AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Meera Varman, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Infectious Diseases, Creighton University Medical Center
Meera Varman is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Coauthor(s):
Debra Whaley, MD, Staff Physician, Department of Pediatrics, University of Nebraska Medical Center, Creighton University Joint Pediatric Residency Program;
Mary Carmen Y Mancao, MD, Associate Professor, Department of Pediatrics, University of South Alabama College of Medicine;
Christine A Reyes, MD, Medical Director, Medical Technology School, Methodist Hospital; Consulting Staff, Department of Pathology, Methodist Hospital, Children's Hospital
Editors: Gary J Noel, MD, Department of Pediatrics, Clinical Associate Professor, Weill Medical College of Cornell University; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Mark R Schleiss, MD, American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota School of Medicine; Robert W Tolan Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Author and Editor Disclosure
Synonyms and related keywords:
mucormycosis, Mucorales infection, fungal infection, Rhizopus species infection, Rhizomucor species infection, Absidia corymbifera infection, A corymbifera infection, Apophysomyces elegans infection, A elegans infection, Cunninghamella bertholletiae infection, C bertholletiae infection, Mucor species infection, Saksenaea vasiformis infection, S vasiformis infection
Background
Mucormycosis usually refers to fungal infections in immunosuppressed hosts caused by ubiquitous molds found in organic matter and soil. Such molds belong to the order Mucorales. The infections they cause manifest in the rhinocerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and central nervous systems. Mucormycosis is often life threatening. Therefore, prompt diagnosis and institution of antifungal therapy are vital, as is appropriate management of the underlying disease process. In addition to cases involving immunosuppressed children, mucormycosis has also been observed in neonates (especially premature infants), patients with burns, and children with a history of incidental trauma.
Pathophysiology
The fungus gains entry into the body through the nasopharynx. It can be inhaled into the lungs, or it can extend to the sinuses, orbit, and brain. The occurrence of mucormycosis depends on host immunity, but the mechanisms of increased susceptibility in certain hosts remain perplexing. Regardless of the anatomic site is involved, characteristic histopathologic findings include angioinvasion with subsequent tissue infarction and necrosis leading to tissue destruction.
The fungal pathogens that cause mucormycosis belong to the class Zygomycetes and the order Mucorales. Rhizopus species are the agents most commonly isolated in mucormycosis, followed by Rhizomucor species, Absidia corymbifera, Apophysomyces elegans, Cunninghamella bertholletiae, Mucor species, and Saksenaea vasiformis.
On microscopic examination, fungi of the Mucorales order are characterized by aseptate hyphae, which vary in width up to 50 µm. These hyphae are broad and branch from the main hyphal trunk; they are often angled 90°. Identification of most of the Zygomycetes is accomplished by observing the morphology of the sporangia, such as presence or absence of the columellae and apophyses, arrangement and number of sporangiospores, and absence or presence of rhizoids.
Frequency
United States
Mucormycosis occurs mostly in immunocompromised hosts, though cases in immunocompetent patients also are reported. Underlying diseases, such as diabetes mellitus and malignancy, are risk factors. Aside from these, environmental spore exposure (from exposure to construction activity) has also led to clinical cases of mucormycosis. Other cases have been reported in patients with traumatic skin injury, eg, associated with the use of nonsterile adhesive tape or with use of tongue depressors as splints in neonates. Exposure to voriconazole, which is not active against mucormycosis, is noted to be a risk factor in patients with cancer.
Mortality/Morbidity
The overall mortality rate in adults is 50%, though survival rates higher than this were recently reported. Survival rates largely depend on early diagnosis and resolution of the patient's underlying condition.
Race
No racial predilection is reported.
Sex
No sexual predilection is reported.
Age
Most cases of mucormycosis occur in immunosuppressed adults.
In a pooled review, Kline described 41 cases of rhinocerebral mucormycosis occurring in children and adolescents aged 2 months to 18 years. About 49% of cases were found in patients with diabetes mellitus, and 15% of cases were found in those with leukemia. Four of the 41 children (10%) had no predisposing conditions.
History
Symptoms of mucormycosis vary depending on the involved anatomic site.
- The most common signs and symptoms of rhinocerebral mucormycosis are altered mental status, fever, and pain and swelling over the involved site. Most of these findings occur in patients with diabetic ketoacidosis.
- Persistence of altered mental status after metabolic abnormalities are corrected, especially in patients with diabetic ketoacidosis, should alert the physician to consider mucormycosis involving the CNS.
- Fever, dyspnea, hemoptysis, and cough are observed in patients with pulmonary mucormycosis.
- Unexplained or persistent fever in a patient who has immunosuppression and who is receiving broad-spectrum antibiotics should alert the clinician to look for possible foci of mucormycosis.
