Mucormycosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis is a fatal fungal infection occuring usually in immunocompromised and diabetic patients. Impairment of host defense mechanisms leads to development of the fungus within the human body. The causative agents of mucormycosis include fungi from the phylum Zygomycota, which includes the sub-phylums Mucorales and Entomophthorales. Mucorales subphylum contains the main agents causing mucormycosis. Clark, in 1968, supported use of the term “mucormycosis” for the diseases caused by species of Mucorales, to distinguish them from “subcutaneous phycomycosis” caused by fungi belonging to Entomophthorales. Species of Mucorales are distributed worldwide. The pathogenic species of Mucorales cause an acute angioinvasive infection mainly in immunocompromised patients. Mucormycosis may involve various organ systems including brain, lungs, skin, GIT, bones, liver, spleen and can be classified based on the organ system involvement. Disseminated infection is associated with high mortality. The prognosis of mucormycosis is poor and has varied mortality rates depending on its form and severity. In the rhinocerebral form, the mortality rate is between 30% and 70%, whereas disseminated mucormycosis presents with the highest mortality rate in an otherwise healthy patient with a mortality rate of up to 100%. An established criteria exists which can help in diagnosing mucormycosis. Prompt amphotericin B therapy should be administered due to the rapid spread and mortality rate of the disease. Amphotericin B (which works by damaging the cell walls of the fungi) is usually administered for a further 4-6 weeks after initial therapy begins to ensure eradication of the infection. Posaconazole has been shown to be effective against mucormycosis. Surgical therapy can be very drastic for mucormycosis, and in some cases of rhinocerebral disease removal of infected brain tissue may be required. If we reduce the risk factors, the chance of getting the disease is decreased significantly. Posaconazole has been found to be an effective agent for secondary prevention of mucormycosis.

Mucormycosis in humans was was first reported in 1885 by a German pathologoist named Paltauf. Since its discovery, it has been known to be a lethal infection that mainly affects immune compromised and debilitated individuals. Recently, there has been an increase in its incidence across the world possibly due to increased incidence of diabetes, which is a major risk factor for development of the disease. Diagnosing mucormycosis has been a challenge since its discovery and early diagnosis is one of the keys to successful treatment. Much needs to be done regarding the early diagnosis and optimal treatment for this lethal infection. Thrombosis with eventual necrosis is the end point in mucormycosis infection. Patient history is an important part of the diagnosis and aids in ruling out other differentials

Mucormycosis may involve various organ systems including brain, lungs, skin, GIT, bones, liver, spleen and can be classified based on the organ system involvement. Disseminated infection is associated with high mortality.

Mucormycosis is a fatal fungal infection usually occurring in immunocompromisedand diabetic patients. Impairment of host defense mechanisms leads to development of the fungus within the human body. Iron is important for growth of the mucorales fungus. Thrombosis with eventual necrosis is the end point in mucormycosis infection. Glucose regulated protein 78 receptor plays a vital part in helping the organism attach to endothelial cells and for subsequent vascular invasion and dissemination. On microscopic examination the hyphae of mucorales is found to have few septations, non-pigmented and branches at right angle.

Rhizopus and mucor species are by far the most common causes of mucormycosis but there may be other fungi that lead to development of the disease.

Mucormycosis can be difficult to diagnose and a high degree of clinical suspicion is required. Mucormycosis should be differentiated from diseases like invasive aspergillosis, orbital cellulitis, extra nodal T cell lymphoma and cutaneous anthrax. Patient history is an important part of the diagnosis and aids in ruling out other differentials. Other features which help differentiate conditions with similar presentations are radiological and histopathological appearance.

Mucormycosis has limited data which outlines the epidemiology and demographics of the disease. Mucormycosis has a high case-fatality rate.

