapid (Covers the Entire Plate within a Few Days)
  • However, if Positive, it Allows for Sensitivity to Be Determined

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• Avoid Tissue Grinding Prior to Culture (Strength of Recommendation A, Quality of Evidence IIIr)
• Culture at 37°C (Strength of Recommendation A, Quality of Evidence IIIr)

Quantitative PCR

• Quantitative PCR May be Used to Identify Rhizomucor, Mucor/Rhizopus, and Lichtheimia Species

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• PCR May Be Used on Fresh Clinical Specimen (Strength of Recommendation B, Quality of Evidence IIu)
  • Fresh Material is Preferred Over Paraffin Slides
  • No Commercial Assay Available
• PCR May Be Used on Paraffin Slides (Strength of Recommendation B, Quality of Evidence IIu)
  • No Commercial Assay Available

Serum/Bronchoalveolar Lavage (BAL) Galactomannan (see Serum Galactomannan, [[Serum Galactomannan]])

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• Serum/Bronchoalveolar Lavage (BAL) Galactomannan May Be Used, But Sensitivity is an Issue (Strength of Recommendation B, Quality of Evidence III)

Serum (1–3)-β-D-Glucan (see Serum (1–3)-β-D-Glucan, [[Serum (1–3)-β-D-Glucan]])

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• Not a Reliable Diagnostic Test for Mucormycosis (Strength of Recommendation D, Quality of Evidence III)

ELISPOT

Recommendations (ESCMID/ECMM Mucormycosis Guidelines) (Clin Microbiol Infect, 2014) [MEDLINE]

• May Be Used to Monitor Treatment in Populations with Hematologic Malignancy (Strength of Recommendation C, Quality of Evidence IIu)
  • No Commercial Assay Available

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Clinical Manifestations

Central Nervous System (Isolated) Mucormycosis

• Epidemiology
  • While Central Nervous System Involvement is Usually Due to Contiguous Extension from the Paranasal Sinuses, Multiple Cases Have Been Reported with Isolated Central nervous System Mucormycosis
  • Risk Factors
    • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
    • Intravenous Drug Use/Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]])
• Physiology
  • Probably Occurs Due to Seeding from Transient Fungemia
• Diagnosis
  • Head CT (see Head Computed Tomography, [[Head Computed Tomography]]): useful for evaluation -> typically, lesions are poorly-enhancing
  • Brain MRI (see Brain Magnetic Resonance Imaging, [[Brain Magnetic Resonance Imaging]]): useful for evaluation
  • Lumbar Puncture (LP) (see Lumbar Puncture, [[Lumbar Puncture]]): cerebrospinal fluid cultures are usually negative
  • Brain/Lesion Biopsy: diagnostic
• Clinical
  • Focal Neurologic Deficits: most have basal gangliar involvement (although isolated frontal lobe involvement has been reported)
  • Lethargy

Cutaneous Mucormycosis

• Physiology: usual portal of entry is the inoculation of spores into dermis
  • Inoculation May Be Due to Trauma/Wound, Surgical Site, Injection Site, Intravenous Catheter Site, or Spider Bite
  • Immunocompromised Host: source may be a seemingly minor break in the skin
  • Immunocompetent Host: source may be major trauma or a contaminated dressing
• Clinical
  • Single Painful Indurated Area of Cellulitis: may develop into a ecthyma-like skin lesion
    • In Presence of an Open Wound, Rapid Progression of Tissue Necrosis May Occur (Due to Ischemic Infarction)
    • Dissemination and Deep Tissue Infection are Uncommon

Gastrointestinal Mucormycosis

• Epidemiology: uncommon
  • Risk Factors
    • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Glucocorticoid Use (see Corticosteroids, [[Corticosteroids]])
    • Prematurity/Malnutrition (Neonates) (see Malnutrition, [[Malnutrition]])
    • Solid Organ Transplant
• Physiology: ingestion of spores
• Diagnostic
  • Endoscopy with Biopsy of Ulcers: diagnostic
• Sites of Involvement
  • Colonic Involvement: common site of involvement
  • Gastric Involvement: common site of involvement
  • Esophageal Involvement: rare site of involvement
  • Ileal Involvement: rare site of involvement
• Clinical
  • Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
  • Acute Mesenteric Ischemia/Infarction (see Acute Mesenteric Ischemia, [[Acute Mesenteric Ischemia]])
  • Hematemesis (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
  • Necrotic Ulcers: may perforate and lead to peritonitis
• Prognosis: poor