- Severe headache and abdominal pain can be manifestations of rhinocerebral and gastrointestinal mucormycosis, respectively.
- Gastrointestinal mucormycosis is mostly encountered in premature neonates and in patients with malnutrition. Severe malnutrition is an independent risk factor.
Physical
- A black eschar of the nasal mucosa or palate usually is a hallmark sign of rhinocerebral mucormycosis. It is a sign of deep infection and tissue destruction of the nasal mucosa. This finding on physical examination should prompt biopsy and empiric treatment.
- A black eschar on the skin of a patient who is immunocompromised should also prompt skin biopsy (see Image 1).
- Loss of extraocular muscular function, along with proptosis and cranial nerve dysfunction of cranial nerves V and VII, are signs of neurologic involvement in mucormycosis. Several other cranial nerves, such as cranial nerves I, III, and IV, can also be involved.
- Progressive cellulitis of skin lesions with gangrene and necrosis is another concern in cutaneous mucormycosis.
Causes
- Risk factors in adults and children include diabetes mellitus (especially with ketoacidosis), which is the underlying condition most commonly associated with mucormycosis. This probably is due to diminished function of phagocytes at low pH.
- Other individuals at risk are patients with malignancy, those with protein calorie malnutrition, those with skin breakdown due to burns, those with trauma or undergoing surgery, those with acute and chronic renal disease, and those with hematologic disease who are receiving deferoxamine.
- Patients with immunosuppression due to AIDS, organ transplantation, neutropenia, or steroid therapy are also at risk.
- Neonates, especially those born prematurely, can be at risk. Unusual incidents of neonatal mucormycosis might have occurred when patients were exposed to contaminated surfaces, such as bandages, tongue depressors used as arm splints, or cardiac-monitor leads.
- See also Frequency above.
Aspergillosis
Other Problems to be Considered
The differential diagnoses of mucormycoses are varied and depend on specific organ involvement. For rhinocerebral mucormycosis, the differential diagnoses include cavernous sinus thrombosis, bacterial orbital cellulitis, and central nervous system aspergillosis.
Lab Studies
- Premortem diagnosis of mucormycosis has recently improved, improving patients' survival.
- Once mucormycosis is suspected, obtaining tissue for culture is vital (see Histologic Findings).
- Specimens should be obtained from areas such as suggestive skin lesions, black eschars found in the nasopharynx, and nasal discharge that may appear like clotted blood. These specimens should be immediately sent to the microbiology laboratory for culturing.
- Direct microscopic findings of hyphal elements in tissue biopsy specimens are important for diagnosis.
- Isolating fungus from infected tissue is usually difficult.
- Although Rhizopus or Mucor species can be contaminants, the laboratory finding of these organisms in specimens from patients who are immunosuppressed or from patients with certain risk factors for mucormycosis should not be ignored.
Imaging Studies
- CT and MRI are valuable in delineating extent of disease for most forms of mucormycosis.
- CT scans and MRIs are also helpful in planning surgical debridement when needed.
- In rhinocerebral mucormycosis opacification of sinuses, bone destruction and osteomyelitis may be noted. In some patients, images may reveal minimal changes even when extensive tissue destruction is present.
Procedures
- Biopsy of necrotic lesions from pulmonary, rhinocerebral, and mucocutaneous sites is appropriate for obtaining specimens for microscopy and cultures.
- Sensitivity is better with tissue staining than with culturing, but collecting tissue for studies is critical for diagnosis.
- Routine stains, such as hematoxylin and eosin (H&E) stains, help in visualizing Mucor hyphae, whereas Grocott methenamine silver (GMS) stain and periodic acid-Schiff (PAS) stains help to demarcate fungal elements in tissue.
- GMS stains may not reveal chlamydospores of Mucor fungi.
- Analysis of nasal and sputum swabs is rarely helpful.
Histologic Findings
Biopsy material can be examined with potassium hydroxide (KOH), H&E, and GMS stains. Another useful stain is cresyl violet, which colors Mucor fungi walls brick red while coloring other fungi purple or blue. Fungal hyphae of Mucor species can often be differentiated from other fungi, such as Aspergillus and Fusarium species. Hyphae of Mucor species are aseptate or pauciseptate, they are broad and thick (6-25 mm wide), they have nonparallel edges, and they possess irregularly shaped fungal elements with relatively infrequent acute-angle and nonrandom branching (see Image 2). Characteristic but not pathognomonic histologic findings include angioinvasion, with the Mucor fungi invading the walls of arteries, resulting in the necrosis and thrombosis of surrounding tissue (see Image 3). Immunohistochemical methods of staining biopsy material are available in specialized laboratories. Perineuronal invasion also can occur (see Image 4).