Mucormycosis is most prevalent in immunocompromised individuals (such as HIV/AIDS, the elderly and SCID) and patients in acidosis (diabetes, burns). Mucormycosis is seen particularly after barrier injury to the skin or mucus membranes, malignancies such as lymphomas and leukemias, renal failure, organ transplant, long term corticosteroid and immunosuppressive therapy, cirrhosis, burns and energy malnutrition. Almost 50-75% of patients diagnosed with mucormycosis are estimated to have underlying poorly controlled diabetes mellitus and ketoacidosis.

There are no screening recommendations for mucormycosis.

The possible complications of mucormycosis include the partial loss of neurological function, blindness and clotting of brain or lung vessels. In most cases, the prognosis of mucormycosis is poor and has varied mortality rates depending on its form and severity. In the rhinocerebral form, the mortality rate is between 30% and 70%, whereas disseminated mucormycosis presents with the highest mortality rate in an otherwise healthy patient with a mortality rate of up to 100%. Patients with AIDS have a mortality rate of almost 100%.

An established criteria exists which can help in diagnosing mucormycosis. The criteria is provided by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. The criteria for diagnosis is based on microscopic findings, clinical features and the characteristics of the fungus.

Signs and symptoms of mucormycosis differ according to the organ system involved. Severe infection of the facial sinuses, which may extend into the brain, is the most common presentation leading to proptosis, redness of skin above sinuses, mental status changes, dark scabbing in nasal cavities, fever and headache. Pulmonary mucormycosis may lead to development of cough, hemoptysis with or without chest pain and fever. Gastrointestinal mucormycosis can present as abdominal pain, hematemesis, diarrhea or constipation.

Patients with mucormycosis usually appear lethargic, weak and debilitated owing to its development in immune compromised patients. Physical examination of patients with mucormycosis is usually remarkable for skin necrosis with a black eschar, fever, chills, myalgias, sore throat, non-productive cough and abdominal pain.

Biopsy with H&E staining of the specimen and PCR may confirm the diagnosis in suspected cases. Laboratory findings are taken into account in the presence of clinical suspicion of An early diagnostic procedure performed within 16 days from the onset of symptom and early initiation of antifungal therapy will lead to successful management of this highly fatal disease.

Chest xray in pulmonary mucormycosis may show cavitation, hilar adenopathy, pleural effusion, lobar or multi-nodular consolidation and nodules.

CT scan should be done immediately if mucormycosis is suspected because it can help in delineating the extent of the disease. In rhinocerebral disease, the lesions are isodense to muscle and bone with a rim of soft tissue thickness around the paranasal sinuses if there is sinus involvement. There may be air fluid levels or complete sinus opacification. The reverse halo sign is an important radiographic finding on CT scan which indicates vascular invasion.

MRI in mucormycosis tends to show isotense or hypointense in all sequences. The black turbinate sign is an important finding in rhinocerebral involvement.

There are no other specific imaging findings for mucormycosis.

There are no additional diagnostic findings for mucormycosis.

If mucormycosis is suspected, prompt amphotericin B therapy should be administered due to the rapid spread and mortality rate of the disease. Amphotericin B (which works by damaging the cell walls of the fungi) is usually administered for a further 4-6 weeks after initial therapy begins to ensure eradication of the infection. Posaconazole has been shown to be effective against mucormycosis, perhaps more so than amphotericin B, but has not yet replaced it as the standard of care. After administration the patient must then be admitted for surgery for removal of the “fungus ball“.

Surgical therapy can be very extensive for mucormycosis, and in some cases of rhinocerebral disease removal of infected brain tissue may be required. In some cases surgery may be disfiguring because it may involve removal of the palate, nasal cavity, or eye structures. Surgery may be extended to more than one operation. It has been hypothesized that hyperbaric oxygen may be beneficial as an adjunctive therapy because higher oxygen pressure increases the ability of neutrophils to kill the organism.

Mucormycosis may be prevented by avoiding the conditions leading to its development. If we reduce the risk factors, the chance of getting the disease is decreased significantly.

