Introduction

Mucormycosis (zygomycosis and phycomycosis) is one of the most acute, fulminant fungal infections known. Invasive fungal infections are major medical complications in immunocompromised patients (Table 1). The recent rise in the incidence of cancer and the increased use of newer medical treatment modalities, including organ transplantations, have resulted in growing numbers of highly immunosuppressed individuals. Although aspergillosis and candidiasis are among the most common invasive mycoses in such patients, there is evidence that the incidence of infectious diseases caused by Zygomycetes has risen significantly over the past decade. Species of the genera Rhizopus and Mucor are the common pathogens of this group. Other genera, including Absidia, Cunninghamella, Rhizomucor, and Apophysomyces, have also been reported to cause disease. Patients with diabetes, malignancies, neutropenia, solid organ or bone marrow transplants, or iron overload and those suffering from severe malnutrition or receiving immunosuppressive agents, deferoxamine therapy, or broad-spectrum antimicrobial drugs are at highest risk for zygomycosis. Also at risk are individuals with primary breakdown in the integrity of the cutaneous barrier due to trauma, surgical wounds, needle sticks, or burns. Less than 5% of cases involve normal adult hosts. The clinical spectrum of zygomycosis is now broader, and it can be difficult to distinguish between mucormycosis and entomophthoramycosis, both of which can manifest as disease ranging from a superficial infection to an angioinvasive infection with high mortality. Treatment of zygomycosis requires several simultaneous approaches: surgical intervention, antifungal therapy, and medical management or correction of the underlying condition that is predisposing the patient to the disease. Lipid formulations of amphotericin B are the antifungal agents of choice for treatment of

TABLE 1 Mucormycosis: Key Points

Overview

Mucormycosis is an acute and rapidly developing fungal infection caused by fungi of the class Zygomycetes and the third most common invasive fungal infection in immunocompromised patients.

The Mucorales organisms are ubiquitous thermotolerant saprophytic fungi, abundant in nature and found in bread, fruits/vegetables, soil, and manure, as well as in the mouth, nose, stool, and sputum of healthy individuals. Unlike most pathogenic fungi, these can grow anaerobically.

Pathophysiology of mucormycosis

Acquisition primarily via inhalation of spores without human-to-human transmission.

Principal site of disease: rhinocerebral, pulmonary, cutaneous, GI, disseminated, central nervous system. Opportunistic infections primarily pulmonary and rhinocerebral.

Diabetic patients appear to be more frequently colonized, and serum from diabetics with ketoacidosis fails to provide normal inhibition of fungal growth.

Other riskfactors include severe burns, hemodialysis with deferoxamine, immunosuppression, severe malnutrition, and neutropenia.

Invasion, thrombosis, and necrosis are the characteristic findings in this disease. After the fungal spores have germinated at the site of infection, the hyphal elements are very aggressive and tend to invade blood vessels, nerves, lymphatics, and tissues. The infarction leads to further tissue hypoxia and acidosis, resulting in a vicious cycle that enhances rapid growth and infection. The paucity of a granulomatous reaction is quite characteristic. The fungal hyphae sometimes have little or no inflammation around them.

Symptomatology (by location of infection)

Rhinocerebral—75% of reported cases, often in poorly controlled diabetics with DKA, neutropenic or immunosuppressed patients, or in azotemic patients. Left undiagnosed, may be rapidly fatal. Hyphae invade the paranasal sinuses and palate from the ironical cavity. From the sinuses, especially the ethmoid sinus, the infection spreads to involve the retro-orbital region or the CNS. Epistaxis, severe unilateral headache, alteration in mental status, and eye symptoms such as lacrimation, irritation, or periorbital anesthesia are common symptoms. Examination of the nose may reveal the classic black necrotic turbinates (too often mistaken for dried blood) or nasal septum perforation; however, at the early stage of infection, the nasal mucosa may appear only inflamed and friable. Facial cellulitis and palatal necrosis may be seen. The early eye findings include mild proptosis, periorbital edema, decreased visual acuity, or lid swelling. In more advanced orbital involvement, exophthalmos, complete ophthalmoplegia, conjunctival hemorrhage, blindness, fixed and dilated pupil, and corneal anesthesia may be found. These conditions result from fungal invasion of the roof of the orbit, affecting the nerves (i.e., the third, fourth, and sixth cranial nerves and the ophthalmic branch of the fifth cranial nerve), muscles, and orbital vessels, a condition also known as the "orbital apex syndrome." The infection can spread through the superior orbital fissure or the cribriform plate to involve the brain. Cavernous sinus thrombosis is a frequent complication, usually resulting from hematogenous spread from the ophthalmic veins. This spread results in additional cranial nerve involvement outside the orbital apex, specifically the trigeminal nerve ganglion and the root of the facial nerve, leading to ipsilateral paresthesia of the face or peripheral facial palsy. Internal carotid artery thrombosis, resulting from retrograde spread from the ophthalmic artery or invasion from the cavernous sinus, is another late complication, leading to cerebral infarction. The middle ear may be involved by means of the blood, CSF, or Eustachian tube. CTor MRI is useful in better defining the bone destruction and soft-tissue involvement, which may be important in guiding subsequent surgical intervention.