Medical Care
A combination of a high index of suspicion with prompt diagnosis and medical and surgical care are vital in the management of mucormycosis.
Regarding medical care, underlying comorbidities such as hyperglycemia, acidosis in diabetic patients, nutritional problems, neutropenia, lymphopenia, and immunosuppression must be addressed.
The drug of choice for treating mucormycosis is amphotericin B, with a dosage of 1-1.5 mg/kg/d. Liposomal amphotericin B at dosages higher than these have also been used to treat disseminated disease. Some authors have suggested doses as high as 10-15 mg/kg.
Azoles (eg, fluconazole, itraconazole) are not helpful in the treatment of mucormycosis. Among new triazoles, posaconazole are effective against mucormycosis. It has oral formulation and undergoes liver metabolism. Studies are being conducted to evaluate combination antifungal therapies.
Surgical Care
Surgical debridement should be undertaken early in the course of the illness, especially in cases of rhinocerebral mucormycosis. Instilling amphotericin B into abscess cavities after debridement has been suggested. Repeat surgery may be necessary to effectively eliminate all necrotic tissue in patients who survive. Reconstructive surgery is inevitable for those who have disfigurement due to severe rhinocerebral mucormycosis.
Consultations
Care of a pediatric patient with mucormycosis should involve several pediatric subspecialists, depending on the patient's underlying risk factors and the extent of disease. Therefore, if the child has an underlying malignancy, the following physicians should be involved in the child's care: oncologist, infectious disease specialist, surgeon (ear, nose, and throat [ENT] specialist and neurosurgeon if the patient has rhinocerebral disease), and critical care specialists.
The drug of choice for the treatment of mucormycosis is amphotericin B.
Drug Category: Antifungal agents
High-dose liposomal amphotericin B have been used to treat disseminated disease. Azoles (eg, fluconazole, itraconazole) are not helpful in the treatment of mucormycosis.
| Drug Name | Amphotericin B (Fungizone) |
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| Description | Produced by Streptomyces nodosus. Mechanism of action is binding of sterols in fungal cytoplasmic membrane, resulting in membrane permeability that impairs survival of fungus and leading to loss of intracellular potassium. Administered IV when used to treat mucormycosis. |
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| Pediatric Dose | 1-1.5 mg/kg/d IV in 5% dextrose solution (incompatible in NaCl solutions) for 6 wk or longer |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Antineoplastic agents may enhance potential to cause renal toxicity, bronchospasm, or hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; cyclosporine increases risk of renal toxicity |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Medical personnel should closely monitor IV initial doses in infants and children; fever and chills not uncommon after first few doses; rare acute reactions include hypotension, bronchospasm, arrhythmias, and shock |
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Deterrence/Prevention
- No method to prevent mucormycosis is recognized.
- Studies in adults have demonstrated some benefit with the use of high-efficiency particulate air (HEPA) filters and different chelating agents instead of deferoxamine to decrease the risk of mucormycosis.
Complications
- In patients with rhinocerebral mucormycosis, cerebral abscess formation, cavernous sinus thrombosis, and thromboembolism internal carotid artery should be suspected as complications.
- If the disease progresses and if the underlying condition remains uncontrolled, death usually ensues.
- Close observation of patients who were treated and who survived the acute infection is important because of chronic manifestation of mucormycosis or late sequelae are possible.
Prognosis
- Early diagnosis and treatment of mucormycosis improve the patient's outcome, as evidenced by high survival rates in some adults.
- In neonates, these invasive fungal infections can rapidly fatal; the time from clinical symptoms to death is in the range of 6-42 days.
- Because the disease is rare and because therapy is not standardized, no studies aid in predicting patient outcomes.
Patient Education
Medical/Legal Pitfalls
- Failure to promptly and correctly make the diagnosis; mucormycosis can be life threatening
- Failure to promptly begin vital antifungal therapy
- Failure to address appropriate management of the underlying disease process
- Failure to closely observe patients who were treated and who survived the acute infection to look for chronic manifestation or late sequelae
Special Concerns
- Because fungi of the order Mucorales contaminate laboratory specimens, use caution when these organisms are isolated from bronchial washings, sinus samples, and sputum obtained from immunosuppressed hosts.
| Media file 1:
Black eschar on the skin of an immunocompromised patient. |
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| Media file 2:
Mucormycosis with broad, aseptate hyphae (hematoxylin and eosin, original magnification X40). |
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| Media file 3:
Angioinvasion (hematoxylin and eosin, original magnification X10). |
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| Media file 4:
Perineural invasion (hematoxylin and eosin, original magnification X20). |
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Mucormycosis excerpt Article Last Updated: Nov 9, 2006
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