Posaconazole has been found to be an effective agent for secondary prevention of mucormycosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis in humans was was first reported in 1885 by a German pathologoist named Paltauf. The disease named “mucormycosis” was subsequently used by an American pathologist R. D. Baker to denote a mycosis caused by some members of Mucorales.

• In 1885, German pathologist Paltauf, reported the first case of mucormycosis in humans and later published a case of upper airway mucormycosis, entitled: “mucormycosis mucorina” in the Virchows archives of pathology and anatomy.^[1]
• In 1943, Gregory et al described the first case of of rhino-orbital cerebral mucormycosis associated with diabetes. Harris in 1955 reported the first known survivor.
• The term “mucormycosis” was coined by an American pathologist R. D. Baker.^[2][3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis can be classified according to the organ system involved including brain, lungs, skin, GIT, bones, liver, spleen. Disseminated infection affects multiple organ systems.

Mucormycosis may be classified based on the organ system involvement as follows:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis is a fatal fungal infection occuring most commonly in immunocompromised and diabetic patients. Impairment of host defense mechanisms leads to development of the fungus within the human body. Iron is important for growth of the mucorales fungus. Thrombosis with eventual necrosis is the end point in mucormycosis infection. Glucose regulated protein 78 receptor plays a vital part in helping the organism attach to endothelial cells and for subsequent vascular invasion and dissemination. On microscopic examination, the hyphae of mucorales are found to have few septations, are non-pigmented and branch at right angle.

• Fungi of the order Mucorales (class Zygomycetes) are causes of mucormycosis, a life-threatening fungal infection affecting immunocompromised hosts (transplant recepients, diabetics, leukopenic, acidotic patients and patients on dialysis who receive deferoxamine– an iron chelator) in either developing or industrialized countries. ^{[1] [2] [3] [4] [5]}
• Species belonging to the family Mucoraceae are isolated more frequently from patients with mucormycosis.
• Among the Mucoraceae, Rhizopus oryzae (Rhizopus arrhizus) is by far the most common cause of infection. Increasing cases of mucormycosis have been also reported due to infection with Cunninghamella spp.

• The skin represents a major barrier to fungi causing mucormycosis. The agents of mucormycosis are typically incapable of penetrating intact skin.
• However, burns, traumatic disruption of the skin or implantation of contaminated soil or water, and persistent maceration of skin enables the organism to penetrate into deeper tissues and cause infection.
• In addition, contaminated surgical dressings and nonsterile adhesive tape have been shown to be the source of primary cutaneous mucormycosis.
• Ingestion is the mechanism of transmission for gastrointestinal mucormycosis.
• Inhalation of Mucorales sporangiospores by immunocompromised patients leads to development of pulmonary mucormycosis and eventual hematogenous dissemination.

• Neutrophils play a major part in destroying fungal hyphae, once spores germinate.
• Macrophages and monocytes also play part in host defense mechanisms against fungi causing mucormycosis (specifically alveolar macrophages prevent germination of spores).^[6]
• Consequently, mucormycosis develops exclusively in immunocompromised patients who lack these defense mechanisms.
• Hyperglycemia, acidosis and corticosteroid treatment have also been known to hinder immunity (specifically the actions of phagocytic cells), which also puts patients with diabetes and DKA at an increased risk of acquiring mucormycosis.^[4]
• In order to cause disease, the agents of mucormycosis must acquire from the host sufficient iron for growth, must evade host phagocytic defense mechanisms, and must access vasculature to disseminate.
• In immunocompromised hosts (including diabetics), iron is released from sequestering proteins making it available to fungi for growth within the body.^[7]
• Acidotic conditions decrease the iron-binding capacity, suggesting that acidosis per se disrupts the capacity of transferrin to bind iron, probably by proton-mediated displacement of ferric iron from transferrin.^[8]
• Fungi can obtain iron from the host by using high-affinity iron permeases or low-molecular-weight iron chelators (siderophores). ^[9]
• This process along with a reduced number of neutrophils and phagocytes leads to fungal proliferation.^[10]
• Damage to the endothelial cells by fungi causing mucormycosis leads to vascular invasion, subsequent dissemination and tissue necrosis.
• R. oryzae spores but not germlings (i.e., pregerminated spores) have the ability to attach themselves to subendothelial matrix proteins including laminin and type IV collagen.^{[11] [12]}
• Glucose regulated protein 78 (GRP78) serves as a receptor that promotes the ability of Mucorales to penetrate endothelial cells.
• Increased concentrations of glucose and iron, consistent with those seen during diabetic ketoacidosis, increase GRP78 expression and resulting invasion and damage of endothelial cells in a receptor-mediated manner.^[13] These findings likely explain the unique susceptibility of diabetic ketoacidosis to mucormycosis.

