Epidemiology
Incidence
- Incidence is Difficult to Quantify
- Decreasing Incidence of Diabetes-Related Mucormycosis Since the 1990’s
- May Be Related to the Widespread Use of Statins
- Statins Have In Vitro Inhibitory Activity Against Organisms Which Cause Mucormycosis
Environmental Risk Factors for Mucormycosis
- Combat-Associated Mucormycosis
- Cases Have Been Reported in Association with Blast Injuries in Aghanistan
- Healthcare-Associated Mucormycosis
- Cases Have Been Reported in Association with Intravenous and Other Catheters, Adhesive Tape, surgical wounds, Wooden Tongue Depressors, Adjacent Building Construction, and Hospital Linens
- Natural Disaster-Associated Mucormycosis
- Cases Have Been Reported in Association with Tornado, Tsunami, and Volcanic Eruption
Clinical Risk Factors
General Comments
- All Human Mucormycosis Infections Occur in the Presence of Some Underlying Immunocompromising Condition
Malignancy
- General Comments
- Hematologic Malignancy is a Common Risk Factor for Mucormycosis
- Voriconazole Prophylaxis Appears to Increase the Risk of Mucormycosis
- Possibly Due to Increased Selective Pressure for the Organisms Which Cause Mucormycosis
- Carcinoma
- Leukemia
- Lymphoma (see Lymphoma, [[Lymphoma]])
Organ Transplantation
- General Comments
- Transplantation is a Common Risk Factor for Mucormycosis
- Hematopoietic Stem Cell Transplant (HSCT) (Bone Marrow Transplant (see Hematopoietic Stem Cell Transplant, [[Hematopoietic Stem Cell Transplant]])
- Graft vs Host Disease Increases the Risk of Mucormycosis (see Graft vs Host Disease, [[Graft vs Host Disease]])
- Voriconazole Prophylaxis Increases the Risk of Mucormycosis (see Voriconazole, [[Voriconazole]])
- Possibly Due to Increased Selective Pressure for the Organisms Which Cause Mucormycosis
- Solid Organ Transplant
- Risk Factors for Mucormycosis in Patients with Solid Organ Transplant
Pharmacologic Immunosuppression
- Corticosteroids (see Corticosteroids, [[Corticosteroids]])
- Corticosteroids Inhibit Neutrophil and Alveolar Macrophage Function
- Cytotoxic Therapy
- Cytotoxics Inhibit Neutrophil and Alveolar Macrophage Function
Other
- Burns (see Burns, [[Burns]])
- Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
- Deferoxamine (Desferal, DFO) (Deferoxamine, [[Deferoxamine]])
- Deferoxamine-Iron Chelate Acts as Siderophore for Rhizopus: increases Rhizopus iron uptake, stimulating fungal growth and tissue invasion
- In Contrast, Deferasirox and Deferipone Do Not Act as Siderophores for Rhizopus and Do Not Increase the Risk of Mucormycosis
- Highest Risk for Deferoxamine-Related Mucormycosis is Observed in Those Who Have Received Multiple Blood Transfusions with Subsequent Deferoxamine Treatment
- Mortality rate is almost 90% in deferoxamine-associated mucormycosis cases
- Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
- Diabetes Mellitus is Probably the Most Common Risk Factor for Mucormycosis
- Risk of Mucormycosis is Especially High with Diabetic Ketoacidosis (DKA): due to impaired neutrophil function and elevated free iron present in diabetic ketoacidosis
- Free Iron Enhances the Growth of Rhizopus at Acidic (But Not Alkaline) pH
- Mucormycosis May Occur as the Initial Presentation of Diabetes Mellitus
- Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
- Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]])
- Iron Overload (see Iron Overload, [[Iron Overload]])
- Iron Overload Itself Increases the Risk of Mucormycosis
- Malnutrition (see Malnutrition, [[Malnutrition]])
- Prematurity (Neonates)
- Trauma
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
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)
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
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
- 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
- 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
- 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
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
- 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%
Treatment
Elimination of Predisposing Factors
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
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]