Mucormycosis

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

  • 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

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]