Mucormycosis (Zygomycosis)

Mucormycosis (Zygomycosis)

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Mucormycosis, previously called zygomycosis, refers to several different diseases caused by infection with fungi in the order Mucorales. Rhizopus species are the most common causative organisms. In descending order, the other genera with mucormycosis-causing species include Mucor, Cunninghamella, Apophysomyces, Lichtheimia (formerly Absidia), Saksenaea, Rhizomucor, and other species. [1, 2]

Most mucormycosis infections are life-threatening, and risk factors such as diabetic ketoacidosis and neutropenia are present in most cases. Severe infection of the facial sinuses, which may extend into the brain, is the most common presentation. Pulmonary, cutaneous, and gastrointestinal (GI) infections are also recognized.

Successful mucormycosis treatment requires correction of the underlying risk factor(s), antifungal therapy (traditionally with a polyene), and aggressive surgery.

The following is a postmortem image of a patient who had diabetic ketoacidosis and left rhinocerebral mucormycosis.

See also Pediatric Mucormycosis and Rhinocerebral Mucormycosis.

Immunocompromising conditions are the main risk factor for mucormycosis. Patients with uncontrolled diabetes mellitus, especially those with ketoacidosis, are at high risk. Other high risk groups include patients with cancer, especially those who are neutropenic and receiving broad-spectrum antibiotics, and individuals receiving immunosuppressive agents, including oral or intravenous steroids and tumor necrosis factor (TNF)-alpha blockers. In addition, patients with hematologic cancer who have opportunistic herpetic infections (eg, cytomegalovirus) and graft versus host disease (GVHD) are at an increased risk.

Extreme malnutrition is also linked to mucormycosis, especially the gastrointestinal (GI) form. Iron is a growth stimulant for Mucorales, and deferoxamine acts as a siderophore that delivers iron to the fungi. Older iron chelators such as deferoxamine and all causes of iron overload are additional risk factors for mucormycosis. Trauma and the use of contaminated medical supplies over wounds are associated with cutaneous mucormycosis. In addition, patients with burns and those who use intravenous drugs are at a higher risk.

Some patients with mucormycosis have no identifiable risk factors. [3, 4]

Mucorales are ubiquitous fungi that are commonly found in soil and in decaying matter. Rhizopus can be found in moldy bread. Given the ubiquitous nature of these fungi, most humans are exposed to these organisms on a daily or weekly basis. Nonetheless, they rarely cause disease because of the low virulence of the organisms; instead, they mainly affect individuals with immunocompromising conditions. Immunocompromised hosts with poorly controlled diabetes mellitus (especially with ketoacidosis), who are receiving glucocorticosteroids, who have neutropenia in the setting of hematologic or solid malignancy, who have undergone transplantation, who have iron overload, and who have burns are at risk for disease.

The major route of infection is via inhalation of conidia; other routes include ingestion and traumatic inoculation (see the images below). Ingestion leads to GI disease and occurs primarily among malnourished patients but can also occur after ingesting nonnutritional substances (pica). Regarding cutaneous disease, nonsterile tape and contaminated wooden splints have caused wound infections. [5, 6] Such cases are associated with trauma/surgery, the presence of a preexisting wound or line, or both. In addition, mucormycosis should be considered in the differential diagnoses of a necrotic-appearing wound or one with a poor response to antibiotic treatment following natural disasters (eg, hurricanes, tsunamis, tornadoes). [7, 8, 9]

When spores are deposited in the nasal turbinates, rhinocerebral disease develops (see Rhinocerebral Mucormycosis); when spores are inhaled into the lungs, pulmonary disease develops; when ingested, GI disease ensues; and when the agents are introduced through interrupted skin, cutaneous disease develops.

Mucoraceae are molds in the environment that become hyphal forms in tissues. Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, necrosis, and thrombosis. Neutrophils are the key host defense against these fungi; thus, individuals with neutropenia or neutrophil dysfunction (eg, diabetes, steroid use) are at highest risk. [10] Few cases of mucormycosis have been reported in patients with acquired immunodeficiency syndrome (AIDS), suggesting that the host defense against this infection is not primarily mediated by cellular immunity.

Based on anatomic localization, mucormycosis can be classified as 1 of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. [11] Rhinocerebral disease is the most common form in the United States, accounting for more than half of the cases. Most cases occur among severely immunocompromised persons. Mucormycosis has been reported in immunocompetent individuals, mostly after traumatic inoculation of fungal spores, but this is rare.