Pulmonary mucormycosis usually occurs in patients with hematologic malignancies or diabetes. The presentation usually is acute, and patients are often profoundly ill, with variable complaints of cough and fever. No pathognomonic clinical or radiographic findings exist. Sputum culture usually is negative.

Cutaneous mucormycosis is rare and is primarily a nosocomial infection in burn and blunt trauma victims. Local infection has resulted from using contaminated elastic bandages. The involved area is erythematous and painful, with various degrees of central necrosis that can progress to gangrenous cellulitis.

(Continued )

TABLE 1 Mucormycosis: Key Points (Continued)

GI mucormycosis is the least common form of infection. It is seen primarily in patients suffering from intrinsic abnormalities of the GI tract or severe malnutrition. The infection is thought to arise from fungi entering the body with food. Any part of the GI tract is susceptible to infection, with the stomach, terminal ileum, and colon being the most common sites. Wall invasion, ischemic infarction, and ulceration are characteristic. The diagnosis is frequently made at autopsy.

Disseminated mucormycosis is defined as an infection occurring in two or more noncontiguous organ systems. The distant sites are infected by bloodstream invasion from a local site. Although any organ can be affected, the lungs and CNS are the two common sites. The outcome of this infection is almost invariably fatal.

Isolated CNS mucormycosis results from hematogenous spread and is seen primarily in intravenous drug addicts.

Diagnosis

The diagnosis of any form of mucormycosis depends on direct and histologic examinations of scrapings and biopsies of necrotic material. In contrast to most fungi, these organisms are readily seen in H&E-stained tissue. The Gomori methenamine silver stain usually is adequate.

Swabs of discharge or abnormal tissue are not adequate and can give erroneous information. Fungal cultures are occasionally positive, but a negative culture result does not exclude the diagnosis or make it less likely.

No skin tests or serologic methods are adequate for diagnosing mucormycosis, and blood cultures are not helpful.

Treatment

Successful outcome in treating this aggressive infection relies on early diagnosis by invasive procedures, immediate correction of the underlying predisposing condition, urgent surgical debridement, and early systemic amphotericin therapy.

Endoscopic surgery has a role in early rhinocerebral cases.

Amphotericin B is the only drug with proven clinical efficacy, and a high therapeutic dosage (e.g., 1.0-1.5 mg/kg/day, if tolerated) should be achieved as soon as possible. This may be reduced to alternate-day dosing after the patient is stabilized. Typically, a cumulative dose of 2-5 g may be needed to achieve cure. Lipid-complexed amphotericin could enable continued aggressive therapy in the nephrotoxic patient.

Colony-stimulating factors may accelerate neutrophil return in neutropenic patients.

Prognosis

Mucormycosis remains a disease with guarded prognosis.

Rhinocerebral mucormycosis is the most common form of infection and is thought to have an overall mortality rate of about 50%.

Patients who develop hemiplegia or nasal deformity have higher mortality rates.

Deeper cutaneous infections of the extremities usually require amputation, and when the head or trunk is involved, the condition is commonly fatal.

The most aggressive approach we can take toward this lethal disease is rapid diagnosis and immediate institution of surgical debridement plus systemic and local chemotherapy.

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; GI, gastrointestinal; H&E, hematoxylin and eosin; MRI, magnetic resonance imaging.

zygomycosis. A novel antifungal triazole, posaconazole, has been developed and may become approved for treatment of zygomycosis. The clinical experience with adjunctive treatments such as colony-stimulating factors, interferon-g, and hyperbaric oxygen therapy is still limited.

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