Pulmonary Mucormycosis

• Epidemiology
  • Risk Factors
    • Deferoxamine Use (see Deferoxamine, [[Deferoxamine]])
    • Glucocorticoid Use (see Corticosteroids, [[Corticosteroids]])
    • Hematologic Malignancy
    • Prior Voriconazole Use (see Voriconazole, [[Voriconazole]])
    • Solid Organ Transplant
• Physiology
  • Usual Portal of Entry is Inhalation of Spores into the Lower Airways
• Diagnosis
  • CXR/Chest CT Patterns (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])
    • Focal Consolidation
    • Nodules/Masses
      • Halo Sign (Focal Ground-Glass Infiltrate Surrounding a Lung Nodule, Which is Characteristic of Infection with an Angioinvasive Fungus): may be observed
      • Reversed Halo Sign (Atoll Sign) (Focal Ground-Glass Infiltrate Surrounded by a Ring of Consolidation): has also been observed (in fact, mucormycosis is the most common condition to cause a reversed halo sign in an immunocompromised host)
    • Pleural Effusions
  • Sputum Gram Stain/Culture (see Sputum Culture, [[Sputum Culture]]): low sensitivity (probably around 25%)
  • Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): low sensitivity (probably around 25%)
    • Transbronchial Biopsy (TBB): organism may be demonstrated by methenamine silver stain
  • Open Lung Biopsy (see Lung Biopsy, [[Lung Biopsy]]): diagnostic
• Clinical: usually subacute or slowly progressive (but may be rapidly progressive in some cases)
  • Fever (see Fever, [[Fever]])
  • Hemoptysis (see Hemoptysis, [[Hemoptysis]]): may be massive
  • Lung Nodule/Mass (see Lung Nodule or Mass, [[Lung Nodule or Mass]]): nodules may be multiple in some cases
  • Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
    • Pleural Fluid May Appear Black in Color
  • Pneumonia (see Pneumonia, [[Pneumonia]]
    • Infiltrate May Be Wedge-Shaped or Pleural-Based
    • Infiltrate May Be Accompanied by Infarction, Necrosis, or Abscess Formation
    • May Spread Contiguously to Mediastinum or Heart
    • May Spread Hematogenously to Other Organs
• Prognosis: 87% mortality

Renal Mucormycosis

• Risk Factors
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
  • Intravenous Catheter Use
  • *Intravenous Drug Use/Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]])
• Physiology
  • Probably Occurs Due to Seeding from Transient Fungemia
• Diagnosis
  • Abdominal/Pelvic CT (see Abdominal/Pelvic Computed Tomography, [[Abdominal-Pelvic Computed Tomography]]): useful to demonstrate renal lesion(s)
  • Urine Culture (see Urine Culture, [[Urine Culture]]): usually not diagnostic
  • Percutaneous Biopsy: may be diagnostic
  • Nephrectomy (see Nephrectomy, [[Nephrectomy]]): diagnostic
• Clinical
  • Fever (see Fever, [[Fever]])
  • Flank Pain (see Flank Pain, [[Flank Pain]])

Rhino-Orbital-Cerebral Mucormycosis

• Epidemiology: most common clinical presentation
  • Most Cases Occur in Diabetic Ketoacidosis (DKA)
  • There are Rare Reports of Rhino-Orbital-Cerebral Mucormycosis Occurring in the Absence of Any Risk Factors
• Physiology
  • Usual Portal of Entry is Inhalation of Spores into the Paranasal Sinuses
  • Most Common Etiology: Rhizopus oryzae
  • Hyperglycemia (Often with with Metabolic Acidosis) is the Most Common Concomitant Risk Factor
• Diagnosis
  • Head CT (see Head Computed Tomography, [[Head Computed Tomography]]): necessary to define extent of spread
  • Brain MRI (see Brain Magnetic Resonance Imaging, [[Brain Magnetic Resonance Imaging]]): necessary to define extent of spread
• Clinical: usually acute, rapidly progressive course (although cases with indolent course have been reported)
  • Acute Rhinosinusitis (see Acute Rhinosinusitis, [[Acute Rhinosinusitis]]): nasal congestion, purulent nasal discharge, and sinus pain
    • May Spread Contiguously to Other Sinuses, Palate, Orbit, and Brain
  • Fever (see Fever, [[Fever]])
  • Headache (see Headache, [[Headache]])
  • Nasal Mucosal/Palatal Involvement
    • Nasal Ulceration
    • Black Eschar Over Nasal Mucosa or Palate Indicates Tissue Necrosis Due to Vascular Invasion
  • Overlying Skin Involvement: erythema/edema/cyanosis of facial skin overlying the affected sinus
  • Orbital Involvement: peri-orbital edema, proptosis, blindness
  • Cranial Nerve-5 Involvement: facial numbness (due to infarction of sensory branches of the 5th cranial nerve)
  • Frontal Lobe of Brain Involvement: obtundation/coma
  • Cavernous Sinus Involvement: due to spread from adjacent sphenoid sinuses
    • Cranial Nerve Palsies
    • Cavernous Sinus Thrombosis (see Cerebral Venous Thrombosis, [[Cerebral Venous Thrombosis]])
    • Carotid Artery Involvement
  • Hematogenous Spread: rare (unless hematologic malignancy with neutropenia is present)
• Poor Prognostic Factors
  • Bilateral Sinus Involvement
  • Deferoxamine Use (see Deferoxamine, [[Deferoxamine]])
  • Delay in Diagnosis
  • Leukemia
  • Presence of Hemiparesis/Hemiplegia
  • Renal Disease/Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])