• The lesions in cutaneous or rhinocerebral mucormycosis appear varied in size, and ranging from raised red nodules or plaques, which sometimes produce purulent material, to ulcerated lesions with central cavitation, red exuding centres and raised epidermal margins.
• Older lesions may be covered either partly or fully by thickened and irregular epidermis. There may be a black eschar indicating necrosis and ischemia.^[14]

• Histological examination of skin biopsies reveal discrete, poorly encapsulated granulomas, or more commonly a diffuse granulomatous or pyogranulomatous inflammationInflammatory infiltrate consists of neutrophils or eosinophils, few plasma cells and lymphocytes, numerous macrophages and occasional multinucleated giant cells. Fibrovascular tissue is diffusely and irregularly scattered in the granulomatous areas.^[14]
• Nonpigmented, wide (5- to 20-μm), thin-walled, ribbon-like hyphae with few septations (pauciseptate) and right-angle branching^[15]
• In lesions exposed to air, thick-walled spherical structures can form at the ends of the hyphae.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Rhizopus and mucor species are by far the most common causes of mucormycosis but there may be other fungi that lead to development of the disease.

The different types of fungi causing mucormycosis include :^[1][2][3]

• Rhizopus species
• Mucor species
• Lichtheimia (formerly Absidia)
• Rhizomucor

• Cunninghamella bertholletiae
• Apophysomyces
• Saksenaea
• Rhizopodiformis
• Absidia corymbifera
• Rhizomucor pusillus
• Syncephalastrum
• Cokeromyces
• Mortierella

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis can be difficult to diagnose and a high degree of clinical suspicion is required. Mucormycosis should be differentiated from diseases like invasive aspergillosis, orbital cellulitis, extra nodal T cell lymphoma and cutaneous anthrax. Patient history is an important part of the diagnosis and aids in ruling out other differentials. Other features which help differentiate conditions with similar presentations are radiological and histopathological appearance.

Mucormycosis must be differentiated from other conditions with similar presentation. Invasive fungal disease should be considered in any immunocompromised patient presenting with a new cranial neuropathy or ocular motility abnormality^[1] for example, invasive aspergillosis. Other differential diagnoses which may involve progressive facial swelling, ulceration and destruction and resemble mucormycosis include orbital cellulitis, extra nodal T cell lymphoma and cutaneous anthrax. Histopathologically mucormycosis may resemble pancreatic and gouty panniculitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Mucormycosis has limited data which outlines the epidemiology and demographics of the disease. It is known to have a high case fatality rate.

• Mucormycosis has limited national data available in the United States .^[2]
• The data available is population-based, varies according to the geographic region and is reported over a time period.
• The prevalence is 36000 per 100,000 patients for diabetics.
• The prevalence of mucormycosis for individuals for no underlying condition is 19000 per 100,000 individuals.
• The prevalence of mucormycosis for patients with malignancy is 17000 per 100,000 patients.
• The prevalence rate of mucormycosis infection was generally 4200 per 100,000 patients of hematologic malignancies in a study conducted in Iran.^[3]

• A population-based surveillance study in San Francisco, California, from 1992 to 1993 revealed that the annual incidence of mucormycosis was 1.7 cases per 100,000 individuals (roughly 500 cases per year).^[4]
• A more recent study in a more general population in Spain found a lower incidence 0.43 cases per 100,000 individuals.^[5]

• Extremes of age predispose an individual to mucormycosis infection.