Mucormycosis is extremely rare, and its incidence is difficult to calculate accurately. Further, since mucormycosis is not a reportable disease, the true incidence is unknown. An estimated 500 cases occur in the United States annually. [1]

A review of mucormycosis cases at one US cancer center found that 0.7% of patients had mucormycosis at autopsy and that 20 patients per 100,000 admissions had the disease. [12] The 1-year cumulative incidence of mucormycosis has been estimated at approximately 4 cases per 1000 stem cell transplantations and 0.6 case per 1000 solid organ transplantations, accounting for 7% and 2% of all fungal infections in these populations, respectively. [13]

The incidence of mucormycosis appears to be increasing secondary to rising numbers of immunocompromised persons. There are also increasing reports of breakthrough mucormycosis in the setting of antifungal prophylaxis or treatment (eg, voriconazole, echinocandins) that is effective against most fungi, namely Aspergillus, but not mucormycosis. With improvements in early diagnosis via modalities such as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), polymerase chain reaction (PCR), and 18s rRNA sequencing, it has been suggested that mucormycosis is the cause of more than 10% of invasive fungal infections. [14, 15]

Additionally, several cases of cutaneous mucormycosis due to the Mucormycete Apophysomyces trapezi­formis were described among wound-injured victims from a tornado. [8, 16, 17]

Descriptions of mucormycosis appear to be increasing, likely owing to rising numbers of at-risk persons. [18] Mucormycosis was found in 1% of patients with acute leukemia in an Italian multicenter review. [19]

A related disease, entomophthoramycosis, is rare in the United States but is most commonly found in Africa, Southeast Asia, Australia, and Central America. Entomophthoramycosis consists of two diseases: conidiobolomycosis (caused by Conidiobolus infection) and basidiobolomycosis (caused by Basidiobolus infection). Conidiobolomycosis presents as a painless, firm, subcutaneous mass that primarily involves the head and face, whereas basidiobolomycosis involves the trunk and/or extremities. In contrast with mucormycosis, entomophthoramycosis is associated with a lower mortality rate and usually affects immunocompetent hosts.

No clear racial or age factors that predispose people to mucormycosis exist. Reviews of cases from single institutions show an equal sex distribution, however a review of all published cases of pulmonary mucormycosis performed by Lee et al showed a male-to-female ratio of 3:1. [20]

Rhinocerebral disease causes significant morbidity in patients who survive, because treatment usually requires extensive, and often disfiguring, facial surgery.

Surviving mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy.

Mucormycosis carries a mortality rate of 50-85%. The mortality rate associated with rhinocerebral disease is 50-70%. Pulmonary and gastrointestinal (GI) diseases carry an even higher mortality rate, because these forms are typically diagnosed late in the disease course. Disseminated disease carries a mortality rate that approaches 100%. Cutaneous disease carries the lowest mortality rate (15%). The advent of novel antifungals such as isavuconazole may offer improvement in these mortality rates; however, further studies are needed.

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Philip J McDonald, MD Fellow, Division of Infectious Diseases, Department of Internal Medicine, Detroit Medical Center, Wayne State University School of Medicine

Philip J McDonald, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, Michigan Infectious Disease Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Pranatharthi Haran Chandrasekar, MBBS, MD Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Pranatharthi Haran Chandrasekar, MBBS, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, International Immunocompromised Host Society, Infectious Diseases Society of America

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Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Pranatharthi Haran Chandrasekar, MBBS, MD Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Pranatharthi Haran Chandrasekar, MBBS, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, International Immunocompromised Host Society, Infectious Diseases Society of America

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Nancy F Crum-Cianflone, MD, MPH Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego

Nancy F Crum-Cianflone, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Infectious Diseases Society of America

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Mark T Duffy, MD, PhD Consulting Staff, Division of Oculoplastic, Orbito-facial, Lacrimal and Reconstructive Surgery, Green Bay Eye Clinic, BayCare Clinic; Medical Director, Advanced Cosmetic Solutions, A BayCare Clinic

Mark T Duffy, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Ophthalmic Plastic and Reconstructive Surgery, Sigma Xi, and Society for Neuroscience

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Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

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Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

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Maria D Mileno, MD Associate Professor of Medicine, Division of Infectious Diseases, The Warren Alpert Medical School of Brown University

Maria D Mileno, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society of Travel Medicine, and Sigma Xi

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Ron W Pelton, MD, PhD Private Practice, Colorado Springs, Colorado

Ron W Pelton, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Society of Ophthalmic Plastic and Reconstructive Surgery, AO Foundation, and Colorado Medical Society

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Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology

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Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Kimberly G Yen, MD Associate Professor of Ophthalmology, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine

Kimberly G Yen, MD is a member of the following medical societies: American Academy of Ophthalmology and American Association of Pediatric Ophthalmology & Strabismus (AAPOS)

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Michael T Yen, MD Associate Professor of Ophthalmology, Division of Ophthalmic Plastic, Lacrimal, and Orbital Surgery, Cullen Eye Institute, Medical Director, BCM Ambulatory Surgery Center, Program Director, ASOPRS Fellowship, Baylor College of Medicine

Michael T Yen, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Ophthalmic Plastic and Reconstructive Surgery, and Association for Research in Vision and Ophthalmology

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