Disseminated Mucormycosis

• Epidemiology: rare
  • Risk Factors
    • Burns (see Burns, [[Burns]])
    • Deferoxamine Use (see Deferoxamine, [[Deferoxamine]])
    • Severely Immunocompromised State
    • Prematurity (Neonate)
• Prognosis: mortality rate is 96%

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Treatment

Elimination of Predisposing Factors

• Crucial

Surgery

• Indications
  • Rhino-Orbital-Cerebral Mucormycosis: aggressive surgical debridement is usually necessary
  • Localized Pulmonary Disease: lobectomy may be attempted in select cases with isolated pulmonary disease
    • Hemoptysis may necessitate resection

Antifungal Treatment

General Comments

• Early Anti-Fungal Therapy Improves Mortality Rate in Mucormycosis

Liposomal Amphotericin (see Amphotericin, [[Amphotericin]]): drug of choice for initial treatment

• Initial Dose: 5 mg/kg IV qday (may go as high as 10 mg/kg qday, as required to control the infection)
• The Total Cumulative Dose of Amphotericin Has Not Been Studied in Mucormycosis

Posaconazole (Noxafil, Posanol) (see Posaconazole, [[Posaconazole]])

• Oral Posaconazole Step-Down Therapy: step-down to oral posaconazole after initial clinical response to amphotericin (which has been given for at least a period of several weeks)
  • Dose: posaconazole delayed-release tablets 300 mg PO BID x 1 day, then 300 mg PO qday thereafter
  • Posaconazole Oral Suspension Has Poor Bioavailability and Requires Fatty Food for Absorption: therefore, it is not the preferred oral formulation
• Intravenous Posaconazole Salvage Therapy: posaconazole can be used in patients with lack of response to amphotericin or poor amphotericin tolerance
  • Dose: 300 mg q12hrs IV x 1 day, then 300 mg IV qday thereafter
  • Avoid Intravenous Posaconazole Formulation with CrCl <50 mL/min: due to potential accumulation of the SBECD vehicle
• Oral Posaconazole Salvage Therapy: posaconazole delayed-release tablets may be used when intravenous posaconazole cannot be used
  • Although Oral Posaconazole Suspension Has Also Been Studied as Salvage Therapy, its Current Role is Unclear

Isavuconazole (Cresemba) (see Isavuconazole, [[Isavuconazole]])

• May Be Used as an Alternative to Posaconazole

Duration of Anti-Fungal Therapy

• Continue Antifungal therapy Until There is Resolution in Signs/Symptoms/Radiographic Findings and Until There is Resolution of the Underlying Immunosuppression
  • Anti-Fungal Therapy is Usually Continued for a Period of Months

Other

• General Comments
  • Voriconazole/Fluconazole/Flucytosine are Not Active Against the Organisms Which Cause Mucormycosis
• Deferasirox (Exjade) (see Deferasirox, [[Deferasirox]]): possible benefit has been observed in mouse studies -> currently, not recommended
• Echinocandins (Caspofungin, Micafungin)
  • Although Echinocandins Have No In Vitro Activity Against Mucormycosis, Rhizopus Oryzae Possesses the Target Enzyme for the Echinocandins
    • Based on this Observation and Studies, Echinocandins May Be Added onto Amphotericin Therapy: without further data, this cannot be recommended though
• Hyperbaric Oxygen (HBO) (see Hyperbaric Oxygen, [[Hyperbaric Oxygen]]): unclear benefit

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References

• The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts. Clin Infect Dis. 2011 May;52(9):1144-55. doi: 10.1093/cid/cir122 [MEDLINE]
• Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012 Feb;54 Suppl 1:S23-34. doi: 10.1093/cid/cir866 [MEDLINE]
• ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014 Apr;20 Suppl 3:5-26. doi: 10.1111/1469-0691.12371 [MEDLINE]
• Our 2014 approach to mucormycosis. Mycoses. 2014 Sep;57(9):519-24. doi: 10.1111/myc.12203. Epub 2014 May 15 [MEDLINE]
• Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014 Dec;44(12b):1333-49. doi: 10.1111/imj.12598 [MEDLINE]
• Isavuconazole: A New Option for the Management of Invasive Fungal Infections. Ann Pharmacother. 2015 Jul;49(7):825-42. doi: 10.1177/1060028015581679. Epub 2015 May 4 [MEDLINE]