• There is no racial predilection for mucormycosis.

• There is no gender predilection for mucormycosis.

• Mucormycosis is frequently a life-threatening infection. A review of published mucormycosis cases found an overall all-cause mortality rate of 54000 per 100,000 indiviudals.

• The overall case fatality rate for patients with diabetes is 44000 100,000 patients.
• The overall case fatality rate for individuals with no underlying condition is 35000 per 100,000 individuals.
• The overall case fatality rate for patients with malignancy like acute myeloid leukemia and myelodysplastic syndrome is 66000 per 100,000 patients.

• Data suggests that there is a seasonal variation among patients acquiring mucormycosis infection with a peak during the Autumn season.^[6][7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

While most individuals are exposed to the fungi on a regular basis, those with immune disorders are more prone to an infection. In humans mucormycosis is most prevalent in immunocompromised patients (HIV/AIDS, the elderly, SCID, etc) and patients in acidosis (diabetes, burns), particularly after barrier injury to the skin or mucus membranes, malignancies such as lymphomas and leukemias, renal failure, organ transplant, long term corticosteroid and immunosuppressive therapy, cirrhosis, burns and energy malnutrition. Some 50-75% of patients diagnosed with mucormycosis are estimated to have underlying poorly controlled diabetes mellitus and ketoacidosis.

The following conditions predispose patients to mucormycosis:

• Immunodeficient states:
  • Transplant recepients
  • Diabetes (including diabetic ketoacidosis)
  • AIDS
  • Severe lymphocytopenia
  • Malignancy

• Dialysis patients on Iron chelation therapy (deferoxamine).
• Conatct with contaminated surgical instruments.
• Major trauma ^[1]
• Iron overload
• Aluminium overload

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

In most cases, the prognosis of mucormycosis is poor and has varied mortality rates depending on its form and severity. In the rhinocerebral form, the mortality rate is between 30% and 70%, whereas disseminated mucormycosis presents with the highest mortality rate in an otherwise healthy patient, with a mortality rate of up to 100%. Patients with AIDS have a mortality rate of almost 100%. Possible complications of mucormycosis include the partial loss of neurological function, blindness and clotting of brain or lung vessels.

If left untreated, mucormycosis can be fatal. The survival rate of immunosuppressed patients with rhino sinusal mucormycosis without cerebral involvement is between 50-80%, and only 10% if the infection spreads into the brain. In uncontrolled diabetes mellitus patients with ketoacidosis, who are diagnosed with rhino-orbital mucormycosis, cerebral spread of infection should be suspected, if there is no improvement after 24 hours since the beginning of treatment. In 70% of cases mucormycosis occurs in diabetics, and the percentage increases if there is concomitant immunosupression and comorbities.

• Patients with mucormycosis may develop the following complications:
  • Extensive necrosis
  • Fungemia leading to septic shock
  • Stroke
  • Paralysis
  • Ophthalmoplegia
  • Intracranial hemorrhage
  • Mediastinitis
  • Bronchial perforation
  • Pulmonary gangrene
  • Renal mucormycosis

• The overall survival rate of patients with mucormycosis is approximately 50%, although survival rates approaching up to 85% have been reported.
• Differences in prognosis are due to the various forms of the disease.
• Rhinocerebral mucormycosis has a higher survival rate than does pulmonary or disseminated mucormycosis because the rhinocerebral disease can frequently be diagnosed earlier and the most common underlying cause, diabetic ketoacidosis, can be treated readily.
• Pulmonary mucormycosis has a high mortality (around 65 percent at 1 year)^[4]
• Mortality in patients with disseminated disease approaches 100%, majorly due to surgical removal of infected tissues is not feasible and in part because these patients are usually most highly immunocompromised.^[5]

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